AU678202B2

AU678202B2 - Acyloxyhexanoic acid derivatives

Info

Publication number: AU678202B2
Application number: AU57588/94A
Authority: AU
Inventors: Shripad Dr. Bhagwat; Guido Dr. Bold; Hans-Georg Dr. Capraro; Alexander Dr. Fassler; Marc Dr. Lang
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1993-03-11
Filing date: 1994-03-04
Publication date: 1997-05-22
Anticipated expiration: 2014-03-04
Also published as: EP0618222A3; IL108920A0; KR940021577A; CZ54194A3; HU9400720D0; ZA941668B; FI941064A0; AU5758894A; NO940853D0; MA23133A1; FI941064A7; NZ260056A; EP0618222A2; CA2118661A1; HUT67089A; MXPA94001822A; NO940853L; JPH07316191A; CN1112125A

Description

Our Ref: 499420 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Address for Service: Invention Title: Ciba-Geigy AG Klybeckstrasse 141 CH-4002 BASLE

SWITZERLAND

DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Acyloxyhexanoic acid derivatives The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 1- 11. I A 4-19482/A Acygoyhexanoic Acid Derivatives The invention relates to novel chemical compounds that are derivatives of nonhydrolysable analogues of peptides that are cleavable by aspartate proteases, that is to say acylated 5-amino-4-hydroxy-hexanoic e.pd derivatives and novel precursors thereof, to processes for the preparation of those compounds, to pharmaceutical compositions comprising those peptide analogues, and to the use thereof as medicaments or in the preparation of pharmaceutical compositions for combating diseases caused by retroviruses.

Since the disease first appeared at the beginning of the 1980s, AIDS (Acquired Immunodeficiency Disease Syndrome) and its devastating consequences have been the subject of numerous publications of a scientific or other nature. With the exception of minor opinions to the contrary, the disease is thought to be caused by the HIV virus (Human Immunodeficiency Virus) of which two forms (HIV-1 and HIV-2) have been described in detail hitherto. At present, the treatment of the disease involves principally the use of inhibitors of reverse transcriptase (a virus-specific enzyme), for example 3'-azidothymidine (AZT), although they have severe toxic side-effects. However, attempts have also been made to introduce into the body, for example in the form of a recombinant molecule or molecule fragment, the T4-cell receptor which is present in certain cells of the defence system of the human body and which is responsible for the anchoring and introduction of infectious virus particles into those cells and thus for their infection. The desired result is that binding sites on the virus particles would be titrated out and the virions would therefore no longer be able to bind to the cells. Although treatment with CD4 and derivatives appears to have the advantage of low toxicity, there is as yet no data relating to its therapeutic effectiveness.

HIV has a genome organisation comparable to that of other retroviruses: the genome is organised into the regions gag/pol/env. It has been shown that in HIV and other retroviruses the proteolytic maturation of the gag and gag/pol-fusion proteins is brought about by a protease, HIV-protease, which is itself encoded by the pol-region of the viral genome. Without that proteolytic cleavage, it is not possible for infectious virus particles -2to be formed, because, for example, the so-called "core proteins", that is to say structural proteins of the virus core, cannot be freed from their precursors.

According to WHO estimates, about ten million people are infected by HIV at present.

The disease; is fatal in virtually all cases.

HIV- 1 and HIV-2 have in their genom e regions that code for the HIV-protease which is formed from a precursor protein that is thought to be cleaved autoproteolytically.

The protease has an aspartate residue in its catalytic centre and is homologous with other aspartate proteases. In the case of HIV it consists of 99 amino acids. The HIV-protease, which has since been obtained also as a recombinant and as a chemically synthesised molecule, has been treated with various inhibitors, it having been shown that it too functions as an aspartate protease. X-ray structural analysis of the HIV-protease and a Srelated enzyme from Rous' sarcoma virus supports the view that the enzyme, which is in the form of a dimer in the active form, acts as an aspartate protease.

0* Owing to the central role of the HIV-protease in the processing of the said core proteins, it is assumed that effective inhibition of that enzyme in vivo will suppress the assembly of mature virions, so that corresponding inhibitors can be used therapeutically.

Prerequisites of therapeutic activity in vivo are the achievement of good inhibition of virus replication in cell experiments and good bioavailability, for example a high level in the S blood that is sufficient to achieve adequately high concentrations in infected cells in the body.

The aim of the present invention is to provide novel compounds that exhibit advantageous pharmacological properties.

Surprisingly it has now been found that the compounds according to the invention are capable of achieving that aim.

The compounds according to the invention are especially compounds of formula I' -3-

T

S

R

3 H R4 R N

R

A

"AyN (r)

B

1 R5 0 R2 wherein T is an acyl radical of formula Z Rz 0 C

(Z)

OC

wherein

R

z is unsubstituted or substituted hydrocarbyl wherein at least one carbon atom has been replaced by a hetero atom with the proviso that a hetero atom is not bonded directly to the carbonyl to which the radical Rz is bonded, alkyl having two or more carbon atoms, lower alkenyl, lower alkynyl, aryl or unsubstituted or substituted amino, and wherein

R

1 is hydrogen, lower alkoxycarbonyl, heterocyclylcarbonyl, benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals selected independently of one another from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, heterocyclyloxycarbonyl wherein heterocyclyl is bonded via a carbon atom, one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group, heterocyclylsulfonyl, lower alkylsulfonyl or N-(heterocyclyl-lower alkyl)-N-lower alkyl-aminocarbonyl,

B

1 is a bond or a bivalent residue of an a-amino acid bonded N-terminally to R 1 and Cterminally to the amino group at the carbon atom carrying R 2

-CH

2

R

2 and R 3 are each independently of the other phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals selected independently of one another from hydroxy, lower alkoxy, halogen, halo-lower alkyl, sulfo, lower alkylsulfonyl, cyano and nitro,

A

1 is a bond between -C=0 and A 2 or is a bivalent residue of an a-amino acid honded N-terminally to the group -C=O and C-terminally to A 2

A

2 is a bivalent residue of an a-amino acid bonded N-terminally to A 1 and C-terminally -4to the group NR 4

R

5 or

A

1 and A 2 together form a bivalent residue of a dipeptide the central amide bond of which has been reduced and which is bonded N-terminally to the group -C=O and Cterminally to the group NR 4

R

5 and

R

4 and R 5 together withthe bonding nitrogen atom form unsubstituted or substituted thiomorpholino or morpholino, or salts of those compounds where salt-forming groups are present.

In the description of the present invention, unless expressly defined to the contrary, the term "lower" used in the defin;tion of groups or radicals, for example lower alkyl, lower alkoxycarbonyl etc., means that the groups or radicals so defined contain up to and including 7 and preferably up to and including 4 carbon atoms.

Asymmetric carbon atoms which may be present in the substituents T, R 1 B R2, R3, A 1 and/or A 2 and also in substituted thiomorpholino or morpholino formed by R 4 and R together with the bonding nitrogen atom, can be in the or (R,S)-configuration, preferably in the or (S)-configuration. Accordingly the present compounds can be in the form of mixtures of isomers or in the form of pure isomers, especially in the form of diastereoisomeric mixtures, pairs of enantiomers or, preferably, pure enantiomers.

The general terms and names used in the description of this invention preferably have the following definitions; in the various categories of definition it is possible to use instead of the general definitions any combinations of or individual radicals from the radicals mentioned hereinabove and hereinbelow: Jnsubstituted or substituted hydrocarbyl Rz wherein at least one carbon atom has been replaced by a hetero atom with the proviso that a hetero atom is not bonded directly to the carbonyl to which the radical Rz is bonded, is a saturated, partially saturated or unsaturated hydrocarbon radical having a maximum of 30 carbon atoms, preferably having up to 22 carbon atoms, and contains in place of at least one carbon atom, preferably in place of each of from one to four carbon atoms, a hetero atom selected from nitrogen, oxygen and sulfur and is unsubstituted or substituted by one or more radicals, preferably by up to threl, substituents, especially by hydroxy, by lower alkoxy, such as methoxy, by lower alkoxylower alkoxy, such as 2-methoxyethoxy, by lower alkoxy-lower alkoxy-lower alkoxy, such as 2-(2-methoxyethoxy)ethoxy, by phenyl- or naphthy!-lower alkoxy-lower alkoxy (wherein phenyl or naphthyl is unsubstituted or substituted by one or more, preferably one, of the radicals halogen, such as fluorine, chlorine or bromine, lower alkyl, such as methyl, halo-lower alkyl, such as trifluoromethyl, hydroxy, lower alkoxy, such as methoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, cyano, carbamoyl, mono- or di-lower alkylcarbamoyl, mono- or di-hydroxy-lower alkyl-carbamoyl, heterocyclyl-lower alkyl wherein heterocyclyl is a saturated, partially saturated or unsaturated single ring containing from 3 to 7, preferably from 5 to 7, ring atoms and up to two hetero atoms selected from nitrogen, sulfur, oxygen and lower alkyl-, benzyl-, diphenylmethyl-, triphenylmethyl- or lower alkanoyl-substituted nitrogen, for example piperidinomethyl, piperazin-1-ylmethyl, 4-lower alkyl-piperazin-1-ylmethyl, such as 4-methyl- or 4-ethyl-piperazin-l-ylmethyl, morpholinomethyl or thiomorpholinomethyl, and nitro, which may be present independently of one another), by phenyl-lower alkanoyloxy, such as benzyloxy, by halogen, such as fluorine, chlorine or bromine, by halo-lower alkyl, such as trifluoromethyl or chloromethyl, by carboxy, by lower alkoxycarbonyl, by phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, by carbamoyl, by lower alkylcarbamoyl, by hydroxy-lower alkylcarbamoyl, by di-lower alkylcarbamoyl, by bis- (hydroxy-lower alkyl)carbamoyl, by cyano, by oxo, by C 3

-C

8 cycloalkyl, such as cyclobutyl, cyclopentyl or cyclohexyl, or by aryl, preferably C 6

-C

14 aryl, such as phenyl, naphthyl, such as 1- or 2-naphthyl, or fluorenyl, such as fluoren-9-yl, those substituents being independent of one another when several are present; a hetero atom preferably being directly adjacent to the carbon atom in the radical hydrocarbyl Rz that is bonded to the carbonyl group that bonds Rz in formula I' (that is to say being in the 3-position starting from the Rz-bonding carbonyl group included in the count); and is especially heterocyclyl, bonded via a ring carbon atom, which is preferably a saturated, partially saturated or unsaturated ring containing from 3 to 7, especially from 5 to 7, ring atoms and containing one or more, especially up to a maximum of four, more especially up to two, hetero atoms selected independently of one another from nitrogen, sulfur and oxygen; the ring being present either as such or being once or twice, especially once, benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused; the ring system being substituted by up to three radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, such as triphenylmethyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, such as benzyloxy, diphenylmethoxy or triphenylmethoxy, hydroxy-lower alkyl, such as hydroxymethyl, halogen, such as fluorine, chlorine or bromine, cyano, lower alkoxycarbonyl, such as methoxy- or tert-butoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, and halo-lower alkyl, such as chloromethyl or trifluoromethyl, or preferably being unsubstituted; selected espe- -6cially from pyrrolyl, 2,5-dihydropyrrolyl, indolyl, indolizinyl, isoindolyl, pyrrolidinyl, such as pyrrolidin-3-yl or especially pyrrolidin-2-yl (in the or preferably the or (S)-configuration), hydroxypyrrolidinyl, such as 3- or especially 4-hydroxypyrrolidinyl, furyl, such as furan-3-yl or especially furan-2-yl, tetrahydrofuryl, thienyl, cyclohepta[b]pyrrolyl, imidazolyl, such as imidazol-2-yl, imidazol-3-yl or especially N-triphenyl-lower alkyl-imidazolyl, such as N-triphenylmethyl-imidazolyl, pyrazolyl, especially pyrazol-3-yl, oxazolyl, isoxazoyl, such as isoxazol-3-yl or -5-yl, thiazolyl, isothiazolyl, such as isothiazol-3-yl or -5-yl, triazolyl, such as 1,2,3-triazol-4- or -5-yl or 1,2,4-triazol-5-yl, tetrazolyl, pyridyl, such as pyridin-4-yl or -3-yl or especially pyridin- 2-yl, quinolyl, such as quinolin-2-yl, isoquinolyl, especially isoquinolin-1-yl or -3-yl, piperidyl, especially piperidin-2-yl, y-pyranyl, 4,5-dihydropyranyl, 4H-chromenyl, chromanyl, y-tlhiopyranyl, pyridazinyl, cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, pyrimidinyl, pyrazinyl, phenazinyl, phenoxazinyl, phenothiazinyl, morpholinyl and thiazinyl, each of which is bonded via a ring carbon atom; very special preference is given to those of the mentioned radicals which contain a ring hetero atom directly adjacent to the bonding ring carbon atom. Strong preference is given to the radicals furan-2-yl, or (R)-pyrrolidin-2-yl and imidazol-4-yl, pyridin-2-yl, -3-yl or -4-yl, or isoquinolin-3-yl; and also tetrahydropyranyl, such as 4-tetrahydropyranyl; lower alkyl (especially methyl, ethyl, n-propyl or n-butyl) which is substituted by at least one radical selected from etherified or esterified hydroxy or (unoxidised or oxidised by 1 or 2 oxo groups) mercapto, unsubstituted or substituted amino and heterocyclyl, especially by one of the mentioned radicals, and which may carry as a further substituent aryl, which is as defined below at the end of this section, wherein S etherified hydroxy is especially lower alkoxy, such as methoxy, ethoxy or n-butoxy, or lower alkoxy, such as methoxy, ethoxy or n-butoxy, substituted by one or two substituents, especially by aryl, more especially phenyl or naphthyl, by lower alkoxy, such as ethoxy or methoxy, by lower alkylthio, such as methylthio or ethylthio, by lower alkoxy-lower alkoxy, such as 2-methoxyethoxy, by lower alkylthio-lower alkoxy, such as 2-methylthioethoxy, by aryloxy or arylthio wherein aryl is as defined below, especially phenyl or m- or p-chlorophenyl, for example p-chlorophenyloxy, by amino, N-lower alkylamino or N,N-di-lower alkylamino, such as 2-amino, 2-(N-lower alcyl)amino or 2-(N,N-di-lower alkyl)amino, for example 2-dimethylamino, by heterocyclyl as defined above for heterocyclyl RZ bonded via a ring carbon atom, especially 3- or 4pyridyl, or (additionally or preferably) by lower alkoxycarbonyl, such as methoxy- -7carbonyl, by lower alkanoyloxy-lower alkoxycarbonyl, such as pivaloyloxymethoxycarbonyl or acetyloxymethoxycarbonyl, by carboxy, by phenyl-lower alkoxycarbonylamino-lower alkoxy, such as 2-(benzyloxycarbonylamino)-ethoxy, by aminolower alkoxy, such as 2-aminoethoxy, by di-lower alkylamino-lower alkoxy, such as 2-(dimethylamino)-ethoxy, or by N,N-di-lower alkylamino-lower alkoxy, such as 2-(dimethylamino)-ethoxy, or is aryloxy, especially phenyloxy, or (additionally or especially) tetrahydropyranyloxy, such as 4-tetrahydropyranyloxy; esterified hydroxy is especially lower alkanoyloxy, such as acetyloxy, benzoyloxy or phenyl-lower alkanoyloxy, such as phenylacetyloxy; etherified mercapto is especially lower alkylthio, such as methylthio, ethylthio or n-butylthio, or lower alkylthio, such as methylthio, ethylthio or n-butylthio, substituted by one or two substituents, especially by aryl, more especially phenyl or naphthyl, by lower alkoxy, such as ethoxy or methoxy, by lower alkylthio, such as methylthio or ethylthio, by lower alkoxy-lower alkoxy, such as 2-methoxyethoxy, by lower alkylthiolower alkoxy, such as 2-methylthioethoxy, by aryloxy or arylthio wherein aryl is as defined below, especially phenyl or m- or p-chlorophenyl, for example p-chlorophenyloxy, by amino, N-lower alkylamino or N,N-di-lower alkylamino, such as 2-amino, 2-(N-lower alkyl)amino or 2-(N,N-di-lower alkyl)amino, for example 2-dimethylamino, by heterocyclyl as defined above for heterocyclyl RZ bonded via a ring carbon atom, especially 3- or 4-pyridyl, or (additionally or especially) by lower alkoxycarbonyl, such as methoxycarbonyl, or is arylthio, such as phenylthio; it being possible for the mercapto sulfur atom additionally or especially to be oxidised by one or preferably two oxo groups, especially in lower alkoxycarbonyl-lower alkylsulfo, such as methoxycarbonyl-methylsulfo; esterified mercapto is especially lower alkanoylthio, benzoylthio or phenyl-lower alkanoylthio, such as phenacetylthio; 'unsubstituted or substituted amino is especially amino or amino substituted by one or two radicals selected from lower alkyl, such as methyl, heterocyclyl-lower alkyl wherein heterocyclyl is as defined for heterocyclyl RZ bonded via a ring carbon atom, especially heterocyclylmethyl, such as imidazolylmethyl, for example 4-imidazolylmethyl, or pyridylmethyl, for example 3- or 4-pyridylmethyl, each bonded via a ring carbon atom, aryl-lower alkyl, such as phenyl- or naphthyl-lower alkyl, for example phenyl- or naphthyl-methyl, lower alkanoyl, such as acetyl, lower alkoxycarbonyl, such as tertbutoxycarbonyl, and aryl-lower alkoxycarbonyl, such as phenyl-lower alkoxycarbonyl, for example benzyloxycarbonyl; very especially one of the substituents of amino is lower alkyl, especially methyl, and the other is hydrogen or one of the radicals mentioned above as substituents of amino; and heterocyclyl is especially as defined above for heterocyclyl Rz bonded via a ring carbon atom and is preferably a saturated, partially saturated or unsaturated ring and may also be fused or substituted as above, especially as pyridin-2-yl, -3-yl or -4-yl; or heterocyclyl-lower alkyl wherein lower alkyl is preferably methyl, 1- or 2-ethyl or 3-propyl and wherein heterocyclyl is as defined above for heterocyclyl Rz bonded via a ring carbon atom, which is preferably a saturated, partially saturated or unsaturated ring and may also be fused or substituted as above but may also be bonded via a ring nitrogen atom, especially imidazol-1-yl, imidazol-2-yl, imidazol-5-yl or more especially imidazol- 4-yl, N-triphenyl-lower alkylimidazolyl, such as N-triphenylmethyl-imidazol-5-yl or especially -4-yl, or pyrazolyl, such as pyrazol-1-yl, -3-yl, -4-yl or Alkyl Rz having two or more carbon atoms is especially ethyl, n-propyl, isopropyl, n-butyl or 1,1-dimethylethyl, or more especially C 7

-C

20 alkyl, so that T is, for example, propionyl, butyryl, methylpropionyl, valeroyl or pivaloyl, or especially octanoyl, decanoyl or palmitoyl.

Lower alkenyl R z is especially C 2

-C

7 alkenyl, more especially C 2

-C

3 alkenyl, wherein the double bond is preferably in the 1-position, so tkb't T is, for example, acryloyl, crotonoyl, isocrotonoyl or methacryloyl.

Lower alkynyl Rz is especially C2-C 7 alkynyl, more especially C 2

-C

3 alkynyl, wherein the triple bond is preferably in the 1-position, so that T is, for example, propynoyl.

Aryl Rz by itself or aryl as a substituent in the above-mentioned radicals R z with the exception of aryl itself is especially C 6

-C

1 4 aryl, more especially phenyl, naphthyl, such as 1- or 2-naphthyl, or fluorenyl, such as 9-fluorenyl, and is unsubstituted or substituted by up to three radicals selected independently of one another from lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, such as benzyloxy, diphenylmethoxy or triphenylmethoxy, hydroxy-lower alkyl, such as hydroxymethyl, halogen, such as fluorine, chlorine or bromine, cyano, lower alkoxycarbonyl, such as methoxy- or tertbutoxy-carbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, halo-lower alkyl, such as chloromethyl or trifluoromethyl, heterocyclyl-lower alkyl wherein heterocyclyl is a saturated, partially saturated or unsaturated single ring containing from 3 to 7, preferably from 5 to 7, ring atoms and up to two hetero atoms selected from nitrogen, sulfur, oxygen and lower alkyl-, benzyl-, diphenylmethyl-, triphenylmethyl- or lower alkai.oyl-substituted nitrogen, for example piperidinomethyl, piperazin-1-ylmethyl, 4-lower alkyl-piperazin-1-yl-methyl, such as 4-methyl- or 4-ethyl-piperazin-1-ylmethyl, morpholinomethyl or thiomorpholinomethyl, and nitro, which may be present independently of one another, especially correspondingly substituted phenyl. Special preference is given to m- or p-chlorophenyl, chloro-lower alkylphenyl, such as p-chloromethyl- Sphenyl, p-(morpholino-lower alkyl)phenyl, such as p-morpholinomethyl-phenyl, or p-(thiomorpholino-lower alkyl)phenyl, such as p-thiomorpholinomethyl-phenyl, or also phenyl.

Unsubstituted or substituted amino Rz carries at the nitrogen atom 1 or 2 substituents selected independently of one another from unsubstituted or substituted lower alkyl wherein the substituents of lower alkyl are preferably selected from hydroxy, lower S: alkoxy, lower alkanoyloxy, phenyl-lower alkanoyloxy, such as benzoyloxy or phenylacetyloxy, halogen, such as fluorine, chlorine, bromine or iodine, especially fluorine or chlorine, carboxy, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, cyano, oxo and phenyl or naphthyl each of which is unsubstituted or monoor poly-substituted, preferably mono-substituted, for example by lower alkyl, for example methyl, halo-lower alkyl, such as chloro- or bromo-methyl, halogen, for example fluorine or chlorine, hydroxy, lower alkoxy, such as methoxy, lower alkanoyloxy, carboxy, lower alkyloxycarbonyl, phenyl-lower alkoxycarbonyl, halo-lower alkyl, such as trifluoromethyl, cyano and/or by nitro, especially phenyl substituted in the p-position by one of the mentioned radicals; especially selected from unsubstituted lower alkyl, such as methyl or ethyl; and aryl that preferably has from 6 to 14 carbon atoms and is unsubstituted or mono- or poly-substituted, preferably mono-substituted, for example by lower alkyl, for example methyl, halo-lower alkyl, such as chloro- or bromo-methyl, halogen, for example fluorine or chlorine, hydroxy, lower alkoxy, such as methoxy, lower alkanoyloxy, carboxy, lower alkyloxycarbonyl, phenyl-lower alkoxycarbonyl, halo-lower alkyl, such as trifluoromethyl, cyano and/or by nitro, the nitrogen atom of the resulting N-substituted carbamoyl group T carrying not more than one aryl radical; amino Rz being especially amino, mono- or di-lower alkylamino, such as N-methyl-, N-ethyl-, N,N-dimethyl- or N,N-diethyl-amino, or phenyl-lower alkylamino wherein phenyl is unsubstituted or substituted by lower alkyl, for example methyl, halo-lower alkyl, such as chloro- or bromomethyl or trifluoromethyl, halogen, for example fluorine or chlorine, hydroxy, lower alkoxy, such as methoxy, carboxy and/or by cyano, preferably by up to three of those substituents selected independently of one another, especially by one of those substituents, for example in the p-position, such as in N-benzyl-, N-(4-fluorobenzyl)-, N-(4-chlorobenzyl)-, N-(4-trifluoromethylbenzyl)- or N-(4-cyanobenzyl)-amino; special preference is given to amino substituted at the nitrogen atom by only one radical, for example N-lower alkylamino, such as N-methyl- or N-ethyl-amino, or phenyl-lower alkylamino wherein phenyl is unsubstituted or substituted by lower alkyl, such as methyl, halo-lower alkyl, such as chloro- or bromo-methyl or trifluoromethyl, halogen, such as fluorine or chlorine, hydroxy, lower alkoxy, such as methoxy, carboxy and/or by cyano, preferably by up to three of those substituents selected independently of one another, especially by one of those substituents, for example in the p-position, such as in N-benzyl-, N-(4-fluorobenzyl)-, N-(4-chlorobenzyl)-, N-(4-trifluoromethylbenzyl)- or N-(4-cyanobenzyl)-amino.

The definitions falling under the definition of unsubstituted or substituted amino Rz and the radical aminocarbonyloxy R 5 may preferably be omitted from any of the definitions of compounds of formula I' mentioned hereinabove and hereinbelow.

Especially preferred for Rz are the mentioned definitions with the exception of alkyl having more than 2 carbon atoms, lower alkenyl and lower alkynyl; and also with ihe exception of aryl.

In all definitions preference is given especially to those radicals Rz that contain in the 2-position or also in a higher position, such as the 3- or 4-position, a hetero atom selected from nitrogen, oxygen and sulfur, especially nitrogen (especially valuable properties, for example especially casy removal of T, are obtained in that case).

T is especially pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, such as or (S)-pyrrolidin- 2-ylcarbonyl or (L)-prolyl), furan-3- or especially furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or especially pyridyl-2-ylcarbonyl, isoquinolin-1- or especially isoquinolin- 3-ylcarbonyl, pyrazin-2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, such as methoxyacetyl, n-butoxyacetyl or 3-methoxypropionyl, phenyl- or naphthyl-lower alkoxy-lower alkylcarbonyl, such as benzyloxyacetyl, cX-lower alkoxy-a-phenyl-lower alkylcarbonyl, such as or (S)-a-methoxy-cc-phenylacetyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(methoxyethoxy)acetyl, lower alkoxy-lower alkoxy-lower alkoxylower alkylcarbonyl, such as 2-(2-(methoxyethoxy)ethoxy)ar~etyl, m- or p-chlorophenyloxy-lower alkoxy-lovver alkylcarbonyl, N,N-di-lower alkylb.,mino-lower alkoxylower alkylcarbonyl, such as 2-(N,N-dimethylamino)ethyloxy-acetyl or -3-propionyl, 2-, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, such as pyridin-2-ylmethoxyacetyl, phenylomy-lower alkylcarbonyl, such as phenoxyacetyl, lower alkylthio-lower alkylcarbonvi, such rethylthioacetyl, phenyl-lower alkylthio-lower alkylcarbonyl, such as benzylthioacetyl, N,N-di-lower alkylamino-lower alkylcarbonyl, such as N,N-dimethylamino-acetyl, -3-propionyl or -4-butyryl, N-lower alkylamino-lower alkylcarbonyl, such as N-met 7 iylamino-acetyl or -3-propionyl, N-imidazol(-2-, or alkylamino-lower alkylcarbonyl, such as N-(imidazol-4-ylmethyl)-N-methylaminoacetyl, N-pyridin(-2-, or -4-)ylmnethyl-N-lower aikylamnino-lower alkylcarbonyl, such as 0.000 N-pyridin-2-ylmethyl-N-mnethylaminoacetyl, N-phenyl-lower alkoxycarbonyi-N-lower ~:alkylamino-lower alkyicarbonyl, such as N-benzyloxycarbonyl-N-metliylaxninoacetyl, imidazol or -5-)yl-lower alkylcarbonyl, such as 3-(imidazol-4-yl)propiony1, or N' triphenyl-lower allcylimidazol(-4- or -5-)yl-lower alkylcarbonyl, such as 3-(N-tripheny1miethylimidazol-4-yl)propionyl, or pyrazol(-1l-, -4 or -5-)yl-lower alkylcarbonyl, such as pyrazol-1I-ylacetyl, or also halo-lower alkylbenzoyl, such as p-chloromethylbenzoyl, p- (morpholino- or thiomorpholino-methyl)benzoyl or benzoyl, and (additionally or especially) lower alkanoyloxy-lower alkylcarbonyl, such as acetyloxyacetyl, lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, such as methoxycarbonylmethoxy-acetyl, lower alkoxycarbonyl-lower alkylthio-lower alkylcarbonyl, such as methoxycarbonylmethylthio-acetyl, lower alkoxycarbonyl-lower alkylsulfo-lower alkylcarbonyl, such as methoxycarbonylmethylsulfo-acetyl, lower alkanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, such as pivaloyloxymethoxycarbonyl-metfloxyacetyI or *00* acetyloxymethoxycarbonyimethoxy-acetyl, carboxy-lower alkoxy-lower alkylcarbonyl, such as carboxymethoxyacetyl., N-phenyl-lower alkoxycarbonylamnino-lower alkylcarbonyl, such as 3-benzyloxycarbonylamino-propionyl, amino-lower alkylcarbonyl, such as 3-aminopropionyl, di-lower alkylamino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as [2-(2-dimethylaminoethoxy)-ethoxy]-acetyl, N-phenyl-lower alkoxycarbonylamnino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-N-beuizyloxycarbonylaminoethoxy)ethoxy-acetyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl. such as 2-(2-aminoethoxy)ethoxy-acetyl, or tetrahydrofuranyloxy-lower alkylcarbonyl, such as 2-(4-tetrahychofuranyloxy)-acetyl or or also 2(R,S)-(4-tetrahydrofuranyloxy)-propionyl.

-12- Lower alkoxycarbonyl R 1 preferably contains a branched lower alkyl radical, especiaiiy a sec- or tert-lower alkyl radical, and is, for example, butoxycarbonyl, such as tert-butoxy..

carbonyl or isobutoxycarbonyl or (additionally or especially) ethoxycarbonyl. Tertbutoxycarbonyl is especially preferred.

Heterocyclylcarbonyl R, contains especially a 5- or 6-membered heterocycle that contains from 1 to 3 hetero atoms selected independently of one another from S, O and N, is unsaturated or fully or partially saturated and is once or up to three times benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused, it being possible for the mentioned fused rings to contain a further nitrogen atom as hetero atom, for example a heterocyclyl radical selected from pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, P-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be fully or partially saturated, but are preferably partially saturated, or is selected from pyridylcarbonyl, for example pyridyl-3-carbonyl, morpholinylcarbonyl, for example morpholinocarbonyl, and benzofuranoyl, for example 3-benzofuranoyl, and also alternatively or in addition thereto tetrahydroisoquinolylcarbonyl, for example tetrahydroisoquinolyl-3-carbonyl, preferably tetrahydroisoquinolyl-3(S)-carbonyl.

:1 Benzyloxycarbonyl R 1 is unsubstituted or substituted by up to three radicals selected independently of one another from fluorine, halo-lower alkyl, for example trifluoromethyl or pentafluoroethyl, lower alkanoyl, such as acetyl, propanoyl, butyryl or pivaloyl, sulfo, S lower alkylsulfonyl, for example methylsulfonyl, ethylsulfonyl, n-propylsulfonyl or isopropylsulfonyl, and cyano. Preference is given to bcnzyloxycarbonyl that is unsubstituted or m- or p-substituted, especially p-substituted, in the phenyl ring by a radical selected from fluorine, trifluoromethyl, sulfo, methylsulfonyl, ethylsulfonyl and cyano, for Sexample: benzyloxycarbonyl, fluorophenylmethoxycarbonyl, such as p-fluorophenylmethoxycarbonyl, trifluoromethylphenylmethoxycarbonyl, such as p-trifluoromethylphenylmethoxycarbonyl, methylsulfonylphenylmethoxycarbonyl, such as p-methylsulfonylphenylmethoxycarbonyl, or cyanophenylmethoxycarbonyl, such as p-cyanophenylmethoxycarbonyl.

Heterocyclyloxycarbonyl R 1 contains as heterocyclyl especially a 5- or 6-membered heterocycle that contains from 1 to 3 hetero atoms selected independently of one another from S, O and N, is unsaturated or fully or partially saturated and is once or up to three -13times benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused, it being possible for the mentioned fused rings to contain a further nitrogen atom as hetero atom, for example a radical selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, P-carbolinyl, or additionally or especially y-pyranyl or furanyl, and a benzo-fused, cyclopenta-, cyclohexaor cyclohepta-fused derivative of those radicals, which may also be fully or partially saturated, the heterocyclyl radicals being bonded via a ring carbon atom to the oxygen of the associated oxycarbonyl radical, preferably selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, p-carbolinyl and a fully or partially saturated derivative of those radicals, for example a partially saturated derivative of those radicals or indol-3-yl-oxycarbonyl, benzothiazol-6-yl-oxycarbonyl or quinol-8-yl-oxycarbonyl, additionally or especially tetrahydropyranyloxycarbonyl, such as 4-tetrahydropyranyloxycarbonyl, or tetrahydrofuranyloxycarbonyl, such as or also 3(R,S)-tetrahydrofuranyloxycarbonyl. In a very especially preferred variant of the definition of R 1 the radicals falling under the definition of the substituents heterocyclyloxycarbonyl are not included in any categories of definition.

In the radicals mentioned it is also possible for the bonding carbonyl group to have been replaced by a thiocarbonyl group. A carbonyl group is preferred.

Lower alkylsulfonyl lower alkyl-SO 2

R

1 is preferably methylsulfonyl, ethylsulfonyl, n-propylsulfonyl or isopropylsulfonyl. The compounds of formula I' wherein R 1 is lower alkylsulfonyl and the remaining radicals are as defined may preferably be omitted from the definition of the compounds of formula or they are especially preferred.

Heterocyclylsulfonyl preferably contains as heterocyclyl one of the hete-ocycles mentioned for heterocyclylcarbonyl R 1 that is unsubstituted or substituted by lower alkyl, such as methyl or ethyl, preference being given to heterocycles containing at least one nitrogen atom that is bonded to the sulfur atom of the sulfonyl group, and is especially piperidinosulfonyl, or piperazin-l-yl-sulfonyl, pyrrolidin-1-yl-sulfonyl, imidazolidin-1-yl-sulfonyl, pyrimidin- -yl-sulfonyl, quinolin-1-ylsulfonyl, morpholinosulfonyl or thiomorpholinosulfonyl, especially thiomorpholinosulfonyl or morpholinosulfonyl, that is unsubstituted or substituted by lower alkyl, such as methyl, at the nitrogen atom not bonded to the sulfonyl sulfur atom. The compounds of formula I' wherein R 1 is heterocyclylsulfonyl and the remaining radicals are as defined may preferably be omitted from -14the definition of the compounds of formula or they are especially preferred.

N-(heterocyclyl-lower alkyl)-N-lower alkyl-aminocarbonyl R, preferably contains as heterocyclyl one of the heterocycles mentioned for heterocyclylcarbonyl RI, especially pyridyl, such as 3- or 4-pyridyl, pyrazinyl, pyrimidinyl, morpholinyl, such as morpholino, thiomorpholinyl, such as thiomorpholino, or quinolyl, such as 2- or 3-quinolyl, and is especially N-(heterocyclylmethyl)-N-methyl-aminocarbonyl, for example N-(pyridylmethyl)-N-methyl-aminocarbonyl, such as N-(2-pyridylmethyl)-N-methyl-aminocarbonyl.

The compounds _-Jrmla I' wherein R, is N-(heterocyclyl-lower alkyl)-N-lower sikylaminocarbonyl and the remaining radicals are as defined may perferably be omitted from the definition of compounds of formula or they are especially preferred.

A bivalent residue B of an a-amino acid bonded N-terminally to R, and C-terminally to the amino group at the carbon atom carrying R 2

-CH

2 is preferably selected from glycine (H-Gly-OH), alanine (H-Ala-OH), valine. (H-Val-OH), norvaline (c-aminovaleric acid), leucine (H-Leu-OH), isoleucine, (H-le-OH), norleucine (a-aminohexanoic acid, H-Nle-OH), serine (H-Ser-OH), homoserine (ac-amino-y-hydroxybutyric acid), threonine (H-Thr-OH), methionine (H-Met-OH), cysteine (H-Cys-OH),, proline (H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH), p-fluorophenylalanine tyrosine (H-Tyr-OH), p-lower alkoxy-phenylalanine wherein lower alkoxy may be unbranched or branched, such as p-methoxy-phenylalanine (H-(p-CH 3 O-Phe)-OH), or also 4-isobutyloxyphenylalanine (H-(4-isobutyloxy-Phe)-OH) or (especially) 4-(n-butyloxy)-phenylalanine (H-(4-n-butyloxy-Phe)-OH), p-phenyl-lower o o.alkoxy-phenylalanine, such as p-benzyloxyphenylalanine zlOPhe)-OH), 4-aminophenylalanine, 4-chiorophenylalanine, 4-carboxyphenylalanine, j3-phenylserine (j3-hydroxyphenylalani-ne), phenylglycine, a-naphthylalanine (H-Nal-OH), cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-0-H), indoline-2-carboxylic acid, 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aminomnalonic acid, am-inomalonic acid monoamide, aspartic acid (Hj-Asp-OH), asparagine (H-Msn-OH), glutamic acid (H-Glu-OH), glutamine (H-Gin-OH), histidine (H-His-OH), arginine (H-Arg-OH), lysine (H-Lys-OH), 8-hydroxylysine, ornithine (a,8&diaminovaleric acid), a,,y-diaminobutyric acid and ax,1-diaminopropionic acid, or alternatively and in addition thereto 4-cyanophenylalanine (H-(p-CN-Phe)-OH), especially preferably the radical of a hydrophobic amino acid, for example proline, phenylalanine, p-fluorophenylalanine, p-methoxyphenylalanine, p- ben zyloxy-phenylalanine, tyrosine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine, or also 4-isobutyloxy- or- especially 4-n-butyloxyphenylalanine, or an aliphatic a-amino acid selected from glycine, valine, norvaline, alanine, leucine, norleucine and isoleucine, especially valine, each of the mentioned a-amino acids being in the L- or (D,L)-form, preferably in the L-form, and being linked especially to radicals R 1 selected from lower alkoxycarbonyl, for example tertbutoxycarbonyl, and heterocyclylcarbonyl, for example morpholinocarbonyl.

When B 1 is a bond, R 1 is bonded directly to the amino nitrogen atom that is bonded to the carbon atom carrying the radical R 2

-CH

2 in formula I'.

Phenyl or cyclohexyl R 2 or R 3 is unsubstitated or substituted by up to three radicals selected independently of one another from hydroxy, lower alkoxy which may be unbranched or branched, such as methoxy or ethoxy or (additionally or especially) isobutyloxy or n-butyloxy (preferred), phenyl-lower alkoxy, such as benzyloxy, halogen, for example fluorine, halo-lower alkyl, for example trifluoromethyl, sulfo, lower alkylsulfonyl, for example methyl- or ethyl-sulfonyl, cyano and nitro, preferably by one or two of those radicals, especially selected from hydroxy, methoxy, benzyloxy, fluorine, trifluoromethyl, sulfo, lower alkylsulfonyl, for example methyl- or ethyl-sulfonyl, and cyano, and in the case of phenyl selected very especially from fluorine and cyano, and in the case of cyclohexyl very especially from fluorine, trifluoromethyl, sulfo and lower alkylsulfonyl, more especially fluorine; the mentioned substituents are bonded in the 2-, 3- or 4-position of the phenyl or cyclohexyl ring, especially in the 4-position, such as in phenyl, cyclohexyl, 3- or 4-fluoro- or 3- or 4-cyano-phenyl or 4-fluorocyclohexyl, especially in phenyl, cyclohexyl, 4-cyanophenyl or 4-fluorophenyl.

Especially preferably R 2 is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-benzyloxyphenyl, 4-fluorophenyl, cyclohexyl and 4-trifluoromethylphenyl, while R 3 is selected from phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, cyclohexyl, 3- or 4-fluorophenyl, 4-trifluoromethylphenyl and 3- or 4-cyanophenyl.

More especially R 2 is selected from phenyl, 4-fluorophenyl and cyclohexyl, while R 3 is selected from phenyl, cyclohexyl, 4-fluorophenyl and 4-cyanophenyl.

Greatest preference is given to the combinations: R 2 phenyl and R3 phenyl; R 2 cyclohexyl and R 3 4-cyanophenyl; R 2 cyclohexyl and R 3 4-flucrophenyl; and R 2 and R 3 each cyclohexyl. Alternatively or in addition thereto, greatest preference is given also to the combinations R 2 phenyl and R 3 4-fluorophenyl; R 2 phenyl and R 3 4-cyanophenyl; R 2 -16- 4-fluorophenyl and R 3 4-fluorophenyl; R 2 4-fluorophenyl and R 3 4-trifluoromethylphenyl;

R

2 4-trifluoromethylphenyl and R 3 phenyl; R 2 4-trifluoromethylphenyl and R 3 4-fluorophenyl; R 2 4-trifluoromethylphenyl and R 3 4-trifluoromethylphenyl; R 2 hydroxyphenyl and R 3 phenyl; R 2 phenyl and R 3 hydroxyphenyl; R 2 phenyl and R 3 p-trifluoromethylphenyl; R 2 cyclohexyl and R 3 p-methoxyphenyl; R 2 cyclohexyl and R 3 p-trifluoromethylphenyl; R 2 phenyl and R 3 p-benzyloxyphenyl; R 2 p-methoxyphenyl and R 3 p-benzyloxyphenyl; R 2 p-benzyloxyphenyl and R 3 phenyl; R 2 p-benzyloxyphenyl and R 3 p-benzyloxyphenyl; R 2 phenyl and R 3 o-fluorophenyl; R 2 phenyl and R 3 m-fluorophenyl; R 2 phenyl and R 3 p-methoxyphenyl; R 2 p-methoxyphenyl and R 3 p-hydroxyphenyl; R 2 p-methoxyphenyl and R 3 phenyl; R 2 phenyl and R 3 o-methoxyphenyl; R 2 phenyl and R 3 m-methoxyphenyl; R 2 p-methoxyphenyl and R 3 p-methoxyphenyl; R 2 p-methoxyphenyl and R 3 m-methoxyphenyl; R 2 p-methoxyphenyl and R 3 o-methoxyphenyl; R 2 phenyl and R 3 m-cyanophenyl; R 2 phenyl and R 3 o-cyanophenyl; or R 2 4-hydroxyphenyl and R 3 S. 4-hydroxyphenyl; and (additionally or especially) R 2 phenyl and R 3 2,4-difluorophenyl; R, phenyl and R 3 4-isobutyloxyphenyl; R 2 cyclohexyl and R 3 4-benzyl- S. oxyphenyl; R 2 cyclohexyl and R3 4-hydroxyphenyl; R 2 phenyl and R 3 3,4-dimethoxyphenyl; R 2 phenyl and R 3 3,4,5-trimethoxyphenyl; or R 2 phenyl and R 3 S 2,3,4-trimethoxyphenyl.

Strong preference is given to the compounds wherein one of the radicals R 2 and R 3 is pmethoxyphenyl and the other has one of the meanings mentioned, especially p-methoxyphenyl, p-fluorophenyl, phenyl or p-trifluoromethylphenyl.

A bivalent resid!e of an a-amino acid A, bonded N-terminally to the group -C=O and S C-terminally to A 2 is, for example, one of the a-amino acids mentioned above for B 1 it being possible for those amino acids to be in the or (D,L)-form, preferably in the or (L)-form, especially in the (L)-form. Preference is given to the hydrophobic aamino acids, especially the aliphatic hydrophobic a-amino acids, mentioned under B 1 for example glycine, valine or isoleucine, or additionally or especially leucine or phenylglycine. In the mentioned a-amino acids the carboxy group bonded to A 2 is not reduced or is reduced, especially to a methylene group, for example in the mentioned hydrophobic a-amino acids, such as in the reduced amino acid residues Gly(red), Val(red) or Ile(red), especially in Val(red), the suffix (red) indicating the reduction of the carbonyl group of the corresponding amino acid residue to the methylene group.

When A, is a bond, A 2 is bonded directly to the carbonyl group at the carbon atom -17carrying the radical R 3

-CH

2 A bivalent residue of an a-amino acid A 2 bonded N-terminally to A, and C-terminally to the group NR 4

R

5 is, for example, one of the a-amino acids mentioned above for B 1 it being possible for those amino acids to be in the or (D,L)-form, preferably in the or (L)-form, especially in the (L)-form. Preference is given to the hydrophobic aamino acids mentioned for B 1 for example glycine, alanine, valine, leucine, isoleucine, phenylalanine, p-fluorophenylalanine, tyrosine, p-methoxy-phenylalanine, p-benzyloxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine or cyclohexyiglycine, preferably glycine, alanine, valine, leucine, phenylalanine, p-fluorophenylalanine, pmethoxy-phenylalanine, p-benzyloxyphenylalanine or cyclohexylalanine, or also 4-isobutyloxyphenylalanine or (especially) 4-n-butyloxyphenylalanine, the mentioned residues being in the or (L)-form, but preferably in the (L)-form with the exception of phenylalanine which is in the or the (D)-form.

A bivalent residue of a dipeptide, formed by A, and A 2 the central peptide bond of which has been reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR 4

R

5 preferably consists of two of the above-mentioned hydrophobic a-amino acids, especially an N-terminal amino acid residue selected from Gly(red), Val(red) and Ile(red) and a C-terminal amino acid selected from glycine, phenylalanine, tyrosine, p-methoxyphenylalanine, p-benzyloxyphenylalanine, cyclohexylalanine and S p-fluorophenylalanine, and also 4-isobutyloxyphenylalanine and (especially) 4-n-butyloxyphenylalanine.

S Especially preferably A, and A 2 together form a bivalent residue of a dipeptide of the formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Val-Gly, Val-(p-F-Phe), Gly-(p-F-Phe); and alternatively or additionally th- residue of a dipeptide of the formula Val-Tyr, Ile-Tyr, Gly-Tyr, Ile-Gly, Val-(p-BzlOPhe), Val-Ile, Val-Ala, Val-Leu or Val-Val, or (additionally or especially) phenylglycyl-(p-CH30-Phe), Val-(4-isobutyloxy- Phe) or Val-(4-n-butyloxy-Phe); wherein the amino acids are in the or (L)-form, especially in the (L)-form, with the exception of (L)-Val-Phe in which Phe is in the or (D)-form, or a derivative thereof having a reduced central amide bond, for example of the formula Val(red)-Phe, bonded N-terminally to the group -C=O and C-terminally to the group NR 4

R

5 A preferred form of the invention relates either to compounds of formula I' wherein B 1 is -18one of the mentioned bivalent residues of an a-amino acid and one of the radicals A 1 and

A

2 is a bond and the other is one of the mentioned a-amino acids, or to compounds of formula I' wherein B 1 is a bond and A 1 and A 2 are each one of the mentioned bivalent residues of an a-amino acid or together form one of the mentioned bivalent residues of a dipeptide having a reduced central amide bond.

Thiomorpholino or morpholino formed by R 4 and R 5 together with the bonding nitrogen atom is unsubstituted or substituted at one or more of the carbon atoms, preferably at one or two carbon atoms, for example one carbon atom, by lower alkyl, such as ethyl, propyl, butyl, isobutyl, tert-butyl or especially methyl, by phenyl- or naphthyl-lower alkyl, such as benzyl, 1- or 2-naphthylmethyl or phenyl-1- or phenyl-2-ethyl, especially phenyl-1- or phenyl-2-ethyl, by hydroxy, by lower alkoxy, such as methoxy, ethoxy or tert-butoxy, by amino, by lower alkylamino, such as methyl- or ethyl-amino, or by di-lower alkylamino, Ssuch as dimethylamino or diethylamino, by lower alkanoyl, such as acetyl or propionyl, by phenyl- or naphthyl-lower alkanoyl, such as phenylacetyl or 1- or 2-naphthylacetyl, by carboxy, by lower alkoxycarbonyl, such as isopropoxycarbonyl or tert-butoxycarbonyl, by phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl or 9-fluorenylmethoxycarbonyl, by carbamoyl, by mono- or di-lower alkylcarbamoyl, such as dimethylcarbamoyl, by mono- or di-hydroxy-lower alkyl-carbamoyl, such as di-hydroxymethyl-carbamoyl, by sulfo, by lower alkylsulfonyl, such as methylsulfonyl or ethylsulfonyl, by phenyl- or naphthyl-sulfonyl, wherein phenyl S may be substituted by lower alkyl, for example methyl or ethyl, for example phenylsulfonyl or toluenesulfonyl, by sulfamoyl, by halogen, for example fluorine or chlorine, by cyano, by nitro and/or by oxo.

Very preferably R 4 and R 5 together with the bonding nitrogen atom form unsubstituted thiomorpholino or morpholino, especially unsubstituted morpholino.

Salts of compounds of formula I' that contain salt-forming groups, that is to say one or more salt-forming groups, are especially acid addition salts, salts with bases or, where several salt-forming groups are present, optionally also mixed salts or internal salts.

Salts are especially the pharmaceutically acceptable salts of compounds of formula I' that are non-toxic when used in the correct dose.

Such salts are formed, for example, from compounds of formula I' having one or more a I -19acidic groups, for example a carboxy group, and are, for example, the salts thereof with suitable bases, such as non-toxic metal salts derived from metals of groups Ia, Ib, IIa and IIb of the Periodic Table of Elements, especially suitable alkali metal salts, for example lithium, sodium or potassium salts, or alkaline earth metal salts, for example magnesium or calcium salts, and also zinc salts or ammonium salts, as well as those salts which are formed with organic amines, such as unsubstituted or hydroxy-substituted mono-, di- or tri-alkylamines, especially mono-, di- or tri-lower alkylamines, or with quaternary ammonium compounds, for example with N-methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- or tris-(2-hydroxy-lower alkyl)-amines, such as mono-, bis- or tris- (2-hydroxyethyl)-amine, 2-hydroxy-tert-butylamine or tris(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy-lower alkyl)-amines, such as N,N-dimethyl-N-(2hyciroxyethyl)-amine or tris(2-hydroxyethyl)amine, N-methyl-D-glucamine or quaternary ammonium salts, such as tetrabutylammonium salts. The compounds of formula I' having one or more basic groups, for example an amino or imino group, may form acid addition salts, for example with inorganic acids, for example a hydrohalic acid, such as hydro- S. chloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, and also with amino acids, for example glutamic acid or aspartic acid, and with methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene- 2-sulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates) or with other acidic organic compounds, such as ascorbic acid. Compounds of formula I' having acidic and basic groups may also form internal salts.

For the purposes of isolation and purification it is also possible to use pharmaceutically unacceptable salts.

The compounds of formula I' have valuable pharmacological properties. In particular, they are active against retroviral diseases, especially against AIDS which is caused by HIV, especially HIV-1 or HIV-2. For example, they act as metabolic precursors of compounds of formula I

R

1 A 1

A

2 A N

B

1

BO

2 0

R

2 which contain a hydrogen atom in place of the radical T in compounds of formula I', while the remaining definitions are as defined for compounds of formula and which have anti-retroviral activity and are especially suitable in the treatment of AIDS as inhibitors of the aspartate proteases of HIV-1 and/or HIV-2 (and possibly other retroviruses that produce AIDS-analogous symptoms). The compounds of formula I' can therefore be used therapeutically against retroviral diseases, especially AIDS.

Compounds of formula I are mentioned and described in the European Patent Application having the publication number EP 0 532 466 (published on 17.03.1993).

The compounds of formula I are released from the compounds of formula I' in the body of the animal to be treated, especially a warm-blooded animal, including a human being.

Using the compounds of formula I' it is possible, for example, especially in the case of enteral, preferably oral, administration of the compounds, to obtain advantageous pharmacokinetics different to those obtained on administration of the compounds of formula I themselves.

The pharmacodynamic properties of the compounds of formula I' can be demonstrated, for example, as follows: The compounds of formula I' to be investigated or (for example as control) the corresponding compounds of formula I are dissolved in an organic solvent, such as dimethyl sulfoxide (DMSO), in a concentration of 240 mg/ml. The resulting solutions are diluted with 20% hydroxypropyl-P-cyclodextrin (HP3CD) in order to obtain a concentration of test compound of 12 mg/ml. That solution is administered to mice orally by artificial special feeding in a dose of 120 mg/kg. 30, 60, 90 and 120 minutes after administration the animals are sacrificed and blood is removed. Three or four animals are investigated per time point. The blood is heparinised and prepared for analysis using one of the following -21 two methods: in accordance with the first method whole blood is deproteinised by mixing one part by volume of blood with one part by volume of acetonitrile; after centrifugation 000 g, 5 minutes) the supernatant is analysed by reversed-phase HPLC. In accordance with the second method 2 l.1 of a 1 mM solution of an internal standard (such as a different compound of formula I) are added to 0.5 ml of heparinised blood. The blood is centrifuged 000 g, 5 minutes) and the plasma is mixed with the same volume of acetonitrile. The precipitated protein is removed by centrifugation (10 000 g, 5 minutes) and the supernatant is concentrated by evaporation in vacuo. The residue is taken up in 0.1 ml of phthalate buffer (0.05M, pH 3) and 20 .1 of 3M NaC1. The mixture is extracted with 1 ml and then again with 0.2 ml of diisopropyl ether (=DIPE; Merck, Darmstadt). The DIPE fractions are combined and concentrated by evaporation in vacuo. The residue is dissolved in 50% water (Baker) and 50% acetonitrile prior to analysis by reversedphase HPLC.

The analysis by reversed-phase HPLC is carried out using a 125 x 4.6 mm Nucleosil®

C

1 8 -column (reversed-phase material supplied by Macherey-Nagel, Diiren, Federal Republic of Germany, based on silica gel derivatised with hydrocarbon radicals having 18 carbon atoi.is) equilibrated with a mobile phase of acetonitrile in water/0.1% trifluoroacetic acid. Depending upon the compound, the proportion of acetonitrile is advantageously, for example, from 35 to 60 by volume. The flow rate is 1 ml/minute. Detection is effected at 215 nm. Standards for the compounds in blood are worked up analogously to the blood samples and used to establish standard curves on the basis of which the in vivo concentrations are determined.

For the compounds of formula I' or of formula I, the concentration of the component of formula I in the blood of mice 60 minutes after oral administration is preferably up to 104M, preferably from 5 x 10-"M to 5 x a The compounds of formula I exhibit inhibitory action on retroviral aspartate proteases, especially HIV-protease-inhibiting actions. In the tests described below they inhibit especially the action of the HIV-protease of HIV-1 in concentrations of from 10 6 to 10-9M, for example with an IC 50 of from 10 to 1000 nM, especially from 10 to 100 nM. They, and thus also the prodrugs of formula are therefore suitable agents against diseases caused by that or related retroviruses (retroviral diseases), such as against AIDS or against the preliminary stages thereof.

-22- The ability of the compounds of formula I to inhibit the proteolytic activity of, for example, HIV-1-protease can be demonstrated, for example, in accordance with the method described by A. D. Richards et al., J. Biol. Chem. 265(14), 7733-7736 (1990). In that method there is used as substrate for a recombinant HIV-1-protease (prepared in accordance with Billich, et al., J. Biol. Chem. 263(34), 17905 17908 (1990)) a synthetic chromophoric peptide (for example HKARVL[NO2]FEANleS (Bachem, Switzerland; see M. W. Pennington et al., Peptides 1990, ed.: E. Girault and D. Andrew (1991), ESCOM Sci. Publ. pp. 787-789) or an icosapeptide such as RRSNQVSQNYPIVQNIQGRR (prepared by peptide synthesis in accordance with known methods: J. Schneider et al., Cell 54, 363-368 (1988)) that corresponds to one of the cleavage sites of the gag-precursor protein. That substrate and cleavage products thereof can be analysed by high pressure liquid chromatography (HPLC).

For that purpose, an inhibitor of formula I to be tested is dissolved in dimethyl sulfoxide; Sthe enzyme test is carried out by acdipg suitable dilutions of the inhibitor in 20 mM p-morpholinoethanesulfonic acid (MES) buffer pH 6.0 to the assay mix comprising the above-mentioned chromophoric peptide (67.2 M) in 0.3M sodium acetate, 0.1M NaCI pH 7.4, or the above-mentioned icosapeptide (122 giM) in 20 mM MES buffer pH The size of each batch is 100 pl. The reaction is started by the addition of in the first case 2 ptl and in the second case 10 pxl of HIV-1-protease and is stopped in the first case after minutes by the addition of 100 pl of 0.3M HC10 4 and in the second case after one hour's incubation at 37 0 C by the addition of 10 pl of 0.3M HC10 4 After centrifugation of the sample for 5 minutes at 10 000 x g in 100 ptl (batch with chromophoric peptide) or 20 pl (icosapeptide batch) of the resulting supernatant and after application to a 125 x 4.6 mm Nucleosil® C18-5p-HPLC column (Macherey Nagel, Diiren) and elution, the reaction products are quantified with reference to the peak height of the cleavage product at 280 nm (batch with chromophoric peptide) or at 215 nm (batch with icosapeptide), gradient: 100 el.1 50 el.1/50 el.2 75 acetonitrile, 90 0.1 trifluoroacetic acid (TFA); el.2: 75 acetonitrile, 25 H20, 0.08 TFA) in the course of 15 minutes; throughflow rate 1 ml/minute (el. eluant).

In that procedure there are determined for compounds of formula I, for example, values (IC 5 0 concentration that reduces the activity of the HIV-1-protease by 50 in comparison with a control without inhibitor) of approximately 50 x 10- 6 to 109M, especially 10- 7 to 109M.

,I

-23- In a further test it can be shown that the compounds of the present invention protect cells that are normally infected by HIV from such an infection or at least retard such an infection. In the test, the human T-cell leukaemia cell line MT-2 (Science 229, 563 (1985)), which is sensitive to the cytopathogenic effect of HIV, is incubated with HIV-1 alone or with HIV-1 in the presence of one of the compounds according to the invention and after several days the viability of the cells thus treated is assessed. For this purpose the MT-2 cells are kept in RPMI 1640 medium (Gibco, Switzerland; RPMI 1640 comprises an amino acid mixture without L-Gln) that has been supplemented with 10 heat-inactivated foetal calf serum, L-glutamine, Hepes (2-[4-(2-hydroxyethyl)-1-piperazino]-ethanesulfonic acid) and standard antibiotics, at 37 0 C in humidified air containing

CO

2 50 pl of the respective test compound in culture medium and 100 gl of HIV-1 in culture medium (800 TCID50/ml) (TCID50 Tissue Culture Infectious Dose 50 dose that infects 50 of the MT-2 cells) are added to 4x10 3 exponentially growing MT-2 cells S int 50 pl. of culture medium per well in 96-well microtitre plates. Parallel batches on a further microtitre plate with cells and test compound receive 100 l.1 of culture medium without the virus. After incubation for 4 days, the reverse transcriptase (RT) activity in :0 10 1l of the cell supernatant is determined. The RT activity is determined in 50 mM Tris (c,(a,c,a-tris(hydroxymethyl)methylamine, Ultra pur, Merck, Federal Republic of Germany) pH 7.8; 75 mM KC1, 2 mM dithiothreitol, 5 mM MgC1 2 0.05% Nonidet P-40 (detergent; Sigma, Switzerland); 50 gg/ml of polyadenylic acid (Pharmacia, Sweden); 1.6 gg/ml of dT(12-18) (Sigma, Switzerland). The mixture is filtered through a 0.45 g Acrodisc filter (Gelman Sciences Inc., Ann Arbor) and stored at -20 0 C. 0.1% [alpha- 32 P]dTTP is added to aliquots of that solution in order to obtain a final radioactive activity of 10 pCi/ml. 10 gl of the culture supernatant are transferred to a fresh 96-well microtitre o* plate and 30 gl of the said RT cocktail are added thereto. After mixing, the plate is incubated for 1.5 to 3 hours at 37 0 C. 5 gl of that reaction mixture are transferred to DE81-paper (Whatman). The dried filters are washed three times for 5 minutes with 300 mM NaCl/25 mM trisodium citrate and once with 95 ethanol and again dried in the air. Evaluation is made in a Matrix Packard 96-well counter (Packard, Zurich, Switzerland). The ED90 values are calculated and are defined as the lowest concentration of the respective test compound that reduces the RT activity by 90 in comparison with cell batches not treated with the test compound. The RT activity is a measure of the replication of HIV-1.

In that test the compounds of formula I exhibit, for example, an ED90 of from 10 8 to especially from 10 6 to 10 7

M.

le~asl~- ~BC~*C: -24- The novel compounds of formula I of the present invention also exhibit advantageous pharmacological properties, which allow the assumption that they will exhibit the said inhibitory actions in vivo. For example, in the case of intravenous or intraperitoneal adminisiration of 20 mg/kg of one of those compounds to mice, the level in the blood 1 hour after administration is preferably approximately the same as or higher than the in the cell assay.

In the case of peioral administration of 120 mg/kg of one of those compounds, 30 minutes after administration, for example, the concentrations found in the blood of the mice are above the ED90 in the cell assay and preferably constitute approximately 10 times the in the cel! assay.

For example, with Boc-Phe[C](p-CH 3 0)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (see Examples) after 30 minutes a concentration of 10.75 PM can be obtained with an ED90 of 0.1 .M.

The level in the blood can be determined as above for the compounds of formula I in m:ce.

S* In the definitions of compounds of formula I' mentioned hereinbelow, it is advantageously possible, for example in order to replace more general definitions by more specific definitions, to use definitions of radicals from the above-mentioned general definitions or also to omit individual definitions.

Preference is given to compounds of formula I' wherein T is an acyl radical of the abovementioned formula Z wherein Rz is heterocyclyl bonded via a ring carbon atom and selected from pyrrolyl, pyrrolyl, indolyl, indolizinyl, isoindolyl, pyrrolidinyl, such as pyrrolidin-3-yl or especially pyrrolidin-2-yl (in the or preferably or (S)-configuration), hydroxypyrrolidinyl, such as 3- or especially 4-hydroxypyrrolidinyl, fulyl, such as furan-3-yl or especially furan-2-yl, tetrahydrofuryl, thienyl, cyclohepta[b]pyrrolyl, imidazolyl, such as imidazol- 2-yl, imidazol-3-yl or especially imidazol-5-yl, N-triphenyl-lower alkyl-imidazolyl, such as N-triphenylmethyl-imidazolyl, pyrazolyl, especially pyrazol-3-yl, oxazolyl, isoxazolyl, such as isoxazol-3-yl or -5-yl, thiazolyl, isothiazolyl, such as isothiazol-3-yl or 9 triazolyl, such as 1,2,3-triazol-4- or -5-yl or 1,2,4-triazol-5-yl, tetrazolyl, pyridyl, such as pyridin-4-yl or or especially pyridin-2-yl, quinolyl, such as quinolin-2-yl, isoquinolyl, especially isoqamolin--yl or -3-yl, piperidyl, especially piperidin-2-yl, y-pyranyl, 4H-chromenyl, chromanyl, y-thiopyranyl, pyridazinyl, cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, pyrimidinyl, pyrazinyl, phenazinyl, phenoxazinyl, phenothiazinyl, morpholinyl and thiazinyl, each of which is substituted by up to three radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, such as triphenylmethyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, such as benzyloxy, diphenylmethoxy or triphenylmethoxy, hydroxy-lower alkyl, such as hydroxymethyl, halogen, such as fluorine, chlorine or bromine, cyano, lower alkoxycarbonyl, such as methoxy- or tert-butoxycarbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyi and halo-lower alkyl, such as chloromethyl or trifluoromethyl, or preferably is unsubstituted, and each of which Sis bonded via a ring carbon atom; very special preference being given to those of the mentioned radicals which contain a ring hetero atom directly adjacent to the bonding ring carbon atom, more especially the radicals furan-2-yl, or (R)-pyrrolidin-2-yl and imidazol-4-yl, pyridin-2-yl, -3-yl or -4-yl, or isoquinoin-3-yl; or additionally or especially tetrahydropyranyl; or Rz is lower alkyl (especially methyl, ethyl, n-propyl or n-butyl) which is substituted by at least one radical selected from: lower alkoxy, such as methoxy, ethoxy or n-butoxy; lower alkoxy, such as methoxy, ethoxy or n-butoxy, substituted by one or two substituents, especially aryl, more especially phenyl, naphthyl, lower alkoxy, such as ethoxy or methoxy, lower alkylthio, such as methylthio or ethylthio, lower alkoxy-lower alkoxy, such as 2-methoxyethoxy, lower alkylthio-lower alkoxy, such as 2-methylthioethoxy, aryloxy or arylthio, especially phenyloxy or m- or p-chlorophenyloxy, for example p-chlorophenyloxy, amino, N-lower alkylamino or N,N-di-lower alkylamino, such as 2-amino, 2-(N-lower alkyl)amino or 2-(N,N-di-lower alkyl)amino, for example 2-dimethylamino, and/or heterocyclyl as last defined for heterocyclyl RZ bonded via a ring carbon atom, especially 3or 4-pyridyl; aryloxy, especially phenyloxy; lower alkylthio, such as methylthio, ethylthio or n-butylthio; lower alkylthio, such as methylthio, ethylthio or n-butylthio, substituted by one or two substituents, especially aryl, more especially phenyl or naphthyl; arylthio, such as phenylthio; amino or amino substituted by one or two radicals selected from lower alkyl, such as methyl, heterocyclyl-lower alkyl wherein heterocyclyl -26is as defined for heterocyclyl RZ bonded via a ring carbon atom, especially heterocyclylmethyl, such as imidazolylmethyl, for example 4-imidazolylmethyl, or pyridylmethyl, for example 3- or 4-pyridy!methyl, each bonded via a ring carbon atom, aryl-lower alkyl, such as phenyl- or naphthyl-lower alkyl, for example phenyl- or naphthyl-methyl, lower alanoyl, such as acetyl, lower alkoxycarbonyl, such as tert-butoxycarbonyl, and aryl-lower alkoxycarbonyl, such as phenyl-lower alkoxycarbonyl, for example benzyloxycarbonyl, with especially one of the substituents of amino being lower alkyl, especially methyl, and the other being hydrogen or one of the radicals mentioned above as substituents of amino; heterocyclyl as defined above for heterocyclyl Rz bonded via a ring carbon atom, especially as pyridi-2-yl, -3-yl or -4-yl; and heterocyclyl-lower alkyl wherein lower alkyl is preferably methyl, 1- or 2-ethyl or 3-propyl and wherein heterocyclyl is as defined above for heterocyclyl Rz bonded via a ring carbon atom but may also be bonded via a ring nitrogen atom, especially imidazol-1-yl, imidazol-2-yl, or more especially imidazol-4-yl, N-triphenyl-lower alkylimidazolyl, such as N-triphenylmethyl-imidazol-5-yl or especially -4-yl, or pyrazolyl, such as pyrazol- l-yl, -3-yl, -4-yl or -5-yl; and (additionally or preferably) lower alkoxycarbonyl, such as methoxycarbonyl; lower alkanoyloxy-lower alkoxycarbonyl, such as pivaloyloxymethoxycarbonyl or acetyloxymethoxycarbonyl; carboxy; phenyl-lower alkoxycarbonylamino-lower alkoxy, such as 2-(benzyloxycarbonylamino)-ethoxy; amino-lower alkoxy, such as 2-aminoethoxy; di-lower alkylamino-lower a1koxy, such as 2-(dimethylamino)-ethoxy; N,N-di-lower alkylamino-lower alkoxy, such as 2-(dimethylamino)-ethoxy; lower alkoxycarbonyl-lower alkylsulfo, such as methoxycarbonyl-methylsulfo; lower alkanoyloxy, such as acetyloxy; and tetrahydropyranyloxy, such as 4-tetrahydropyranyloxy; and which may carry as a further substituent aryl, which is as defined below; or RZ is aryl, especially chlorophenyl, chloro-lower alkyphenyl, such as m- or p-chloromethylphenyl, p-morpholinomethyl-phenyl, p-thiomorpholinomethyl-phenyl, or also phenyl; aryl in the said definitions being especially phenyl, naphthyl, such s 1- or 2-naphthyl, or fluorenyl, such as 9-fluorenyl, that is unsubstituted or substituted by up to three radicals selected independently of one another from lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, such as benzyloxy, diphenylmethoxy or triphenylmethoxy, hydroxy-lower alkyi, such as hydroxymethyl, halogen, such as fluorine, chlorine or 27bromine, cyano, lower alkoxycarbonyl, such as methoxy- or tert-butoxy-carbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, halo-lower alkyl, such as chloromethyl or trifluoromethyl, piperidinomethyl, piperazin-1-ylmethyl, 4-lower alkylpiperazin-1-yl-methyl, such as 4-methyl- or 4-ethyl-piperazin-1-ylmethyl, morpholinomethyl or thiomorpholinomethyl, and nitro, which may be present independently of one another, and being especially correspondingly substituted phenyl;

R

1 is hydrogen, tert-butoxycarbonyl, isobutyloxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydro-isoquinoline-3-carbonyl, benzyloxycarbonyl substituted by up to three radicals selected independently of one another from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or heterocyclyloxycarbonyl wherein heterocyclyl is bonded via a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, P-carbolinyl, and additionally or especially y-pyranyl and furanyl; and a fully or partially saturated derivative of those radicals, or Swherein the definition heterocyclyloxycarbonyl for R 1 is absent, or is additionally or especially ethoxycarbonyl; B 1 is a bond (preferred) or a bivalent residue of an a-amino acid bonded N-terminally to

R

1 and C-terminally to the amino group at the carbon atom carrying R 2

-CH

2 preferably the residue of a hydrophobic amino acid, for example proline, phenylalanine, p-fluorophenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine, cyclohexylglycine or an aliphatic a-amino acid selected from glycine, alanine, valine, norvaline, leucine, norleucine and isoleucine, especially valine, each of the mentioned a-amino acids preferably being in the L- or (D,L)-form, especially in the L-form, and each of the mentioned amino acids preferably being substituted by one of the radicals mentioned under R 1 selected from hydrogen, N-tert-butoxycarbonyl and morpholinocarbonyl,

R

2 and R 3 are each independently of the other phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three, preferably one or two, radicals selected independently of one another from hydroxy, methoxy, benzyloxy, fluorine, sulfo, lower alkylsulfonyl, trifluoromethyl and cyano, additionally or especially from isobutyloxy and n-butyloxy, as indicated above in the general definitions,

A

1 is a bivalent residue of a hydrophobic a-amino acid, as indicated above under the general definitions, bonded N-terminally to the group -C=O and C-terminally to A 2

A

2 is a bivalent residue of a hydrophobic a-amino acid, preferably as defined above under the general definitions, bonded N-terminally to A 1 and C-terminally to the radical NR 4

R

5 the said amino acid residues being in the or (L)-form, preferably in the (L)-form, with clw -28the exception of phenylalanine which is in the or the (D)-form, especially A, and A 2 form a bivalent residue of a dipeptide of the formula Val-Phe, Ile-Phe, Val-Cha, Ile-Cha, Ile-Gly, Val-Val, Val-Gly, Val-(p-F-Phe), Val-Tyr, Val-(p-BzlOPhe), Val-Ile, Val-Ala, Val-Leu or Gly-(p-F-Phe), or (additionally or especially) p enylglycyl-(p-CH30-Phe), Val-(4-isobutyloxy-Phe) or Val-(4-n-butyloxy-Phe); wherein the amino acids are in the or (L)-form, especially in the (L)-form, with the exception of (L)-Val-Phe in which Phe is in the or (D)-form; or A, and A 2 together form a bival-nt residue of a dipeptide consisting of two hydrophobic a-amino acids, preferably two of those mentioned above under the general definitions, the central amide bond of which has been reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR 4

R

5 as indicated in the general definitions, for example having the formula Val(red)-Phe, and S. R 4 and R 5 together with the bonding nitrogen atom form thiomorpholino or morpholino, especially morpholino, or additionally or especially 2,6-dimethylmorpholino; and alternatively or in addition thereto the compounds of formula I wherein R 1 is morpholinosulfonyl or N-(2-pyridylmethyl)-N-methyl-aminocarbonyl and the remaining radicals are as defined; and the pharmaceutically acceptable salts of those compounds where salt-forming groups are present.

Greater preference is given to compounds of formula wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, such as or (S)-pyrrolidin-2-ylcarbonyl or (L)-prolyl), furan-3- or especially furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or especially pyridyl-2-ylcarbonyl, isoquinolin-1- or especially isoquinolin-3-ylcarbonyl, pyrazin-2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, such as methoxyacetyl, n-butoxyacetyl or 3-methoxypropionyl, phenyl- or naphthyl-lower alkoxy-lower alkyl- S carbonyl, such as benzyloxyacetyl, ax-lower alkoxy-a-phenyl-lower alkylcarbonyl, such as or (S)-a-methoxy-a-phenylacetyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(methoxyethoxy)acetyl, lower alkoxylower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-(methoxyethoxy)ethoxy)acetyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, such as 2-(N,N-dimethylamino)ethyloxyacetyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, such as pyridin-2-ylmethoxyacetyl, phenyloxy-lower alkylcarbonyl, such as phenoxyacetyl, lower alkylthio-lower alkylcarbonyl, such as methylthioacetyl, phenyllower alkylthio-lower alkylcarbonyl, such as benzylthioacetyl, N,N-di-lower alkylamino-lower alkylcarbonyl, such as N,N-dimethylamino-acetyl, -3-propionyl or 29 -4-butyryl, N-lower alkylamino-lower alkylcarbonyl, such as N-methylamino-acetyl or -3-propionyl, N-imidazol(-2-, or -5-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, such as N-(imidazol-4-ylmethyl)-N-methylaminoacetyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, such as N-pyridin-2-ylmethyl- N-methylaminoacetyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino-lower alkylcarbonyl, such as N-benzyloxycarbonyl-N-methylaminoacetyl, imidazol(:-1 or alkylcarbonyl, such as 3-(imidazol-4-yl)propionyl, N-triphenyl-lower alkylimidazol(-4- or -5-)yl-lower alkylcarbonyl, such as 3-(N-triphenylmethylimidazol-4-yl)propionyl, or pyrazol(-1-, or -5-)yl-lower alkylc~rbonyl, such as pyrazol-1-ylacetyl, or also halo-lower alkylbenzoyl, such as p-chloromethylbenzoyl, p-(morpholino- or thiomorpholino-methyl)benzoyl or benzoyl, or (especially) lowe r 23kanoyloxy-lower alkylcarbonyl, such as acetyloxyacetyl, lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, such as methoxycarbonylmiethoxy-acetyl, lower alkoxycarbonyl-lower alkylthio-lower alkyle,-rbonyl., such as methoxycarbonylmu-thylthio-acetyl, lower alkoxycarbonyl-lower alkylsulfo-lower alkylcarbonyl, such as methoxycarbonylmethylsulfoacetyl, Ic-:.er alkanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, such as pivaloyloxymethoxycarbonyl-methoxyacetyl or acetyloxymethoxycarbonylmethoxyacetyl, carboxy-lower alkoxy-lower alkylcarbonyl, such as carb( xymethoxyacetyl, N-phenyl-lower alkoxycarbonylamnino-lower alkylcarbonyl, such as 3-benzyloxycarbonlylamino-propionyl, aminc-lower alkylcarbonyl, such as 3-aminopropionyl, di-lower alkylamino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as [2-(2-dimethylarninoethoxy)-ethoxy]-acetyl, N-phenyl-lower alkoxycarbonyl-amino-lower alcoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-N-benzyloxycarbonylaminoethoxy)ethoxyacetyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-aminoethoxy)ethoxy-acetyl, or tetrahydropyranyloxy-lower alkylcarbonyl, such as 2-(4-tetrahydropyranyloxy)-acetyl or or also 2(R,S)-(4-tetrahydropyranyloxy)propionyl; R, is hydrogen, tert-butoxycarbonyl, isobutyloxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1 ,2,3,4-tetrahydro-isoquinoline-3-carbonyl, or especially ethoxycarbonyl, 4-tetrahydropyranyloxycarbonyl or tetrahydrofuran-2(R or S)-yloxycarbonyl; or alternatively and in addition thereto morpholinosulfonyl, N-(2-pyridylmethyl)-N-methyl-aminocarbonyl; B 1 is a bond (preferred) or a bivalent residue of the (x-amino acid valine bonded N-terminally to R, and C-terminally to the amino group at the carbon atom carrying

R

2

-CH

2 in the latter case R, preferably being hydrogen, tert-butoxycarbonyl or morpholinocarbonyl, or alternatively or in addition thereto morpholinosulfonyl or N-(2-pyridylmethyl)-N-methyl-aminocarbonyl,

R

2 and R 3 are each independently of the other phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three, preferably one or two, radicals selected independently of one another from hydroxy, methoxy, benzyloxy, fluorine, sulfo, lower alkylsulfonyl, cyano and trifluoromethyl, and especially from isobutyloxy and n-butyloxy, AI is a bivalent residue of one of the a-amino acids glycine, valine, isoleucine and especially leucine and phenylglycine bonded N-terminally to the group -C=O and C-terminally to A 2

A

2 is a bivalent residue of one of the a-amino acids glycine, alanine, valine, leucine, isolenicine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxy-phenylalanine, p-benzyloxyphenylalanine, p-fluorophenylalanine and especially p-(isobutyloxy)- or p-(nbutyloxy)-phenylalanine bonded N-terminally to A, and C-terminally to the group NR 4

R

5 or AI and A 2 together form a bivalent residue of a dipeptide having a reduced central peptide bond that consists of an N-terminal amino acid residue selected from Gly(red), Val(red) and Ile(red) and a C-terminal amino acid residue selected from glycine, phenylalanine, cyclohexylalanine, tyrosine, p-methoxy-phenylalanine and p-fluorophenylalanine, and that is bonded N-terminally to the group -C=O and C-terminally to the group NR 4

R

5 as defined above for A, and A 2 and

R

4 and R 5 together with the bonding nitrogen atom form thiomorpholino, morpholino or Spreferably 2,6-dimethylmorpholino, especially morpholino, and the phanraceutically acceptable salts of those compounds where salt-forming groups S are present.

Special preferene is given to compounds of formula I' wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, such as or (S)-pyrrolidin-2-ylcarbonyl or (L)-prolyl), furan-3- or especially furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or especially pyridlyl-2-ylcarbonyl, isoquinolin-1- or especially isoquinolin-3-ylcarbonyl, pyrazin-2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, such as methoxyacetyl, nbutoxyacetyl or 3-methoxypropionyl, phenyl- or naphthyl-lower alkoxy-lower alkylcarbonyl, such as benzyloxyacetyl, a-lower alkoxy-a-phenyl-lower alkylcarbonyl, such as or (S)-a-methoxy-a-phenylacetyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(methoxyethoxy)acetyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-(methoxyethoxy)ethoxy)acetyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, such as 2-(N,N-dimethylamino)ethyloxyacetyl, 3- or 4-pyridyl-lower alkyloxy-lower i LI- WI 31 alkylcarbonyl, such as pyridin-2-ylmethoxyacetyl, phenyloxy-lower alkylcarbonyl, such as phenoxyacetyl, lower alkylthio-lower alkylcarbonyl, such as methylthioacetyl, phenyllower alkyhthio-lower alkylcarbonyl, such as benzylthioacetyl, N,N-di-I1ower alkylaminolower alkylcarbonyl, such as N,N-dimethylamino-acetyl, -3-propionyl or -4-butyryl, N-lower alkylamino-lower alkylcarbonyl, such as ,N-methiylamino-acetyl or -3-propionyl, N-imidazol(-2-, or -5-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, such as N- (imidazol-4-ylmethyl)-N-methylaminoacetyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, such as N-pyridin-2-ylmethyl-N-methylaminoacetyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino-lower alkylcarbonyl, such as N-benzyloxycarboniyl-N-methylaminoacetyl, imidazol(- or -5-)yl-lower alkylcarbonyl, such as 3-(imidazol-4-yl)propionyl, N-triphenyl-lower alkylimidazol(-4- or alkyklarbonyl, such as 3-(N-triphenylmethylimidazol-4-yl)propibnyl, or pyrazol(-1-, or -5-)yl-lower alkylcarbonyl, such as pyrazol-1-ylacetyl, or also halo-lower alkylbenzoyl, such as p-chloromethylbenzoyl, p-(morpholino- or thiomorpholino-methyl)benzoyl or benzoyl, R, is hydrogen, tert-butoxycarbonyl, isobutyloxycarbonyl, pyridine-3-carbonyl, morpholinocarbonyl, 3-benzofuranoyl or 1 ,2,3,4-tetrahydro-isoquinoline-3-carbonyl; or alternatively and in addition thereto morpholinosulfonyl or N-(2-pyridylmethyl)-N-methylaminocarbonyl, B is a bond or a bivalent residue of the a-amino acid valine bonded N-terminally to R, and C-terminally to the amino group at the carbon atom carrying R 2

-CH

2 in the latter case R, preferably being hydrogen, tert-butoxycarbonyl or morpholinocarbonyl, or alternatively or in addition thereto morpholinosulfonyl. or N-(2-pyridylmethyl)-N-methylaminocarbonyl,

R

2 and R 3 are each independently of the other phenyl. or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals selected independently of one another from hydroxy, methoxy, benzyloxy, fluorine, sulfo, lower alkylsulfonyl, cyano and trifluoromethyl, A, is a bivalent residue of one of the o:-amino acids glycine, valine and isoleucine bonded N-terminally to the group -C=O and C-termninally to A 2

A

2 is a bivalent residue of one of the a-amino acids glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxy-phenylalanine, p-benzyloxyphenylalanine and p-fluorophenylalanine bonded N-terminally to A, and C-terminally to the group NR 4

R

5 or A, and A 2 together form a bivalent residue of a dipeptide having a reduced central peptide bond that consists of an N-terminal amino acid residue selected from Gly(red), Val(red) -32and Ile(red) and a C-terminal amino acid residue selected from glycine, phenylalanine, cyclohexylalanine, tyrosine, p-methoxy-phenylalanine and p-fluorophenylalanine, and that is bonded N-terminally to the group -C=O and C-terminally to the group NR 4

R

5 as defined above for A, and A 2 and

R

4 and R 5 together with the bonding nitrogen atom form thiomorpholino or morpholino, especially morpholino, and the pharmaceutically acceptable salts of those compounds where salt-forming groups are present.

Very special preference is given to a compound of formula P' wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, such as or (S)-pyrrolidin-2-ylcarbonyl or (L)-prolyl), furan-3- or especially furan-2-ylcarbonyl, pyridyl-4-., pyridyl-3- or e especially pyridyl-2-ylcarbonyl, isoquinolin-1I- or especially isoquinolin-3-ylcarbonyl, pyrazin-2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, such as methoxyacetyl, n-butoxy-acetyl or 3-methoxypropionyl, phenyl- or naphthyl-lower alkoxy-lower alkylcarbonyl, such as benzyloxyacetyl, a-lower alkoxy-a-phenyl-lower, aLkylcarbonyl, such as or (S)-c-methoxy-a-phenylacetyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(rnethoxyethoxy)acet yl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-(methoxyethoxy)ethoxy)acetyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkyk,-arbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, such as 2-(N,N-dimethylamino)ethyloxyacetyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, such as pyridin-2-ylmethoxyacetyl, phenyloxy-lower alkylcarbonyl, such as phenoxyacetyl, lower allcylthio-lower alkylcarbonyl, such as methylthioacetyi, phenyllower alkylthio-lower alkylcarbonyl, such as benzylthioacetyl, N,N-di-lower aikylaminolower alkylcarbonyl, such as N,N-dimethylamino-acetyl, propionyl or -4-butyryl, N-lower a~kylamino-lower alkylcarbonyl, such as N-methylamino-acetyl or -3-propionyl, 00 N-imidazol(-2-, or -5-)ylmiethyl-N-lower alkylamino-lower alkylcarbonyl, such as N-(imidazol-4-ylmethyl)-N-methylaminoacetyl, N-pyridin(-2-, or -4-)ylmethyl- N-lower alkylamino-lower alkylcarbonyl, such as N-pyridin-2-ylmethyl-N-methylaminoacetyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino-lower alkylcarbonyl, such as N-benzyloxycarbonyl-N-inethylaminoacetyl, imidazol(-l1-, or -5-)yl-lower alkylcarbonyl, such as 3-(imidazol-4-yl)propionyl, N-triphenyl-lower alkylimidazol(-4- or yl-lower alkylcarbonyl, such as 3-(N-triphenylmethylimidazol-4-yl)propioflyl, or pyrazolor -5-)yl-lower alkylcarbonyl, such as pyrazol-l1-ylacetyl, or also halo-lower alkylbenzoyl, such as p-chloromethylbenzoyl, p-(morpholino- or thiomorpholino-methyl)benzoyl or benzoyl, -33-

R

1 is tert-butoxycarbonyl,

R

2 is phenyl, cyclohexyl, p-hydroxyphenyl, m- or p-methoxyphenyl, p-benzyloxyphenyl, m- or p-fluorophcnyl, p-trifluoromethylphenyl or m- or p-cyanophenyl, especially phenyl, p-hydroxyphenyl, p-methoxyphenyl, p-benzyloxyphenyl, p-fluorophenyl or p-trifluoromethylphenyl,

R

3 independently of R 2 has one of the definitions given for R 2 A, is a bivalent residue of one of the a-amino acids glycine, (L)-valine and (L)-isoleucine bonded N-terminally to the group -C=O and C-terminally to A 2

A

2 is a bivalhent residue of one of the a-amino acids glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxy-phenylalanine, pbenzyloxyphenylalanine or p-fluorophenylalanine bonded N-terminally to A, and C-terminally to the group NR 4

R

5 and R 4 and R 5 together with the bonding nitrogen atom form m-orpholino and salts thereof where salt-forming groups are present, or (additionally or especially) the compounds of formula I, or salts thereof, wherein T is lower alkanoyloxy-lower alkylcarbonyl, such as acetyloxyacetyl, lower alkoxycarbonyllower alkoxy-lower alkylcarbonyl, such as methoxycarbonylmethoxy-acetyl, lower alkoxycarbonyl-lower alkylthio-lower alkylcarbonyl, such as methoxycarbonylmethylthio-acetyl, lower alkoxycarbonyl-lower alkylsulfo-lower alkylcarbonyl, such as methoxycarbonylmethylsulfo-acetyl, lower alkanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, such as pivaloyloxymethoxycarbonyl-methoxyacetyl or acetyloxynethoxycarbonylmetht :y-acetyl, carboxy-lower alkoxy-lower alkylcarbonyl, such as carboxy- S. methoxyacetyl, N-phenyl-lower alkoxycarbonylamino-lower alkylcarbonyl, such as 3-benzyloxycarbonylamino-propionyl, amino-lower alkylcarbonyl, such as 3-aminopropionyl, di-lower alkylamino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as [2-(2-dimethylaminothoxy)-ethoxy]-acetyl, N-phenyl-lower alkoxycarbonyl-amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-N-benzyloxycarbonylaminoethoxy)ethoxy-acetyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-aminoethoxy)ethoxy-acetyl, or tetrahydropyranyloxy-lower alkylcarbonyl, such as 2-(4-tetrahydropyranyloxy)-acety or or also 2(RS)-(4-tetrahydropyranyloxy)-propionyl and the remaining radicals are as defined immediately above.

Great preference is given to a compound of formula I' wherein T is an acyl radical of formula Z, as indicated above, wherein is hydrocarbyl wherein at least one carbon atom has been replaced by a hetero atom -34with the proviso that a hetero atom is not bonded directly to the carbonyl to which the radical RZ is bonded, alkyl having two or more carbon atoms, lower alkenyl, lower alkynyl or aryl, preferably as defined above, especially wherein RZ is heterocyclyl bonded via a ring carbon atom and selected from pyrrolyl, pyrrolyl, indolyl, indolizinyl, isoindolyl, pyrrolidinyl, such as pyrrolidin-3-yl or especially pyrrolidin-2-yl (in the or preferably the or (S)-configuration), hydroxypyrrolidinyl, such as 3- or especially 4-hydroxypyrrolidinyl, furyl, such as furan-3-yl or especially furan-2-yl, tetrahydrofuryl, thienyl, cyclohepta[b]pyrrolyl, imidazolyl, such as imidazol-2-yl, imidazol-3-yl or especially imidazol-5-yl, N-triphenyl-lower alkyl-imidazolyl, such as N-triphenylniethyl-imidazolyl, pyrazolyl, especially pyrazol-3-yl, oxazolyl, isoxazolyl, such as isoxazol-3-yl or -5-yi, thiazolyl, isothiazolyl, such as isothiazol-3-yl or -5-yl, triazolyl, such as 1,2,3-triazol-4- or -5-yl or 1,2,4-triazol-5-yl, tetrazolyl, pyridyl, such as pyridin-4-yl or -3-yl or especially pyridin-2-yl, quinolyl, such as quinolin-2-yl, isoquinolyl, especially isoquinolin-l-yl or -3-yl, piperidyl, especially piperidin-2-yl, y-pyranyl, 4,5-dihydropyranyl, 4H-chromenyl, chromanyl, y-thiopyranyl, pyridazinyl, cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, pyrimidinyl, pyrazinyl, phenazinyl, phenoxazinyl, phenothiazinyl, mo.pholinyl and thiazinyl, each of which is substituted by up to three radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tripheny] lower alkyl, such as triphenylmethyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, such as benzyloxy, diphenylmethoxy or triphenylmethoxy, hydroxy-lower alkyl, such as hydroxymethyl, halogen, such as fluorine, chlorine or bromine, cyano, lower alkoxycarbonyl, such as methoxy- or tert- S butoxy-carbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl and halolower alkyl, such as chloromethyl or trifluoromethyl, or preferably is unsubstituted, and S each of which is bonded via a ring carbon atom; very special preference being given to S those of the mentioned radicals which contain a ring hetero atom directly adjacent to the bonding ring carbon atom, more especially the radicals furan-2-yl, or (R)-pyrrolidin- 2-yl and imidazol-4-yl, pyridin-2-yl, -3-yl or -4-yl, or isoquinolin-3-yl; or additionally or especially tetrahydropyranyl; or RZ is lower alkyl (especially methyl, ethyl, n-propyl or n-butyl) which is substituted by at least one radical selected from lower alkoxy, such as methoxy, ethoxy or n-butoxy; lower aikoxy, such as methoxy, ethoxy or n-butoxy, substituted by one or two substituents, especially aryl, more espe- 4-, cially phenyl, naphthyl, lower alkoxy, such as ethoxy or methoxy, lower alkylthio, such as methylthio or ethylthio, lower alkoxy-lower adkoxy, such as 2-methoxyethoxy, lower alkylthio-lower alkoxy, such as 2-methylthioethoxy, aryloxy or arylthio, especially phenyloxy or m- or p-chlorophenyloxy, for example p-chlorophenyloxy, amino, N-lower alkylamino or N,N-di-lower alkylamino, such as 2-amino, 2-(N-lower alkyl)amino or 2-(N,N-di-lower alkyl)amino, for example 2-dimethylamino, and/or heterocyclyl as last defined for heterocyclyl RZ bonded via a ring carbon atom, especially 3- or 4-pyridyl; aryloxy, especially phenyloxy; lower alkylthio, such as methylthio, ethylthio or n-butylthio; lower alkylthio, such as methylthio, ethylthio or n-butylthio, substituted by one or two substituents, especially aryl, more especially phenyl or naphthyl; arylthio, such as phenylthio; amino or amino substituted by one or two radicals selected from lower alkyl, such as methyl, heterocyclyl-lower alkyl wherein heterocyclyl o is as defined for heterocyclyl RZ bonded via a ring carbon atom, especially heterocyclylmethyl, such as imidazolylmethyl, for example 4-imidazolylmethyl, or pyridylmethyl, for example 3- or 4-pyridylmethyl, each bonded via a ring carbon atom, aryl-lower alkyl, such as phenyl- or naphthyl-lower alkyl, for example phenyl- or naphthyl-methyl, .*,lower alkanoyl, such as acetyl, lower alkoxycarbonyl, such as tert-butoxycarbonyl, and aryl-lower alkoxycarbonyl, such as phenyl-lower alkoxycarbonyl, for example benzyloxycarbonyl, with especially one of the substituents of amino being lower alkyl, Sespecially methyl, and the other being hydrogen or one of the radicals mentioned above Sas substituents of amino; heterocyclyl as defined above for heterocyclyl RZ bonded via a ring carbon atom, especially as pyridin-2-yl, -3-yl or -4-yl; and heterocyclyl-lower alkyl wherein lower alkyl is preferably methyl, 1- or 2-ethyl or 3-propyl and wherein heterocyclyl is as defined above for heterocyclyl RZ bonded via a ring carbon atom but may also be bonded via a ring nitrogen atom, especially imidazol-1-yl, imidazol-2-yl, or more especially imidazol-4-yl, N-triphenyl-lower alkylimidazolyl, such Sas N-triphenylmethyl-imidazol-5-yl or especially -4-yl, or pyrazolyl, such as pyrazol-1-yl, -3-yl, -4-yl or -5-yl; or (additionally or preferably) lower alkoxycarbonyl, such as methoxycarbonyl; lower alkanoyloxy-lower alkoxycarbonyl, such as pivaloyloxymethoxycarbonyl or acetyloxymethoxycarbonyl; carboxy; phenyl-lower alkoxycarbonylamino-lower alkoxy, such as 2-(benzyloxycarbonylamino)-ethoxy; amino-lower alkoxy, such as 2-aminoethoxy; di-lower alkylamino-lower alkoxy, such as 2-(dimethylamino)-ethoxy; or N,N-di-lower alkylamino-lower alkoxy, such as 2-(dimethylamino)-ethoxy; lower alkoxycarbonyl-lower alkylsulfo, such as methoxycarbonyl-methylsulfo; lower alkanoyloxy, such as acetyloxy; and tetrahydropyranyloxy, such as 4-tetrahydropyranyloxy,

I--

-36and which may also carry as a further substituent aryl, which is as defined below; or R' is aryl, especially chlorophenyl, chloro-lower alkylphenyl, such as m- or p-chloromethylphenyl, p-morpholinomethyl-phenyl, p-thiomorpholinomethyl-phenyl, or also phenyl; aryl in the said definitions being especially phenyl, naphthyl, such as 1- or 2-naphthyl, or fluorenyl, such as 9-fluorenyl, that is unsubstituted or substituted by up to three radicals selected independently of one another from lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower al-koxy, such as benzyloxy, diphenylmethoxy or wriphenylmethoxy, hydi -,y-lower alkyl, such as hydroxymethyl, halogen, such as fluorine, chlorine or bromine, cyano, lower alkoxycarbonyl, such as methoxy- or tert-butoxy-carbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, halo-lower alkyl, such as chloromethyl or trifluoromethyl, piperidinomethyl, piperazin-1-ylmethyl, 4-lower alkylpiperazin-l1-yl-methyl, such as 4-methyl- or 4-ethyl-piperazin- 1-ylmethyl, morpholinomethyl or thiomorpholinomethyl, and nitro, which may be present independently of one another, and being especially correspondingly substituted phenyl; T in the most preferred form being in the form of pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, such as or (S)-pyrrolidin-2-ylcarbonyl or (L)-prolyl), furan-3- or especially furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or especially pyridyl-2-ylcarbonyl, isoquinolin- 1 or especially isoquinolin-3-ylcarbonyl, pyrazin-2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, such as methoxyacetyl, n-butoxyacetyl or 3-methoxypropionyl, phenyl- or naphthyl-iower aLkoxy-lower alkylcarbonyl, such as benzyloxyacetyl, a-lower alkoxy-aphen yl-lower alkylcarbonyl, such as or (S)-a-methoxy-cx-phenylacetyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(methoxyethoxy)acetyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-(methoxyethoxy)ethoxy)acetyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-dilower alkylamino-lower alkoxy-lower alkylcarbonyl, such as 2-(N,N-dimethylamino)ethyloxyacetyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, such as pyridin- 2-ylmethoxyacetyl, phenyloxy-lower alkylcarbonyl, such as phenoxyacetyl, lower alkylthio-lower alkylcarbonyl, such as mnethylthioacetyl, phenyl-lower alkylthio-lower alkylcarbonyl, such as benzylthioacetyl, N,N-di-lower alkylamino-lower alkylcarbonyl, such as N,N-dimethylamino-acetyl, -3-propionyl or -4-butyryl, N-lower alkylamino-lower alkylcarbonyl, such as N-methylamino-acetyl or -3-propionyl, N-imidazol(-2-, or 37 methyl- N-lower alkylamino-lower alkylcarbonyl, such as N-(imidazol-4-ylmethyl)- N-methylaminoacetyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, such as N-pyridin-2-ylmethyl-N-methylaminoacetyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino-lower alkylcarbonyl, such as N-benzyloxycarbonyl- N-methylaminoacetyl, imidazol(-l1-, or -5-)yl-lower alkylcarbonyl, such as 3- (imidazol-4-yl)propionyl, or N-triphenyl-lower alkylimidazol(-4- or -5-)yl-lower alkylcarbonyl, such as 3-(N-triphenylmethylimidazol-4-yl)propionyl, or pyrazol(-1-, or alkylcarbonyl, such as pyrazol- 1 ylacetyl, or also in the form of halo-lower alkylbenzoyl, such as p-chloromethylbenzoyl, p-(morpholino- or thiomorpholino-methyl)benzoyl or benzoyl, especially in the form of methoxyacetyl or in the form of 2-pyridylcarbonyl; or (additionally or especially) lower alkanoyloxy-lower alkylcarbonyl, such as acetyloxyacetyl, lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, such as methoxycarbonylmethoxy-acetyl, lower alkoxycarbonyl-lower alkylthio-lower alkylcarbonyl, such as methoxycarbonylmethylthio-acetyl, Lower alkoxycarbonyl-lower alkylsulfo-lower alkyicarbonyl, such as methoxycarbonylmethylsulfo-acetyl, lower ailcanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, such as pivaloyloxy- ~:methoxycarbonyl-methoxyacetyl or acetyloxymethoxycarbonylmethoxy-acetyl, carboxylower alkoxy-lower alkylcarbonyl, such as carboxymethoxyacetyl, N-phenyl-lower alkoxycarbonylamino-lower alkylcarbonyl, such as 3-benzyloxycarbonylamino-propionyl, amino-lower alkylcarbonyl, such as 3-aminopropionyl, di-lower aikylamino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as [2-(2-dimethylaminoethoxy)-ethoxy]acetyl, N-phenyl-lower alkoxycarbonyl-aminolower alkoxy-lower alkoxy-lower alkyl- 0 carbonyl, such as 2-(2-N-benzyloxycarbonylaminoethoxy)ethoxy-aceiyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, such as 2-(2-aminoethoxy)ethoxy-acetyl, or tetrahydropyranyloxy-lower alkylcarbonyl, such as 2-(4-tetrahydropyranyloxy)-acetyl or or also 2(R,S)-(4-tetrahydropyranyloxy)-propionyi; and wherein either (especially preferred) R, is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is phenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2

A

2 is the bivalent resiue of phienylalanine bonded N-terminally to A, and C-terminally to the group -NR 4

R

5 and R 4 and

R

5 together with the bonding nitrogen atom form mnorpholino; or R, is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-methoxyphenyl; A, is the 3S bivalent residue utI (L)-valine bonded N-terminally to the group -C=0 and C-terminally to A 2

A

2 is the bivalent residue of p-methoxy-phenylalanine 3 O-Phe)-) bonded N-terminally to and C-terminally to the group -NR 4

R

5 s; and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or R, is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-fluorophenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=0 and C-terminally to

A

2

A

2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4

R

5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or R, is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-fluorophenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=0 and C-terminally to

A

2

A

2 is the bivalent residue of p-methoxy-phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4

R

5 and R 4 and R 5 together with the bonding nitrogen atom form niorpholino; or (especially preferred) R, is tert-butoxycarbonyl; B, is a bond; R 2 is phen~yl; R(3 is p-methoxyphenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to .A 2

A

2 is the bivalent residue of phenylalaninebonded N-terminally to A, and C-terminally to the group -NR 4

R

5 and R 4 and

R

5 together with the bonding nitrogen atom form morpholino; and pharmaceutically acceptable salts thereof where salt-forming groups are present.

Very special preference is given to a compound of formula P' wherein T is 4(S)- (2-furanylcarboxy); 4(S)-[4-(dimethiyl-amino)-butyryloxy]; 4(S)-(N-Z-N-methyl-aminoacetyloxy); 4(S)-(methylamino-acetyloxy); 4(S)-[N-(imidazole-4-methyl)-N-methylaminoaLetyloxy]; -triphenylmethyl-imidazol-4-yl)-propionyloxy]; imidazolyl)-propionyloxy]; 4(S)-(methoxy-acetyloxy); 4(S)-(2-picolinoyl); 4(S )-(benzyloxy-acetyloxy); 4(S)-[(S)-cx-methoxy-a-phenyl-acetyloxy]; 4(S)-[(R)-a-methoxy- (x-phenyl-acetyloxy]; 1-,pyrazolylacetyloxy); 4(S)-(isoquinoline-3-carbonyloxy); 4(S)-(pyrazinecarbonyloxy); 4(S)-(4-ct-chloromethyl-benzo),oxy)3 4(S)-[4-(4-morpholino)methyl-benzoyloxy]; 4(S)-(isonicotinoyloxy); 4(S)-(nicotl,,oyloxy); 4(S)-(3-methoxypropanoyloxy); 4(S)-[(4-chlorophenoxy)methoxyacetyloxy]; 4(S)-[2-(2-methoxyethoXy)acetyloxy]; 4(S)-(butyloxyacetyloxy); (2-methoxyethoxy)ethoy~y] acetyloxy)l; 0 -39- 4 (S)-(methoxyacetyloxy); 4(S)-(phenoxyacetyloxy); 4(S)-Ij(S )-a-methoxy-ax-phenylacetylb oxy); [(R)-ax-methoxy-a-phenylacetyloxy]; (N,N-dimethyl-aminoacetyloxy); 4(S)- [N-(pyridine-2-methyl)-N4-methyl-aminoacetyloxy]; 4(S)-[3-(dimethyl-amino)-propionyloxy]; 4(S)-[3-(N-Z-N-methyl-amino)-propionyloxy]; 4(S)-(3-methyl-amino-propionyloxy); 4(S)-[(dimethylaminoethoxy)-acetyloxy]; 4(S)-[(27pyridylmethioxy)-acetyle'7yJ; 4(S )-(methoxy-acetyloxy),; 4(S)-(pyridine-2-carboxy); 4(S)-(methylthioacetylo: t (benzylthioacetyloxy); 4(S)-((L)-prolyloxy); 4(S)-((D)-prolyloxy); r*oy) oxy); 4(S)-((D)-(N-Z-prolyl)oxy); 3-(N-Z-amino)-propionyloxy; 3-amino-propionyloxy; (3-dimethylamino-propoxy)-acetyloxy; 2-(2-dimethylamino-ethoxy)-ethoxy-acetyloxy; (4-dimethylamino-butoxy)-acetyloxy; (2-benzyloxy)acetyloxy; (2-acetyloxy)acetyloxy; 2-(4-tetrahydropyranyloxy)acetyloxy; 2(R)-(4-tetrahydropyranyloxy)-propionyloxy; 2-(2amino-ethoxy)ethoxy-acetyloxy); 2-(2-benzyloxycarbonylamino-ethoxy)ethoxy-acetyloxy; (methoxycarbonyl-methoxy)-acetyloxy; (methoxycarbonyl-methylthio)-acetyloxy; (methoxycarbonyl-methylsulfo)-acetyloxy; (pivaloyloxymethoxycarbonyl)-methoxy -acetyl; (carboxymethoxy)-acetyloxy; or (acetoxymethoxycarbonyl-methoxy)-acetyloxy; and R, is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is phenyl; A 1 is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2

A

2 is the bivalent residue of phentylalanine bonded N-terminally to A, and C-terminally to the group -NR 4

R

5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or the compound of formula I' whereinT1 is as last defined, and has especially one of the mentioned meanings, and R, is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-methoxyphenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2

A

R

5 and R 4 and R 5 togetherwith the bonding nitrogen atom form morpholino; or in each case a pharmaceutically acceptable salt thereof where salt-forming groups are present.

Greater preference is given to a compound of formula 1' wherein T is methoxyacetyl or pyridin-2-ylcarbonyl and 40 either R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is phenyl; A 1 is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to

A

2

A

2 is the bivalent residue of phenylalanine bonded N-terminally to A 1 and C-terminally to the group -NR 4

R

5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino (especially preferred); or R 1 is tert-butoxycarboayl; B 1 is a bond; R 2 is phenyl; R 3 is p-methoxyphenyl; A 1 is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to

A

2

A

2 is the bivalent residue of p-methoxy-phenylalanine bonded N-terminally to A 1 and C-terminally to the group -NR 4

R

5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; S' or R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-fluorophenyl; A 1 is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to

A

2

A

2 is the bivalent residue of phenylalanine bonded N-terminally to A 1 and C- terminally to the group -NR 4 R; an and and R 5 together with the bonding nitrogen atom form morpholino; or R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-fluorophenyl; A 1 is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to

A

2

A

2 is the bivalent residue of p-methoxy-phenylalanine bonded N-terminally to A t and C-terminally to the group -NR 4

R

5 and R 4 and R 5 together with the bonding nitrogen atom S* form morpholino; or R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R3 is p-methoxyphenyl; A 1 is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to

A

2

A

R

5 and R 4 and R5 together with the bonding nitrogen atom form morpholino (especially preferred); and pharmaceutically acceptable salts thereof where salt-forming groups are present.

Greatest preference is given to all compounds of formula I' or the individual compounds of formula I' mentioned in the Examples and the pharmaceutically acceptable salts thereof where salt-forming groups are present.

I

-41- The compounds of formula I' and salts of those compounds having at least one saltforming group are obtained in accordance with processes known per se, for example as follows: a) for the preparation of a compound of formula

H

A

2

R

S

5S 0 wherein R 1 has the meanings given for R 1 in compounds of formula I' with the exception of hydrogen, the hydroxy group present at the carbon atom adjacent to the carbon atom carrying the radical R 2

-CH

2 is in free or protected form and the remaining radicals are as defined for compounds of formula an acid of formula

R

1

'-OH

or a reactive acid derivative thereof, wherein R 1 has the meanings given for R 1 in compounds of formula I' with the exception of hydrogen, is condensed with an amino compound of formula 0* 50 a

N

H-BI H B 1 or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula free functional groups in the starting materials of fonnulae II and III', with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or b) for the preparation of a compound of formula 42-

H

R BN

B

1 2 R 5 wherein B 1 may be the same residues as B 1 in compounds of formula I' but may not be a bond, the hydroxy group present at the carbon atom adjacent to the carbon atom carrying the radical R 2

-CH

2 is in free or protected form and the remaining radicals are as defined for compounds of formula a carboxylic acid of formula

R

1

-BI'-OH

(IV),

0* 0 or a reactive acid derivative thereof, wherein R 1 is as defined for compounds of formula I' and B 1 is as last defined, is condensed with an amino compound of formula

H

N

H/

A 2 1 Az 'eR en 0.

C

or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula free functional groups in the starting materials of formulae IV and with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or c) a carboxylic acid of formula

H

R, \N.

B

1

(VI),

or a reactive derivative thereof, wherein the radicals are as defined for compounds of

I:-

-43formula is condensed with an amino compound of formula A, NR4 H A 2

(VII),

or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula free functional groups in the starting materials of formulae VI' and VII, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or d) for the preparation of a compound of formula o o 0

H

R BN

B,

A

1 N

R

A

2

R

a wherein A 1 and A 2 are as defined for A 1 and A 2 in compounds of formula but A 1 is not a bond and the peptide bond between A 1 and A 2 is not in reduced form, the hydroxy group present at the carbon atom adjacent to the carbon atom carrying the radical R 2

-CH

H

R, N

B

1

A'OH

'OH

-44or a reactive derivative thereof, wherein the radicals are as last defined, is condensed with an amino compound of formula H A 2 N or with a reactive derivative thereof, wherein the radicals are as last defined, free functional groups in the starting materials of formulae VIII' and IX, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or e) a carboxylic acid of formula

T

H R3 R N

OH

A -2 R2 or a reactive derivative thereof, wherein the radicals are as defined for compounds of formula is condensed with an amino compound of formula R4 H H R5 (XI), or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula free functional groups in the starting materials of formulae X' and XI, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or f) in a compound of formula I' wherein the substituents are as defined above with the proviso that in the compound of formula I' in question at least one functional group is protected by protecting groups, the protecting groups are removed, or g) a compound of formula I H OH

R

RR

B

1 R2 wherein the radicals are as defined for compounds of formula is reacted with a S° carboxylic acid of formula XXV T-OH

(XXV),

wherein T is as defined for compounds of formula or with a reactive acid derivative thereof, free functional groups in the starting materials of formulae XXV and I, with the exception of those participating in the reaction, being if necessary in protected form, and, S* if desired, any protecting groups present are removed, or h) for the preparation of a compound of formula I' wherein T is a radical of formula Z wherein Rz is lower alkyl substituted by etherified or esterified hydroxy or mercapto, by unsubstituted or substituted amino or by heterocyclyl bonded via nitrogen, and the remaining radicals are as defined for compounds of formula a compound of formula 0

W,

(C mH2m) O C

R

3 H 0

R

4 (XXVI) BR A -i O wherein W 1 is a leaving group, -(CmH2m)- is a lower alkylene radical (m is from 1 to 7) I, -46and the r eaining radicals are as defined for compounds of formula is reacted with a compound of formula L-h (XXVII), wherein L is etherified or esterified hydroxy or mercapto, unsubstituted or substituted amino, or heterocyclyl bonded via nitrogen, or with a reactive derivative thereof, free functional groups in the starting materials of formulae XXVI and XXVII, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, and/or, if desired, a compound of formula I' obtainable in accordance with any one of the above processes a) to h) having at least one salt-forming group is converted into its salt and/or an obtainable salt is converted into the free compound or into a different salt and/or isomeric mixtures of compounds of formula I' which may be obtainable are separated and/or a compound of formula I' according to the invention is converted into a different compound of formula I' according to the invention.

The above-defined processes are described in detail below: *00 *Process a) (Formation of an amide bond) 00 *0 o In starting materials of formulae II and III', functional groups, with the exception of groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

Protecting groups for functional groups in starting materials the reaction of which is to be avoided, especially carboxy, amino, hydroxy, mercapto and sulfo groups, include especially those protecting groups (conventional protecting groups) which are customarily used in the synthesis of peptide compounds, and also in the synthesis of cephalosporins and penicillins as well as nucleic acid derivatives and sugars. Those protecting groups may already be present in the precursors and are intended to protect the functional groups in question against undesired secondary reactions, such as acylation, etherification, esterification, oxidation, solvolysis, etc.. In certain cases the protecting groups can additionally 47cause the reactions to proceed selectively, for example stereoselectively. It is characteristic of protecting groups that they can be removed easily, i.e. without undesired secondary reactions taking place, for example by solvolysis, reduction, photolysis, and also enzymatically, for example also under physiological conditions. Protecting groups may also be present in the end products, however. Compounds of formula I' having protected functional groups may have greater metabolic stability or pharmacodynamic properties that are better in some other way than the corresponding compounds having free functional groups.

The protection of functional groups by such protecting groups, the protecting groups themselves and the reactions for their removal are described, for example, in standard works such as J. F. W. McOmie, "Protective Groups in Organic Ch. ,..istry", Plenum Press, London and New York 1973, in Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, in "The Peptides", Volume 3 Gross and J. Meienhofer, eds.), i: Academic Press, London and New York 1981, in "Methoden der organischen Chemie", Houben-Weyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.

Jakubke and H. Jescheit, "Aminosiuren, Peptide, Proteine" ("Amino acids, peptides, proteins"), Verlag Chemie, Weinheim, Deerfield Beach and Basle 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" ("The Chemistry of Carbohydrates: monosaccharides and derivatives"), Georg Thieme Verlag, Stuttgart 1974.

A carboxy group is protected, for example, in the form of an ester group which can be Scleaved selectively under mild conditions. A carboxy group protected in esterified form is esterified especially by a lower alkyl group that is preferably branched in the 1-position of the lower alkyl group or substituted in the 1- or 2-position of the lower alkyl group by suitable substituents.

A protected carboxy group esterified by a lower alkyl group is, for example, methoxycarbonyl or ethoxycarbonyl.

A protected carboxy group esterified by a lower alkyl group that is branched in the 1-position of the lower alkyl group is, for example, tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl.

A protected carboxy group esterificd by a lower alkyl group that is substituted in the 1- or -48- 2-position of the lower alkyl group by suitable substituents is, for example, arylmethoxycarbonyl having one or two aryl radicals, wherein aryl is phenyl that is unsubstituted or mono-, di- or tri-substituted, for example, by lower alkyl, for example tert-lower alkyl, such as tert-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for example chlorine, and/or by nitro, for example benzyloxycarbonyl, benzyloxycarbonyl substituted by the mentioned substituents, for example 4-nitrobenzyloxycarbonyl or 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl substituted by the mentioned substituents, for example di(4-methoxyphenyl)methoxycarbonyl, and also carboxy esterified by a lower alkyl group, the lower alkyl group being substituted in the 1or 2-position by suitable substituents, such as 1-lower alkoxy-lower alkoxycarbonyl, for example methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxycarbonyl, 1-lower alkylthio-lower alkoxycarbonyl, for example 1-methylthiomethoxy- S"carbonyl or 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is benzoyl that is unsubstituted or substituted, for example, by halogen, such as bromine, for I- example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, as well as 2-(tri-substituted silyl)-lower alkoxycarbonyl wherein the substituents are each independently of the others an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon radical that is unsubstituted or substituted, for exar -le, by lower alkyl, lower alkoxy, aryl, halogen and/or by nitro, for example lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl each of which is unsubstituted or substituted as above, for example 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, for example 2-trimethyla, silylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-triarylsilylethoxycarbonyl, such as triphenylsilylethoxycarbonyl.

A carboxy group may also be protected in the form of an organic silyloxycarbonyl group.

An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, for example trimethylsilyloxycarbonyl. The silicon atom of the silyloxycarbonyl group can also be substituted by two lower alkyl groups, for example methyl groups, and by an amino group or carboxy group of a second molecule of formula P. Compounds having such protecting groups can be prepared, for example, using dimethylchlorosilane as silylating agent.

A carboxy group may also be protected in the form of an internal ester with a hydroxy group present in the molecule suitably spaced from the carboxy group, for example in the y-position with respect to the carboxy group, that is to say in the form of a lactone, prefer- 49 ably a y-lactone.

A protected carboxy group is preferably tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl or diphenylmethoxycarbonyl, or a carboxy group protected in the form of a lactone, especially a y-lactone.

A protected amino group may be protected by an amino-protecting group, for example in the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-lower alk- 1 -enylamino or silylamino group or in the form of an azido group.

In an acylamino group, acyl is, for example, the acyl radical of an organic carboxylic acid having, for example, up to 18 carbon atoms, especially an unsubstituted or substituted, for example halo- or arylysubstituted, lower alkanecarboxylic acid or an unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoic acid, or, preferably, of a carbonic acid semiester. Such acyl groups are preferably lower alkanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower alkanoyl, for example 2-haloacetyl, such as 2-chloro-, 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichioro-acetyl, unsubstituted or substituted, for example halo-, lower alkoxy- or nitro-substituted, benzoyl, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, lower alkoxycarbonyl, preferably lower alkoxycarbonyl that is branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, for example tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl, arylmethoxycarbonyl having one, two or three aryl radicals which are phenyl that is unsubstituted or mono- or poly-substituted, for example, by lower alkyl, especially tert-lower alkyl, such as tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as chlorine, and/or by nitro, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, 9-fluorenylmethoxycarbonyl or di(4-methoxyphenyl)methoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl group is preferably benzoyl that is unsubstituted or substituted, for example, by haloge 7, such as bromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, 2-(tri-substituted silyl)-lower alkoxycarbonyl, for example 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-trimethylsilylethoxycarbonyl or 2-(di-n-butylmethyl-silyl)-ethoxycarbonyl, or triarylsilyl-lower alkoxycarbonyl, for example 2-triphenylsilylethoxycarbonyl.

In an arylmethylamino group, for example a moin;-, di- or especially tri-arylmethylamino group, the aryl radicals are especially unsubstituted or substituted phenyl radicals. Such groups are, for example, benzyl-, diphenylmethyl- or especially trityl-amino.

In an etherified mercaptoamino group the mercapto group is especially in the form of substituted arylthio or aryl-lower alkylthio, wherein aryl is, for example, phenyl that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, for example 4-nitrophenylthio.

In a 2-acyl-lower alk-1-enyl radical that can be used as an amino-protecting group, acyl is, for example, the corresponding radical of a lower alkanecarboxylic acid, of a benzoic acid that is unsubstituted or substituted, for example, by lower alkyl, such as methyl or tertbutyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitro, or especially of a carbonic acid semiester, such as a carbonic acid lower alkyl semiester. Corresponding protecting groups are especially 1-lower alkanoyl-lower alk-l-en-2-yl, for S" example 1-lower alkanoyl-prop-l-en-2-yl, such as 1-acetyl-prop-1-en-2-yl, or lower alkoxycarbonyl-lower alk- 1 -en-2-yl, for example lower alkoxycarbonyl-prop- 1-en-2-yl, such as 1-ethoxycarbonyl-prop-l-en-2-yl.

A silylamino group is, for example, a tri-lower alkylsilylamino group, for example trimethylsilylamino or tert-butyl-dimethylsilylamino. The silicon atom of the silylamino group can also be substituted by only two lower alkyl groups, for example methyl groups, and by the amino group or carboxy group of a second molecule of formula Compounds having such protecting groups can be prepared, for example, using the corresponding chlorosilanes, such as dimethylchlorosilane, as silylating agents.

An amino group can also be protected by conversion into the protonated form; suitable corresponding anions are especially those of strong inorganic acids, such as sulfuric acid, phosphoric acid or hydrohalic acids, for example the chlorine or bromine anion, or of organic sulfonic acids, such as p-toluenesulfonic acid.

Preferred amino-protecting groups are lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-lower alk-l-en-2-yl and lower alkoxycarbonyl-lower alk-l-en-2-yl, especially tert-butoxycarbonyl and benzyloxycarbonyl.

-51 A hydroxy group can be protected, for example, by an acyl group, for example lower alkanoyl that is unsubstituted or substituted by halogen, such as chlorine, such as acetyl or 2,2-dichloroacetyl, or especially by an acyl radical of a carbonic acid semiester mentioned for protected amino groups. A hydroxy group can also be protected by tri-lower alkylsilyl, for example trimethylsilyl, triisopropyisilyl or tert-butyl-dimethylsilyl, a readily removable etherifying group, for example an alkyl group, such as tert-lower alkyl, for example tert-butyl, an oxa- or a thia-aliphatic or -cycloaliphatic, especially 2-oxa- or 2-thia-aliphatic or -cycloaliphatic, hydrocarbon radical, for example 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, such as methoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or 1-ethylthioethyl, or 2-oxa- or 2-thia-cycloalkyl having from 5 to 7 ring atoms, such as 2-tetrahydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analogue, and also by 1-phenyl-lower alkyl, such as benzyl, diphenylmethyl or trityl, wherein the phenyl radicals can be substituted, for example, by halogen, for example chlorine, lower alkoxy, for example methoxy, and/or by nitro. A preferred hydroxy-protecting group is, for example, 2,2,-trichloroethoxycarbonyl, 4-nitrobenzyl- S" oxycarbonyl, diphenylmethoxycarbonyl, benzyl or trityl.

i Two hydroxy groups, especially adjacent hydroxy groups, occurring in a molecule, or a hydroxy group and an amino group that are adjacent to one another, can be protected, for example, by bivalent protecting groups, such as a methylene group that is preferably substituted, for example, by one or two lower alkyl radicals or by oxo, for example unsubstituted or substituted alkylidene, for example lower alkylidene, such as isopropylidene, cycloalkylidene, such as cyclohexylidene, a carbonyl group or benzylidene.

A hydroxy group adjacent to a carboxy group can be protected by the formation of an internal ester (lactone), especially a y-lactone.

Preferably a protected hydroxy group is protected by tri-lower alkylsilyl or in the form of a lactone, especially by tert-butyl-dimethyl-silyl or in the form of a y-lactone.

A mercapto group, for example in cysteine, can be protected especially by S-alkylation with unsubstituted or substituted alkyl radicals, by silylation, by thioacetal formation, by S-acylation or by the formation of asymmetric disulfide groupings. Preferred mercaptoprotecting groups are, for example, benzyl that is unsubstituted or substituted in the phenyl radical, for example by methoxy or by nitro, such as 4-methoxybenzyl, diphenylmethyl 52that is unsubstituted or substituted in the phenyl radical, for example by methoxy, such as di(4-methoxyphenyl)methyl, triphenylmethyl, pyridyldiphenylmethyl, tri',, 'vlsilyl, benzylthiomethyl, tetrahydropyranyl, acylaminomethyl, such as acetamidomr.,tyl, isobutyrylacetamidemethyl or 2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl or alkyl-, especially lower alkyl-aminocarbonyl, such as ethylaminocarbonyl, and also lower alkylthio, such as S-ethylthio or S-tert-butylthio, or S-sulfo.

A sulfo group can be protected, for example, by lower alkyl, fc- example methyl or ethyl, by phenyl or in the form of a sulfonamide, for example in the form of an imidazolide.

In the context of this Application, a protecting group, for example a carboxy-protecting group, is to be understood as being expressly also a polymeric carrier that is bonded in a readily removable manner to the functional group, for example the carboxy group, to be protected, for example a carrier suitable for the Merrifield synthesis. Such a suitable polymeric carrier is especially a polystyrene resin, weakly cross-linked by copolymerisation with divinylbenzene, that carries bridge members suitable for reversible bonding.

The acids of formula II are carboxylic acids or sulfonic acids.

The carboxylic acids of formula II either contain a free carboxy group or are in the form of a reactive derivative, for example in the form of an activated ester derived from the free carboxy compound, in the form of a reactive anhydride, or in the form of a reactive cyclic amide. The reactive derivatives may also be formed in situ.

Activated esters of compounds of formula II having a carboxy group are especially esters unsaturated at the linking carbon atom of the esterifying radical, for example of the vinyl ester type, such as vinyl esters (obtainable, for example, by transesterification of a corresponding ester with vinyl acetate; activated vinyl ester method), carbamoyl esters (obtainable, for example, by treatment of the corresponding acid with an isoxazolium d reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl esters (obtainable, for example, by treatment of the corresponding acid with a lower alkoxyacetylene; ethoxyacetylene method), or esters of the amidino type, such as N,N'-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with a suitable N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide; carbodiimide method), or N,N-disubstituted amidino esters (obtainable, for example, by treatment of the corresponding acid with an N,N-disubstituted cyanamide; cyanamide t.

53method), suitable aryl esters, especially phenyl esters substituted by electron-attracting substituents (obtainable, for example, by treatment of the corresponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-methylsulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-phenyldiazophenol, in the presence of a condensation agent; such as N,N'-dicyclohexylcarbodiimide; activated aryl esters method), cyanomethyl esters (obtainable, for example, by treatment of the corresponding acid with chloroacetonitrile in the presence of a base; cyanomethyl esters method), thioesters, especially unsubstituted or substituted, for example nitro-substituted, phenylthio esters (obtainable, for example, by treatment of the corresponding acid with unsubstituted or substituted, for example nitro-substituted, thiophenols, inter alia by the anhydride or carbodiimide method; activated thiol esters method), or especially amino or amido esters (obtainable, for example, by treatment of the corresponding acid with an N-hydroxyamino or N-hydroxyamido compound, for example N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbomene-2,3-dicarboxylic acid imide, 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-i,2,3-benzotriazin-4-one, for example by the anhydride or carbodiimide method; activated N-hydroxy esters method). Internal esters, for example y-lactones, can also be used.

Anhydrides of acids may be symmetric or preferably mixed anhydrides of those acids, for example anhydrides with inorganic acids, such as acid halides, especially acid chlorides (obtainable, for example, by treatment of the corresponding acid with thionyl chloride, phosphorus pentachloride or oxalyl chloride; acid chloride method), azides (obtainable, for example, from a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid; azide method), anhydrides with carbonic acid semiesters, for example carbonic acid lower alkyl semiesters (obtainable, for example, by treatment of the corresponding acid with chloroformic acid lower alkyl esters or with a 1-lower alkoxycarbonyl-2-lov'er alkoxy- 1,2-dihyd-oquinoline; mixed 0-alkylcarbonic acid anhydrides method), or anhydrides with dihalogenated, especially dichlorinated, phosphoric acid (obtainable, for example, by treatment of the corresponding acid with phosphorus S oxychloride; phosphorus oxychloride method), anhydrides with other phosphoric acid derivatives (for example those obtainable with phenyl-N-phenylphosphoramidochloridate or by reaction of alkylphosphoric acid amides in the presence of sulfonic acid anhydrides and/or racemisation-reducing additives, such as N-hydroxybenzotriazole, or in the presence of cyanophosphonic acid diethyl ester) or with phosphorous acid derivatives, or anhydrides with organic acids, such as mixed anhydrides with organic carboxylic acids (obtainable, for example, by treatment of the corresponding acid with an unsubstituted or Y;i 9- -54substituted lower alkane- or phenyl-lower alkane-carboxylic acid halide, for example phenylacetic acid chloride, pivalic acid chloride or trifluoroacetic acid chloride; mixed carboxylic acid anhydrides method) or with organic sulfonic acids (obtainable, for example, by treatment of a salt, such as an alkali metal salt, of the corresponding acid with a suitable organic sulfonic acid halide, such as a lower alkane- or aryl-, for example methane- or p-toluene-sulfonic acid chloride; mixed sulfonic acid anhydrides method) and symmetric ?nhydrides (obtainable, for example, by condensation of the corresponding r-id in the presence of a carbodiimide or 1-diethylaminopropyne; symmetric anhydrides method).

Suitable cyclic amides are especially amides having five-membered diazacycles of aromatic character, such as amides with imidazoles, for example imidazole (obtainable, for example, by treatment of the corresponding acid with N,N'-carbonyldiimidazole; imidazole method), or pyrazole, for example 3,5-dimethylpyrazole (obtainable, for example, via the acid hydrazide by treatment with acetylacetone; pyrazolide method).

As mentioned, derivatives of carboxylic acids that are used as acylating agents may also be formed in situ. For example, N,N'-disubstituted amidino esters may be formed in situ by reacting, for example in the presence of a suitable base, such as triethylamine, a mixture of the starting material of formula III' and the acid of formula II used as acylating agent, in the presence of a suitable N,N'-disubstituted carbodiimide, for example N,N'-cyclohexylcarbodiimide. In addition, amino nr amido esters of the acids used as acylating agents may be formed in the presence of the starting material of formula III' to 0 be acylated, by reacting a mixture of the corresponding acid and amino starting materials in the presence of an N,N'-disubstituted carbodiimide, for example N,N'-dicyclohexylcarbodiimide, and of an N-hydroxyamine or N-hydroxyamide, for example N-hydrox}- "0 succinimide, where appropriate in the presence of a suitable base, for example 4-dimethylamino-pyridine. Moreover, activation in situ can be achieved by reaction with N,N,N',N'-tetraalkyluronium compounds, such as O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate. Finally, phosphoric acid anhydrides of the carboxylic acids of formula II can be prepared in situ by reacting an alkylphosphoric acid amide, such as hexamethylphosphoric acid triamide, in the presence of a sulfonic acid anhydride, such as 4-toluenesulfonic acid anhydride, with a salt, such as a tetrafluoroborate, for example sodium tetrafluoroborate, or with another derivative of hexamethylphosphoric acid triamide, such as benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluoride, preferably in the presence of a racemisation-reducing additive, such as N-hydroxybenzotriazole.

The amino group of compounds of formula III' that participates in the reaction preferably carries at least one reactive hydrogen atom, especially when the carboxy group reacting therewith is present in reactive form; it may, however, itself have been derivatised, forexample by reaction with a phosphite, such as diethylchlorophosphite, 1,2-phenylenechlorophosphite, ethyl dichlorophosphite, ethylenechlorophosphite or tetraethylpyrophosphite. A derivative of such a compound having an amino group is, for example, also a carbamic acid halide, the amino group that participates in the reaction being substituted halocarbonyl, for example chlorocarbonyl.

Condensation to form an amide bond can be carried out in a manner known per se, for example as described in standard works, such as Houben-Weyl, "Methoden der organischen Chemie", 4th edition, Volume 15/II (1974), Volume IX (1955), Volume E 11 (1985), Georg Thieme Verlag, Stuttgart, "The Peptides" Gross and J. Meienhofer, eds.), Volumes 1 and 2, Academic Prcs;, London and New York, 1979/1980, or M. Bodansky, "Principles of Peptide Synthesis", Springer-Verlag, Berlin 1984.

The condensation of a free carboxylic acid with the corresponding amine can be carried out preferably in the presence of one of the customary condensation agents. Customary condensation agents are, for example, carbodiimides, for example diethyl-, dipropyl-, N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide or especially dicyclohexylcarbodiimide, also suitable carbonyl compounds, for example carbonylimidazole, 1,2.

oxazolium compounds, for example 2-ethyl-5-phenyl-l,2-oxazolium 3'-sulfonate and 2-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, for example 2-ethoxy- 1-ethoxycarbonyl-1,2-dihydroquinoline, N,N,N',N'-tetraalkyluronium S compounds, such as C benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate, also activated phosphoric acid derivatives, for example diphenylphosphoryl azide, diethylphosphoryl cyanide, phenyl-N-phenylphosphoroamidochloridate, bis(2-oxo- 3-oxazolidinyl)phosphinic acid chloride or 1-benzotriazolyloxy-tris(dimethylamino)phosphonium hexafluorophosphate.

In a manner analogous to the types of reaction mentioned for condensation for the carboxylic acids of formula II, in the condensation the sulfonic acids of formula II having a terminal sulfonyl group may also be reacted with compounds of formula II' to form the corresponding sulfonamides of formula Ib'.

-56- For example, it is possible to use activated sulfonic acid esters, for example the corresponding aryl esters, such as phenyl esters, especially those substituted by nitro groups, it being possible for the amine component of formula Ib' also to be used in the form of an alkali metal amide, for example an alkali metal arylamide, such as sodium anilineamide, or an alkali metal salt of nitrogen-containing heterocycles, for example potassium pyrrolide.

It is also possible to use reactive anhydrides, such as the corresponding symmetric acid anhydrides (which can be prepared, for example, by reaction of the alkylsulfonic acid silver salts with alkylsulfonyl chlorides) or, preferably, the corresponding asymmetric acid anhydrides, for example anhydrides with inorganic acids, such as sulfonyl halides, especially sulfonyl chlorides (obtainable, for example, by reaction of the corresponding sulfonic acids with inorganic acid chlorides, for example thionyl chloride, sulfuryl chloride or phosphorus pentachloride), with organic carboxylic acids (obtainable, for example, by treatment of a sulfonic acid halide with the salt of a carboxylic acid, such as S. an alkali metal salt, analogously to the above-mentioned method for the preparation of mixed acid anhydrides), or azides (obtainable, for example, from a corresponding sulfonic acid chloride and sodium azide or via the corresponding hydrazide and treatment thereof with nitrous acid analogously to the above-mentioned azide method).

If desired, an organic base may be added, for example a tri-lower alkylamine having bulky radicals, such as ethyl diisopropylamine, and/or a heterocyclic base, for example pyridine, S 4-dimethylaminopyridine or preferably N-methylmorpholine.

The condensation of activated esters, reactive anhydrides or reactive cyclic amides with the corresponding amines is customarily carried out in the presence of an organic base, for example simple tri-lower alkylamines, for example triethylamine or tributylamine, or one of the above-mentioned organic bases. If desired, a condensation agent is additionally used, for example as described for free carboxylic acids.

The condensation of acid anhydrides with amines can be effected, for example, in the presence of inorganic carbonates, for example ammonium or alkali metal carbonates or hydrogen carbonates, such as sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate), while the reaction of suifonic acid halides, such as sulfonic acid chlorides, can be carried out in the presence of hydroxides, for example -57alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide.

Carboxylic acid chlorides, for example the chlorocarbonic acid derivatives derived from the acid of forr.. la II, are condensed with the corresponding amines preferably in the presence of an organic amine, for example the above-mentioned tri-lower alkylamines or heterocyclic bases, where appropriate in the presence of a hydrogen sulfate.

The condensation is preferably carried out in an inert, aprotic, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, for example formamide or dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in a mixture thereof, as appropriate at reduced or elevated temperature, for example in a temperature range of from approximately -40 0 C to approximately +100 0 C, preferably from approximately -10°C to approximately +50 C, and m ithout an inert gas or under an inert gas atmosphere, for example a nitrogen or argon atmosphere.

Aqueous, for example alcoholic, solvents, for example ethanol, or aromatic solvents, for example benzene or toluene, may also be used. When alkali metal hydroxides are present as basest acetone can also be added where appropriate.

The condensation can also be carried out in accordance with the technique known as solid-phase synthesis which originates from R. Merrifield and is described, for example, in Angew. Chem. 97, 801 817, (1985), Naturwissenschaften 71, 252 258 (1984) or in R. A.

Houghten, Proc. Natl. Acad. Sci. USA 82, 5131 5135 (1985).

The freeing of functional groups protected by protecting groups in the resulting compounds of formula I' having protected functions is effected in accordance with one or more of the methods mentioned under ProcesAs f).

Process b) (Formation of an amide bond) In starting materials of formulae IV and functional groups, with the exception of the groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

FI

0 -58- The protecting groups, ther free carboxylic acids and the reactive derivatives thereof, the free amines and the reactive derivatives thereof and the processes used for condensation are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae II and III' except that carboxylic acids of formula IV are used instead of those of formula II and amino compounds of formula V' are used instead of those of formula Ill'.

The freeing of functional groups protected by protecting groups in the resulting compounds of formula I' having protected functions is effected in accordance with one or more of the methods mentioned under Process f).

Process c) (Formation of an amide bond) In starting materials of formulae VI' and VII, functional groups, with the exception of the groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups, the free carboxylic acids and th. reactive derivatives thereof, the free amines and the reactive derivatives thereof and the processes used for condensation are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae II and III' except that carboxylic acids of formula VI' are used instead of those of formula II and amino compounds of formula VII are used instead of those of formula IlI'.

Process d) (Formation of an amide bond) In starting materials of formulae VIII' and IX, functional groups, with the exception of the groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups, the free carboxylic acids and the reactive derivatives thereof, the

I

-59free amines and the reactive derivatives thereof and the processes used for condensation are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae II and III' except that carboxylic acids of formula VIII' are used instead of those of formula II and amino compounds of formula IX are used instead of those of formula III'.

Process e) (Formation of an amide bond) In starmung materials of formulae X' and XI, functional groups, with the exception of the groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

S. The protecting groups, the free carboxylic acids and the reactive derivatives thereof, the free amines and the reactive derivatives thlereof and the processes used for condensation are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae II and III' except that carboxylic acids of formula X' are used instead of those of formula II and amino compounds of formula XI are used instead of those of formula III'.

A reactive derivative of such a compound of formula XI having an amino group is, for example, also an isocyanate in which the amino group participating in the reaction has been modified in the form of an isocyanate group, in that case there being obtainable only compounds of formula I' that carry a hydrogen atom at the nitrogen atom of the amide group formed by the reaction.

The freeing of functional groups protected by protecting groups in the resulting 0 compounds of formula I' having protected functions is effected in accordance with one or more of the methods mentioned under Prccess f).

Process f) (Removal of protecting groups) The removal of protecting groups that are not constituents of the desired end product of

I

60 formula for example the carboxy-, amino-, hydroxy-, mercapto- and/or sulfo-protecting groups, is effected in a manner known per se, for example by means of solvolysis, especially hydrolysis, alcoholysis or acidolysis, or by means of reduction, especially hydrogenolysis or by means of other reducing agents, as well as photolysis, as appropriate stepwise or simultaneously, it being possible also to use enzymatic methods. The removal of the protecting groups is described, for example, in the standard works mentioned hereinabove in the section relating to protecting groups.

For example, protected carboxy, for example tert-lower alkoxycarbonyl, lower alkoxycarbonyl substituted in the 2-position by a trisubstituted silyl group or in the 1-position by lower alkoxy or by lower alkylthio, or unsubstituted or substituted diphenylmethoxycarbonyl can be converted into free carboxy by treatment with a suitable acid, such as formic acid, hydrogen chloride or trifluoroacetic acid, where appropriate with the addition of a nucleophilic compound, such as phenol or anisole. Unsubstituted or substituted benzyloxycarbonyl can be freed, for example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the presence of a metal hydrogenation catalyst, such as a palladium catalyst. In addition, suitably substituted benzyloxycarbonyl, such as 4-nitro- .benzyloxycarbonyl, can be converted into free carboxy also by reduction, for example by treatment with an alkali metal dithionite, such as sodium dithionite, or with a reducing metal, for example zinc, or a reducing metal salt, such as a chromium(II) salt, for example chromium(II) chloride, customarily in the presence of a hydrogen-yielding agent that, together with the metal, is capable of producing nascent hydrogen, such as an acid, especially a suitable carboxylic acid, such as an unsubstituted or substituted, for example hydroxy-substituted, lower alkanecarboxylic acid, for example acetic acid, formic acid, glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-chloromandelic acid or tartaric acid, or in the presence of an alcohol or thiol, water preferably being added. By treatment with a reducing metal o metal salt, as described above, 2-halo-lower alkoxycarbonyl (where appropriate after conversion of a 2-bromo-lower alkoxycarbonyl group into a corresponding 2-iodo-lower alkoxycarbonyl group) or aroylmethoxycarbonyl can also be converted into free carboxy. Aroylmethoxycarbonyl can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate or sodium iodide. 2-(tri-substituted silyl)-lower alkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl, can also be converted into free carboxy by treatment with a salt of hydrofluoric acid that yields the fluoride anion, such as an alkali metal fluoride, for example sodium or potassium fluoride, where appropriate in the presence of a macrocyclic polyether ("crown ether"), or with a fluoride of an organic quaternary base, such as tetra- -61lower alkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium fluoride, for example tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide. Carboxy protected in the form of organic silyloxycarbonyl, such as tri-lower alkylsilyloxycarbonyl, for example trimethylsilyloxycarbonyl, can be freed in customary manner by solvolysis, for example by treatment with water, an alcohol or an acid, or, furthermore, a fluoride, as described above. Esterified carboxy can also be freed enzymatically, for example by means of esterases or suitable peptidases, for example esterified arginine or lysine, such as lysinc methyl ester, using trypsin. Carboxy protected in the form of an internal ester, such as in the form of y-lactone, can be freed by hydrolysis in the presence of a hydroxidecontaining base, such as an alkaline earth metal hydroxide or, especially, an alkali metal hydroxide, for example NaOH, KOH or LiOH, more especially LiOH, the correspondingly protected hydroxy group being freed at the same time.

A protected amino group is freed in a manner known per se and, according to the nature of the protecting groups, in various ways, preferably by solvolysis or reduction. Lower alkoxycarbonylamino, such as tert-butoxycarbonylamino, can be cleaved in the presence of acids, for example mineral acids, for example a hydrogen halide, such as hydrogeli chloride or hydrogen bromide, especially hydrogen bromide, or sulfuric or phosphoric i* acid, preferably hydrogen chloride, in polar solvents, such as water or a carboxylic acid, such as acetic acid, or ethers, preferably cyclic ethers, such as dioxane; 2-halo-lower alkoxycarbonylamino (where appropriate after conversion of a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower alkoxycarbonylamino group), aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for example, by treatment with a suitable reducing agent, such as zinc in the presence of a suitable carboxylic acid, such as aqueous acetic acid. Aroylmethoxycarbonylamino can be cleaved also by treatment with a nucleophilic, preferably salt-forming, reagent, such as sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with an alkali metal dithionite, for example sodium dithionite. Unsubstituted or substituted diphenylmethoxycarbonylamino, tert-lower alkoxycarbonylamino or 2-(tri-substituted silyl)-lower alkoxycarbonylamino, such as 2-tri-lower alkylsilyl-lower alkoxycarbonylamino, can be cleaved by treatment with a suitable acid, for example formic acid or trifluoroacetic acid, for example in a halogenated hydrocarbon, such as methylene chloride or chloroform (especially when hydroxy protected by benzyl is not to be freed at the same time); unsubstituted or substituted benzyloxycarbonylamino can be cleaved, for example, by means of hydrogenolysi,, i.e. by treatment with hydrogen in the presence of a suitable hydrogena- -62tion catalyst, such as a palladium catalyst, for example bonded to a carrier, such as carbon, preferably in polar solvents, such as di-lower alkyl-lower alkanoylamides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower alkanoic acid lower alkyl esters, for example ethyl acetate, or alcohols, such as methanol, ethanol or propanol, with methanol being especially preferred, preferably approximately at room temperature; unsubstituted or substituted triarylmethylamino or formylamino can be cleaved, for example, by treatment with an acid, such as a mineral acid, for example hydrochloric acid, or an organic acid, for example formic, acetic or trifluoroacetic acid, where appropriate in the presence of water, and triphenylmethylamino can be cleaved especially by hydrogenolysis with a noble metal or noble metal oxide as catalyst, such as platinum, palladium or, especially, palladium hydroxide, the catalyst preferably being bonded to a carrier, such as carbon, silica gel or aluminium oxide, in inert solvents, such as an ether, preferably a lower alkyl-lower alkanoate, such as ethyl acetate, at temperatures of fromn 200 to 80°C, especially from 500 to 70 0 C, if necessary under elevated pressure, for exinple approximately from 1 to 10 bar; and an amino group protected in the form of silylamino can be freed, for example, by means of hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl, for example 2-chloroacetyl, can S. be freed by treatment with thiourea in the presence of a base, or with a thiolate salt, such as an alkali metal thiolate of thiourea, and subsequent solvolysis, such as alcoholysis or hydrolysis, of the resulting substitution product. An amino group protected by 2-(trisubstituted silyl)-lower alkoxycarbonyl, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl, can be converted into the free amino group also by treatment with a salt of hydrofluoric acid that yields fluoride anions, as indicated above in connection with the freeing of a correspondingly protected carboxy group. Likewise, silyl, such as trimethylsilyl or tert-butyl-dimethylsilyl, bonded directly to a hetero atom, such as nitrogen, can be removed using fluoride ions, preferably with a fluoride of an organic quaternary nitrogen base, such as tetra-lower alkylammonium fluoride or tri-lower alkylaryl-lower alkylammonium fluoride, for example tctraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of an aprotic, polar solvent, such as dimethyl sulfoxide or N,N-dimethylacetamide, or especially an ether, such as tetrahydrofuran, at temperatures of from 0 to 50 0 C, especially at about room temperature.

Amino protected in the form of an azido group is converted into free amino, for example, by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, palladium or Raney nickel, by reduction using mercapto compounds, such as dithiothreitol or mercaptoethanol, or by treatment 63 with zinc in the presence of an acid, such as acetic acid. The catalytic hydrogenation is preferably carried out in an inert solvent, such as a halogenated hydrocarbon, for example methylene chloride, or in water or in a mixture of water and an organic solvent, such as an alcohol or dioxane, at approximately from 20 0 C to 25 0 C, or with cooling or heating.

A hydroxy or mercapto group protected by a suitable acyl group, by a tri-lower alkylsilyl group or by unsubstituted or substituted I-phenyl-lower alkyl is freed analogously to a correspondingly protected amino group. A hydroxy or mercapto group protected by 2,2-dichloroacetyl is freed, for example, by basic hydrolysis, and a hydroxy or mercapto group protected by tert-lower alkyl or by a 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical is freed by acidolysis, for example by treatment with a mineral acid or a strong carboxylic acid, for example trifluoroacetic acid. A hydroxy group protected by benzyloxy is freed, for example, by hydrogenolysis, that is to say by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, for example bonded to a carrier, such as carbon, preferably in polar solvents, such as di-lower alkyl-lower alkanoylamides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower alkylalkanoates, for example ethyl acetate, or alcohols, such as methanol, ethanol or propanol, with methanol being especially preferred, preferably at about room temperature. Mercapto protected by pyridyldiphenylmethyl can be freed, for example, using mercury(II) salts at pH 2-6 or by zinc/acetic acid or by electrolytic reduction; acetamidomethyl and isobutyrylamidomethyl can be freed, for example, by reaction with mercury(II) salts at pH 2-6; 2-chloroacetamidomethyl can be freed, for example, using 1-piperidinothiocarboxamide; and S-ethylthio, S-tert-butylthio and S-sulfo can be freed, for example, by thiolysis with thiophenol, thioglycolic acid, sodium thiophenolate or 1,4-dithiothreitol. Two hydroxy groups or an adjacent amino and hydroxy group which are protected together by means of a bivalent protecting group, preferably, for example, by a methylene group mono- or di-substituted by lower alkyl, such as lower alkylidene, for example isopropylidene, cycloalkylidene, for example cyclohexylidene, or benzylidene, can be freed by acid solvolysis, especially in the presence of a mineral acid or a strong organic acid. A tri-lower alkylsilyl group is likewise removed by acidolysis, for example by a mineral acid, preferably hydrofluoric acid, or a strong carboxylic acid. 2-halo-lower alkoxycarbonyl is removed using the above-mentioned reducing agents, for example a reducing metal, such as zinc, reducing metal salts, such as chromium(II) salts, or using sulfur compounds, for example sodium dithionite or preferably sodium sulfide and carbon disulfide. Esterified hydroxy groups, for example lower alkanoyloxy, such as acetyloxy, can also be freed by esterases, and -64acylated amino can be freed, for example, by suitable peptidases.

A sulfo group protected in the form of a sulfonic acid ester or sulfonamide is freed, for example, by acid hydrolysis, for example in the presence of a mineral acid, or preferably by basic hydrolysis, for example with an alkali metal hydroxide or alkali metal carbonate, for example sodium carbonate.

The temperatures for the freeing of the protected functional groups are preferably from to 100 0 C, especially from -200 to 50 0 C, for example from 100 to 35°C, such as in the region of room temperature.

When several protected functional groups are present, if desired the protecting groups can be so selected that more than one such group can be removed simultaneously, for example by acidolysis, such as by treatment with trifluoroacetic acid, or with hydrogen and a hydrogenation catalyst, such as a palladium-on-carbon catalyst. Conversely, the groups can also be so selected that they cannot all be removed simultaneously, but rather in a desired sequence, the corresponding intermediates being obtained.

SProcess g) (Formation of a carboxylic acid ester) S: The acylation of the hydroxy group is effected, for example, in a manner known per se using an acid of formula XXV as defined above wherein T is as defined with the exception of unsubstituted or substituted aminocarbonyl, or a reactive derivative of a compound of formula XXV wherein T is as defined for compounds of formula I. A suitable reactive derivative is, for example, a carboxylic acid of formula XXV' T-ZI

(XXV')

wherein T is one of the radicals defined above for compounds of formula preferably one of the radicals mentioned with the exception of unsubstituted or substituted aminocarbonyl, and wherein Z 1 is reactively activated hydroxy (the compound of formula XXV' therefore contains, instead of a hydroxy function bonded to the carbonyl group, reactively activated hydroxy, preferably as defined below). The free carboxylic acid of formula XXV can be activated, especially also in situ, for example, by strong acids, such as a hydrohalic, sulfuric, sulfonic or carboxylic acid, or acidic ion exchangers, for example by hydrochloric, hydrobromic or hydriodic acid, sulfuric acid, an unsubstituted or substituted, for example halo-substituted, alkanecarboxylic acid, or by an acid of formula XXV, preferably with an excess of the acid of formula XXV, if necessary with the binding of the resulting water of reaction by water-binding agents, with removal of the water of reaction by azeotropic distillation or with extractive esterification, by acid anhydrides, especially inorganic or more especially organic acid anhydrides, for example carboxylic acid anhvdrides, such as lower alkanecarboxylic acid anhydrides (with the exception of formic acid anhydride), for example acetic anhydride, or by suitable activating or coupling reagents of the type mentioned below. T-Z 1 may especially also ie a carboxylic acid azide (ZI azido; obtainable, for example, by reaction of a corresponding acid ester via the corresponding hydrazide and treatment thereof with nitrous acid); a carboxylic acid halide (Z halogen, especially chlorine or bromine), especially an acid chloride or bromide, obtainable, for example, by reaction with organic acid halides, especially with oxalyl dihalides, such as oxalyl dichloride, with inorganic acid halides, for example with acid halides of phosphorus or sulfur, such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, thionyl chloride or thionyl bromide, or especially under mild conditions with S tetra-lower alkyl-a-halo-enamines, for example tetramethyl-a-halo-enamines, especially -chloro-N,N,2-trimethyl-l-propenamine (preferably by reaction under an inert gas, such as nitrogen, in inert solvents, especially chlorinated hydrocarbons, such as methylene chloride or chloroform, or ethers, such as diethyl ether, dioxane or tetrahydrofuran, or mixtures thereof, at preferred temperatures of from -78 to 50 0 C, especially from -60 to 0 C, for example from -10 0 C to room temperature (cf. Devos, et al., J. C. S. Chem.

Commun. 1979, 1180-1181, and Haveaux, et al., Org. Synth. 59, 26 (1980)), it being possible for the resulting acid halide, for example the acid chloride of formula XXV' wherein Z 1 is chlorine, also to be used further directly in situ, for example by reaction with the compound of formula I in the presence of tertiary nitrogen bases, such as pyridine or 4-dimethylaminopyridine (DMAP, which is preferably added in catalytic amounts) or both of those bases, at preferred temperatures of from -20 to 50 0 C, especially from 10 0 C to 0 C; an activated ester wherein Z 1 is the radical of an alcohol having electron-attracting substituents, especially cyanomethoxy or aryloxy wherein aryl is preferably phenyl or S* naphthyl that is mono- or poly-substituted by halogen, nitro and/or by cyano, for example nitrophenoxy, such as 4-nitrophenoxy or 2,4-dinitrophenoxy, or polyhalophenoxy, such as pentachlorophenoxy; or a symmetrical or, preferably, asymmetrical acid anhydride which can be obtained, for example, by the action of a salt, for example an alkali metal salt, of an acid of formula XXV or its reaction partner, preferably a lower alkanecarboxylic acid, such as acetic acid, such as the sodium or potassium salt, on a complementary acid halide, i Y flYPYI B UnBUIU 66 especially, in the case of the reaction with a salt of a carboxylic acid of formula XXV, a carboxylic acid halide, for example chloride, such as acetyl chloride, and, in the case of the reaction of a carboxylic acid halide of formula XXV' wherein Z 1 is halogen, for ex.anple chlorine or bromine, with a salt of a lower alkanecarboxylic acid, especially sodium or potassium acetate. There may be used as activating and coupling reagents for activating carboxylic acids of formula XXV in situ also carbodiimides, for example N,N'-di-C 1

-C

4 alkyl- or N,N'-di-C 5

-C

7 cycloalkyl-carbodiimide, such as diisopropylcarbodiimide or N,N'-dicyclohexylcarbodiimide, advantageously with the eddition of an activating catalyst, isuch as N-hydroxysuccinimide or unsubstituted or substituted, for example halo-, C 1

-C

7 alkyl- or C 1

-C

7 alkoxy-substituted, N-hydroxy-benzotriazole or N-hydroxy-5-norbomene-2,3-dicarboxamide, C 1

-C

4 alkyl haloformate, for example isobutyl chloroformate, suitable carbonyl compounds, for example N,N-carbonyldiimidazole, suitable 1,2-oxazolium compounds, for example 2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate or 2-tert-butyl-5-methyl-isoxazolium perchlorate, suitable acylamino compounds, for example 2-ethoxy-l-ethoxycarbonyl-l,2-dihydroquinoline, or suitable phosphoryl cyanamides or azides, for example diethylphosphoryl cyanamide or diphenylphosphoryl azide, also triphenylphosphine disulfide or 1-C-C4alkyl-2-halopyridinium halides, for example 1-methyl-2-chloropyridinium iodide.

a a If two free carboxy groups are present in the compound of formula XXV it is also possible for an internal anhydride to be present as activated acid derivative.

Z

1 is preferably halogen, such as chlorine or bromine, and also acyloxy, for example lower o alkanoyloxy, such as acetyloxy.

The reaction with an acid halide, such as an acid chloride, of formula XXV' (Z 1 Cl) is carried out especially in an ether, such as dioxane, tetrahydrofuran, or a nitrile, such as a° acetonitrile, or mixtures thereof, in the presence or absence of pyridine and in the absence or, preferably, in the presence of tertiary nitrogen bases, such as 4-dimethylaminopyridine, ethyl diisopropylamine, triethylamine or mixtures of two or more of those bases, with or without a protective gas, such as argon, at temperatures of from 00 to 80 0 C or the reflux temperature, for example from room temperature to 50 0 C or the reflux temperature if that is lower than 50 0

C.

For the specific case where RZ in formula I' is unsubstituted or substituted amino there are suitable for the introduction of the corresponding radical T (unsubstituted or substituted ia raa~~aP~sr~ii -67aminocarbonyl) in the reaction with compounds of formula I especially the compounds of formula XXV' wherein Z 1 is halogen, such as chlorine, and wherein T is unsubstituted or substituted aminocarbonyl, which can be prepared, for example, by reaction of the complementary amines, for example unsubstituted or substituted alkylamines, aryl-lower alk id nines or arylamines, as defined for unsubstituted or substituted amino Rz, with phosgene or analogues thereof that contain instead of chlorine other halogen atoms, especially bromine, preferably in the presence of tertiary nitrogen bases, such as pyridine or triethylamine, and in inert solvents, for example chlorinated hydrocarbons, such as methylene chloride or chloroform, ethers, such as diethyl ether, tetrahydrofuran or dioxane, or carboxylic acid amides, such as dimethylformamide. Also suitable are corresponding N-carbonylazolides of formula XXV' (Z 1 N-containing heterocycle, such as 1-imidazolido) which are obtained, for example, by reaction with the corresponding N,N'-carbonyldiazolides, such as N,N'-carbonyldiimidazole, under conditions as just described for phosgene and analogues having other halogen atoms. The reaction of compounds of formula I with the corresponding compounds of formula XXV' is then likewise carried out under those conditions (cf. Staab, H. Angew. Chemie 74, 407 (1962)).

For the specific case of the introduction of aminocarbonyl T or an N-monosubstituted aminocarbonyl gronp T there is suitable as activated acid derivative especially the corresponding isocyanate of formula XXV" Q-N=C=O (XXV") wherein Q is an amino-protecting group, for example trihaloacetyl, such as trifluoro- or trichloro-acetyl, or one of the unsubstituted or substituted lower alkyl radicals or aryl radicals mentioned above in the definition of unsubstituted or substituted amino Rz wherein the amino group carries a substituent, it being possible, when Q is an aminoprotecting group, to obtain after the reaction with the compound of formula I the corresponding compound of formula I' wherein R 5 is free aminocarbonyloxy by removal of the protecting group Q, as described for the freeing of amino protected by acyl under Process especially by acid hydrolysis, or, when Q is one of the mentioned substituted or unsubstituted lower alkyl radicals or aryl radicals, a corresponding compound of formula I containing aminocarbonyl T monosubstituted at the nitrogen atom. Both aminocarbonyl and N-monosubstituted aminocarbonyl T can be converted into N-disubstituted aminocarbonyl T by alkylation with a further unsubstituted or substituted lower alkyl radical I ly, -68using suitable starting materials and conditions analogous to those described below under "Additional Process Steps".

The mentioned reactions can be carried out under reaction conditions known per se, at customary temperatures, in the presence or, especially when lower alkanoyl anhydrides are used to activate the carboxylic acid of formula XXV, in the absence of inert solvents or diluents, for example in acid amides, for example carboxylic acid amides, such as dimethylformamide, dimethylacetamide or 1,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), or amides of inorganic acids, such as hexamethylphosphoric acid triamide, ethers, for example cyclic ethers, such as tetrahydrofuran or dioxane, or acyclic ethers, such as diethyl ether or ethylene glycol dimethyl ether, halogenated hydrocarbons, such as halo-lower alkanes, for example methylene chbuic or chloroform, ketones, such as acetone, nitriles, such as acetonitrile, acid anhydrides, ;uch as acetic anhydride, esters, such as ethyl acetate, bisalkane sulfines, such as dimethyl sulfoxide, nitrogen heterocycles, such as pyridine, or mixtures of those solvents, especially in anhydrous solvents or solvent mixt.res, it being possible to select for the above-mentioned reactions the particular solvents that are suit' le in each case, there being used, as appropriate and expedient, salts of the compounds used, especially metal salts of carboxylic acid, that are used, such as the alkali metal or alkaline earth metal salts, for example sodium or °potassium salts, in the absence or the presence of catalysts, such as dimethylaminopyridine, condensation agent; or neutralising agents, such as tertiary nitrogen bases, for example pyridine, triethylamine, N-mcthylmorpholine, dimethylaminopyridine or ethyl diisopropylamine, and, depending on the nature of the reaction and/or the reactants, under atmospheric pressure or in a closed vessel, under normal pressure or under elevated S pressure, for example at the pressure produced in the reaction mixture under the reaction conditions in a closed tube, and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere. Preference is given to reaction conditions that are mentioned 2* specifically in any particular case or, especially, that are analogous to those mentioned in the Examples. The course of the reaction is advantageously monitored using customary s methods of analysis, especially using thin-layer chromatography. From those reaction c conditions it is possible to select the reaction conditions that are suitable for each of the reactions described in this text, reaction conditions that are specifically mentioned being especially preferred.

The reaction according to the invention is preferably carried out under mild conditions, especially at temperatures of from -10" to 60 C, for example from 00 to room temperature -rm 69 or at slightly elevated temperatures up to about 50°C, for example approximately from 00 to 40 0 C. Both in the case of the reaction with a carboxylic acid halide of formula XXV' wherein Z 1 is halogen, such as chlorine or bromine, and in the case of the reaction with an anhydride, especially a symmetrical anhydride (Z 1 the corresponding compound of formula XXV' (halide and T-O-T, respectively) is used especially in an approximately equimolar amount in relation to the compound of formula I or in excess, for example from 0.95 to 10 times the molar amount, preferably from 1.05 to 5 times the molar amount.

In starting materials of formulae I, XXV, XXV' and XXV", functional groups, with the exception of groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae II and III'. The freeing of functional groups protected by protecting groups in the resulting compounds of formula I' having protected functions is effected in accordance with one or more of the methods mentioned under Process f).

Process h) (Nucleophilic substitution) In starting materials of formulae XXVI and XXII, functional groups, with the exception of groups that are intended to participate in the reaction or that do not react under the reaction conditions, are protected independently of one another by protecting groups.

The protecting groups are entirely analogous to those described under Process a) for the formation of an amide bond starting from compounds of formulae II and III'.

00* A leaving group Wi is especially a nucleofugal leaving group selected from hydroxy esterified by a strong inorganic or organic acid, such as hydroxy esterified by a mineral acid, for example a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or hydriodic acid, or by a strong organic sulfonic acid, such as a lower alkanesulfonic acid that is unsubstituted or substituted, for example by halogen, such as fluorine, or an aromatic sulfonic acid, for example a benzenesulfonic acid that is unsubstituted or substituted by lower alkyl, such as methyl, halogen, such as bromine, and/or by nitro, for example a methanesulfonic acid, p-bromotoluenesulfonic acid or p-toluenesulfonic acid, 1. and hydroxy esterified by hydrazoic acid.

The reaction between a compound of formula XXVI and a compound of formula XXVII wherein L is etherified or esterified hydroxy or mercapto is preferably carried out in the presence of a base, for example a hydroxide-containing base, such as a metal hydroxide, for example an alkali metal hydroxide, p;:ch as sodium or potassium hydroxide, or especially a metal carbonate or hydrogen carbonate, such as sodium or potassium carbonate or sodium or potassium hydrogen carbonate, there also being suitable in those cases, in addition to the solvents mentioned hereinbelow, preferably ketones, such as lower alkanones, or aqueous and protic solvents, or especially with the use of a metal alcoholate or thiolate as activated compound of formula XXVII or with the preparation thereof in situ in the presence of a strong base, for example an alkali metal hydride, such as sodium hydride, or in the presence of an alkali metal, such as sodium, in the absence or presence of a suitable solvent, especially an aprotic solvent, for example DMPU, an ether, such as S diethyl ether, dioxane or tetrahydrofuran, or a carboxylic acid amide, such as dimethylformamide, at temperatures of from 0 0 C to the reflux temperature, especially from 20 0

C

to the reflux temperature, if necessary under a protective gas, such as nitrogen or argon.

In the case of the reaction of compounds of formula )XVII wherein L is unsubstituted or substituted amino or is heterocyclyl bonded via nitrogen, the reaction is preferably carried out in the absence of a base or in the presence of a sterically hindered nitrogen base, especially a tertiary nitrogen base, such as 4-dimethylaminopyridine, pyridine or triethylamine, in an aqueous or non-aqueous solvent, such as an aqueous or non-aqueous alcohol, for example ethanol or methanol, esters, such as diethyl esters, ethers, such as diethyl ether, dioxane or tetrahydrofuran, carboxylic acid amides, such as dimethylformamide, or acetonitrile, at temperatures of from 0°C to the reflux temperature, especially from 200 to 100 0

C.

Depending on the reaction conditions, the substitution can take place in the form of a first-order or second-order nucleophilic substitution.

Additional Process Steps -71- In the additional process steps, which are optional, functional groups of the starting compounds that are not intended to take part in the reaction may be unprotected or may be in protected form, for example they may be protected by one or more of the protecting groups mentioned above under Process The protecting groups may be retained in the end products or some or all of them may be removed in accordance with one of the methods mentioned under Process f).

Salts of compounds of formula I' having at least one salt-forming group may be prepared in a manner known per se. For example, salts of compounds of formula I' having acid groups may be formed, for example, by treatment with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, for example the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen carbonate, with corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of compounds of formula I' are obtained in customary manner, for example by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of formula I' containing acid and basic salt-forming groups, for example a free carboxy group and a free amino group, may be formed, for example, by the neutralisation of salts, .such as acid addition salts, to the isoelectric point, for example with weak bases, or by treatment with ion exchangers.

Salts can be converted in customary manner into the free compounds; metal and ammonium salts can be converted, for example, by treatment with suitable acids or acidic ion exchangers, and acid addition salts, for example, by treatment with a suitable basic agent or basic ion exchangers.

Stereoisomeric mixtures of compounds of formula that is to say mixtures of diastereoisomers and/or enantiomers, such as, for example, racemic mixtures, can be separated into the corresponding isomers in a manner known per se by suitable separating processes. For example, mixtures of diastereoisomers can be separated into the individual diastereoisomers by fractional crystallisation, chromatography, solvent partition etc. Racemates can be separated from one another, after conversion of the optical antipodes into diastereoisomers for example by reaction with optically active compounds, for example optically -72active acids or bases, by chromatography on column materials covered with optically active compounds or by enzymatic methods, for example by selective reaction of only one of the two enantiomers. This separation can be carried out either at the stage of one of the starting materials or with the compounds of formula I' themselves.

In an obtainable compound of formula I' wherein T is a radical of formula Z wherein Rz is phenyl- or naphthyl-methoxycarbonyl-substituted amino or imino, for example in aminolower alkyl N-substituted by those radicals or amino-lower alkyl N,N-disubstituted by phenyl- or naphthyl-methoxycarbonyl and by lower alkyl, in N-phenyl- or naphthylmethoxycarbonyl-pyrrolidin-2-yl or -amino-lower alkoxy-lower alkoxy-lower alkyl, the amino or imino group in the radical T in question can be converted into the corresponding amino- or N-lower alkylamino-lower alkylcarbonyl group by removal of phenyl- or naphthyl-lower alkoxycarbonyl, for example by hydrogenolysis, that is to say by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, for example bonded to a carrier, such as carbon, preferably in polar solvents, such as di-lower alkyl-lower alkanoylamides, for example dimethylformamide, ethers, such as cyclic ethers, for example dioxane, esters, such as lower alkanoic acid lower alkyl esters, for example ethyl acetate, or alcohols, such as methanol or ethanol, especially at room temperature.

By reductive amination it is possible to convert amino-lower alkyl Rz mono-N-substituted by heterocyclyl-lower alkyl, such as imidazolylmethyl or pyridylmethyl, each bonded via a ring carbon atom, by aryl-lower alkyl, such as phenyl- or naphthyl-lower alkyl, or especially by lower alkyl, as a constituent of T in a compound of formula I' into lower alkyl Rz N,N-disubstituted by an additional radical selected from heterocyclyl-lower alkyl, such as imidazolylmethyl or pyridylmethyl, each bonded via a ring carbon atom, and aryl-lower alkyl, such as phenyl- or naphthyl-lower alkyl. The reaction between a corresponding mono-N-substituted compound of formula I' and a corresponding heterocyclyl- or aryllower alkyl ketone or lower alkanealdehyde is carried out with catalytic hydrogenation, for example in the presence of a noble metal catalyst, such as platinum or especially palladium, bonded to a carrier, preferably carbon, or a heavy metal catalyst, such as Raney nickel, at normal pressures or at pressures of from 1 to 100 bar, preferably in the presence of a noble metal catalyst at approximately normal pressure, in organic solvents, for example alcohols, such as ethanol or especially methanol, in the absence or, preferably, in the presence of a carboxylic acid, such as a lower alkanoic acid, for example acetic acid, at preferred temperatures of from 00 to 50 0 C, for example at room temperature, or with -73reduction by means of a complex boron hydride, such as sodium cyanoborohydride.

In a compound of formula I' wherein T is N-triphenylmethyl-imidazolyl-lower alkylcarbonyl, the triphenylmethyl radical can be removed, as described under Process f), yielding the corresponding compound of formula I' wherein T is imidazol(-2-, or In a compound of formula I' wherein one or more of the radicals R 2

R

3 and A 2 is substituted by benzyloxy, the benzyloxy radical can be removed, as described under Process f), yielding the corresponding compounds of formula I' containing hydroxy in the place of benzyloxy.

In an obtainable compound of formula an amino or carboxamide group can be substituted, a carboxy group present in free or reactive form can be esterified or amidated or an esterified or amidated carboxy group can be converted into a free carboxy group.

The substitution of a carboxamide group or of another primary or secondary amino group, for exa-.ple for the formation of the carbamoyl derivatives mono- or di-lower alkyl- S: carbamoyl and mono- or di-hydroxy-lower alkylcarbamoyl mentioned above as a substituent of thiomorpholino or morpholino formed by R 4 and R 5 together with the bonding nitrogen atom, or with the formation of the above-mentioned derivatives of the substituent amino at thiomorpholino or morpholino formed by R 4 and R 5 together with the bonding nitrogen atom, or for the formation of N,N-disubstituted amino Rz in compounds of formula I' wherein the nitrogen of the amino groups to be reacted is bonded to hydrogen, is effected, for example, by alkylation.

Suitable agents for alkylating a carboxamide group in a compound of formula I' are, for example, diazo compounds, for example diazomethane. Diazomethane can be decomposed in an inert solvent, the free methylene formed reacting with the carboxamide group in the compound of formula The decomposition of diazomethane is carried out preferably catalytically, for example in the presence of a noble metal in finely divided form, for example copper, or a noble metal salt, for example copper(I) chloride or copper(II) sulfate.

Alkylating agents are also mentioned in German Offenlegungsschrift 2 331 133, for example alkyl halides, sulfonic acid esters, Meerwein salts or 1-substituted 3-aryl-

D-

-74triazenes, which can be reacted under the conditions mentioned therein with a compound of formula I' containing a carboxamide group.

F'irther alkylating agents are selected from corresponding alkyl compounds that carry a substituent X wherein X is a leaving group. A leaving group is especially a nucleofugal leaving group selected from hydroxy esterified by a strong inorganic or organic acid, such as hydroxy esterified by a mineral acid, for example a hydrohalic acid, such as hydrochloric, hydrobromic or hydriodic acid, or by a strong organic sulfonic acid, such as an unsubstituted or substituted, for example halo-substituted, such as fluoro-substituted, lower alkanesulfonic acid, or an aromatic sulfonic acid, for example a benzenesulfonic acid that is unsubstituted or substituted by lower alkyl, such as methyl, by halogen, such as bromine, and/or by nitro, for example a methanesulfonic, trimethanesulfonic or p-toluenesulfonic acid, and hydroxy esterified by hydrazoic acid.

SThe reaction can be carried out under the conditions of a first-order or second-order S* nucleophilic substitution.

S" For example, one of the compounds containing a substituent X wherein X is a leaving group with high polarisability of the electron shell, for example bromine or iodine, can be reacted in a polar aprotic solvent, for example acetone, acetonitrile, nitromethane, dimethyl sulfoxide or dimethylformamide. The substitution reaction is carried out if desired at reduced or elevated temperature, for example in a temperature range of from S approximately -400 to approximately 100°C, preferably from approximately -10 to approximately 50C, and if desired under an inert gas, for example under a nitrogen or argon atmosphere.

For the esterification or amidation of a carboxy group in a compound of formula for example for the amidation of a free carboxy group of an amino acid, such as Glu or Asp, with ammonia, or of a free carboxy group at thiomorpholino or morpholino formed by R 4 and R 5 together with the bonding nitrogen atom, if desired the free acid can be used or the free acid can be converted into one of the above-mentioned reactive derivatives and reacted with an alcohol, with ammonia, or with a primary or secondary amine, or, in the case of esterification, the free acid or a reactive salt, for example the caesium salt, can be reacted with a reactive derivative of an alcohol. For example the caesium salt of a carboxylic acid can be reacted with a halide or sulfonic acid ester corresponding to the alcohol. The esterification of the carboxy group can also be carried out with other ~a~ customary alkylating agents, for example with diazomethane, alkyl halides, sulfonic acid esters, Meerwein salts or 1-substituted 3-aryltriazenes, etc.

For the conversion of an esterified or amidated carboxy group into the free carboxy group it is possible to use one of the methods described above for the removal of carboxyprotecting groups or, if desired, alkaline hydrolysis under customary reaction conditions, such as those mentioned in Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin 1988.

In a compound of formula an esterified carboxy group can be converted into an unsubstituted or substituted carboxamide group by aminolysis with ammonia or with a primary or secondary amine. The aminolysis can be carried out in accordance with the customary reaction conditions, such as those mentioned for such reactions in Organikum, edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1976.

A free amino group present in a compound of formula I' can be acylated, for example to introduce one of the radicals mentioned for R 1 other than hydrogen. The acylation is carried out in accordance with the methods mentioned above under Process a) or one of the methods mentioned for protecting groups or, for example, according to one of the processes mentioned in Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1988.

In an obtainable compound of formula I' wherein the substituents are as defined and at least one free hydroxy group is present and the remaining functional groups are in protected form, the free hydroxy group, for example the hydroxy group at thiomorpholino or morpholino formed by R 4 and R5 together with the bonding nitrogen atom, can be acylated or etherified.

-The acylation can be carried out with acylating reagents according to one of the methods mentioned under Processes a) to e) or g) or according to one of the methods mentioned for protecting groups or according to one of the processes mentioned in Organikum, 17th edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1988.

The etherification can be carried out with the above-mentioned alkylating agents and under the same reaction conditions, for example with diazomethane, alkyl halides, sulfonic acid esters, Meerwein salts, 1-substituted 3-aryltriazenes, etc.. Preference is given -76to the reaction with corresponding alkyl halides, such as lower alkyl iodides or bromides, in the presence of caesium carbonate in suitable solvents or solvent mixtures, for example in N,N-di-lower alkyl-lower alkanoylamides, such as dimethylformamide or dimethylacetamide, or ethers, such as dioxane, or mixtures thereof, at temperatures of from 0° to the reflux temperature, preferably from 300 to 60 0 C; for example at about 50 0

C.

In a compound of formula any groups that correspond to protecting groups, and also suitable radicals R 1 other than hydrogen can be removed in accordance with one of the methods mentioned under Process especially by hydrolysis, for example in the presence of bases, such as alkali metal or alkaline earth metal hydroxides, for example sodium hydroxide, or acids, such as organic acids or mineral acids, for example a hydrogen halide, such as hydrogen chloride. The hydrolysis is effected under the customary conditions, for example in aqueous solution or in anhydrous solvents, especially in ethers, such as dioxane, at temperatures of from -50 0 C to the reflux temperature of the reaction mixture in question, for example from 00 to 50°C, preferably in the presence of a protective gas, such as argon or nitrogen, or by hydrogenolysis (for example in the case of benzyloxycarbonyl radicals), preferably in polar solvents, such as alcohols, for example methanol or ethanol, or esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, at the lastmentioned temperatures and in the presence of suitable hydrogenation catalysts, such as a palladium catalyst, which is preferably bonded to a carrier, such as carbon.

In a compound of formula I' wherein at least one of the radicals R 2 and R 3 is a phenyl group and/or one or more of the radicals B 1

A

1 and A 2 is phenylalanine, it being possible for each of the phenyl radicals to be substituted, as described above, the corresponding S phenyl radical(s) can be reduced, for example hydrogenated, selectively to corresponding cyclohexyl radical(s). The hydrogenation is preferably carried out in the presence of a catalyst that allows the selective hydrogenation of double bonds in the presence of peptide bonds, especially a catalyst comprising heavy metal oxides, such as a Rh(III)/Pt(VI) oxide catalyst according to Nishimura Nishimura, Bull. Chem. Soc.

Japan 33, 566 (1960)), in suitable solvents, especially water, alcohols, such as methanol or ethanol, esters, such as ethyl acetate, or ethers, such as dioxane, for example in methanol, at temperatures of from 0 to 1500C, preferably from 10 to 50 0 C, for example at room temperature, and at hydrogen pressures of from 1 to 50 bar, for example at normal pressure.

Pharmaceutical Compositions: -77- The invention relates also to pharmaceutical compositions comprising compounds of formula I' and to novel compounds of formula I.

The pharmacologically acceptable compounds of the pires.nt invention may be used, for example, in the preparation of pharmaceutical compositions that comprise an effective amount of the active ingredient together or in admixture with a significant amount of inorganic or organic, solid or liquid, pharmaceutically acceptable carriers.

The p.hmnnaceutical compositions according to the invention are compositions for enteral, such as nasal, buccal, rectal or oral, or parenteral, such as intramu.cular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration.

The invention relates also to pharmaceutical compositions and a method for treating diseases caused by retroviruses, for example AIDS or the preliminary stages thereof, especially when HIV-2 or more especially HIV-1 is the cause of the disease, preferably 1. wherein a compound of formula I' according to the invention is present in an amount that is therapeutically effective against retroviral diseases, such as AIDS and the preliminary stages thereof, in a pharmaceutical composition that is suitable for administraton to a warm-blooded animal, especially a human being, for the treatment of a retroviral disease, such as AIDS, or wherein a therapeutically effective amount of a compound of formula I' according to the invention is administered in a treatment method to a warm-blooded animal, for example a human being, who on account of one of the mentioned diseases, especially AIDS, requires such treatment, in an amount that is therapeutically effective against retroviral diseases, such as AIDS and the preliminary stages thereof. The dose to be administered to warm-blooded animals, for example human beings of approximately kg body weight, is from approximately 3 mg to approximately 10 g, preferably from approximately 40 mg to approximately 4 g, for example approximately from 300 mg to g per person per day, divided preferably into 1 to 3 single doses which may, for example, be of the same size. Usually, children receive half of the adult dose.

-78- The pharmaceutical compositions comprise from approximately 1 to approximately preferably from approximately 20 to approximately 90 active ingredient.

Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, drag6es, tablets or capsules.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional dissolving, lyophilising, mixing, granulating or confectioning processes.

Solutions of the active ingredient, and also suspensions or dispersions, and especially isotonic aqueous solutions, dispersions or suspensions, are preferably used, it being possible, for example in the case of lyophilised compositions that comprise the active ingredient alone or together with a carrier, for example mannitol, for such solutions, dispersions or suspensions to be made up prior to use. The pharmaceutical compositions may be sterilised and/or may comprise excipients, for example preservatives, stabilisers, S" wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers, and are prepared in a manner known per se, for example by means of conventional dissolving or lyophilising processes. The said solutions or suspensions may i comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil comprise as the oil component the vegetable, synthetic or semisynthetic oils customary for injection purposes. There may be mentioned as such especially liquid fatty acid esters that contain as the acid component a long-chained fatty acid Shaving from 8 to 22, especially from 12 to 22, carbon atoms, for example lauric acid, Stridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, brassidic acid or linoleic acid, if desired with the addition of antioxidants, for example vitamin E, p-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fatty acid esters has a maximum of 6 carbon atoms and is a mono- or poly-hydric, for example a mono-, di- or tri-hydric, alcohol, for example methanol, ethanol, propanol, butanol or pentanol or the isomers thereof, but especially glycol and glycerol. The following examples of fatty acid esters are therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl palmnitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate, Gattefoss6, Paris), "Miglyol 812" (triglyceride of saturated fatty acids with a chain length of C 8 to C 12 Hills AG, Germany), but especially -79vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, so 'ean oil and more especially groundnut oil.

The injection compositions are prepared in customary manner under sterile conditions; the same applies also to introducing the compositions into ampoules or vials and sealing the containers.

Pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture, and processing the mixture, if desired or necessary, after the addition of appropriate excipients, into tablets, drag6e cores or capsules, or by preparing dispersions, preferably with phospholipids, which are introduced into vials. It is also possible for the active ingredients to be incorporated into plastics carriers that allow the active ingredients to diffuse or be released in measured amounts.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes 0: using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above-mentioned starches, also S carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable, optionally enteric, coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Capsules are dry-filled capsules made of gelatin and also soft, sealed capsules made of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may comprise the active ingredient in the form of granules, for example with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired with stabilisers. In soft capsules the active ingredient is preferably dissolved or suspended in suitable oily excipients, such as fatty oils, paraffin oil, fatty acid esters or lower alkylene glycols, such as 1,2-propylene glycol monolaurate (mixture of the two constitutional isomers; Gattefoss6 Saint Priest, France), ®Gelucire (glycerides and partial polyglycerides of fatty acid; Gattefoss6 Saint Priest, France) or liquid polyethylene glyco!s, such as PEG 300, it likewise being possible for stabilisers and/or antibacterial agents to be added.

Dyes or pigments may be added to the tablets or drag6e coatings or to the capsule casings, for example for identification purposes or to indicate different doses of active ingredient.

Especially preferred as pharmaceutical compositions are phospholipid-stabilised dispersions of the active ingredient, preferably for oral administration, comprising a) a phospholipid or several phospholipids of the formula 1

CH

2

R

R -O -CH

O

A I I a A), 3CH2-O- P-O (CnH2n)-N-Rb I \R, 0 c *00o* wherein RA is C 1 0 20 acyl, R is hydrogen or C 10 20 acyl, Ra, Rb and R. are hydrogen or

C

1 4alkyl and n is an integer from two to four, if desired b) a further phospholipid or several further phospholipids c) the active ingredient and d) a pharmaceutically acceptable carrier liquid and, if desired, further excipients and/or preservatives.

The process for the preparation of those dispersions is as follows: a solution or suspension S of components a) and c) or b) and but preferably of a) and b) in a ratio by weight of from 20: 1 to 1: 5, especially from 5 1 to 1: 1, is converted into a dispersion by dilution with water and the organic solvent is then removed, for example by centrifugation, gel filtration, ultrafiltration or especially by dialysis, for example tangential dialysis, preferably against water, and then, preferably after the addition of excipients or preservatives and if necessary with the establishment of an acceptable pH value by the addition of pharmaceutically acceptable buffers, such as phosphate salts or organic acids (pure or dissolved in water), such as acetic acid or citric acid, preferably from pH 3 to 6, for example pH 4 5, the dispersion obtained is concentrated (unless it already has the correct active ingredient concentration) preferably to an active ingredient concentration of from 2 -81to 30 mg/ml, especially from 10 to 20 mg/ml, concentration preferably being effected in accordance with the methods last mentioned for the removal of an organic solvent, especially by ultrafiltration, for example using an apparatus for carrying out tangential dialysis and ultrafiltration.

The phospholipid-stabilised dispersion that can be prepared in accordance with that process is stable for at least several hours at room temperature, is reproducible as regards the proportions of the components and is toxicologically acceptable and is therefore especially suitable for oral administration to human beings.

The size of the particles obtained in the dispersion is variable and is preferably from ap ;oximately 1.0 x 10-8 to approximately 1.0 x 105m, especially from approximately 7 to approximately 2 x 10-6m.

The nomenclature for the phospholipids of formula I and the numbering of the carbon S. atoms are in accordance with the recommendations of the IUPAC-IUB Commission on Biochemical Nomenclature (CBN) (sn-nomenclature, stereospecific numbering) given in the Eur. J. of Biochem. 79, 11-21 (1977) "Nomenclature of Lipids".

In a phospholipid of formula A, RA and Rg having the definitions C 10 20 acyl are preferably straight-chained C 10 20 alkanoyl having an even number of carbon atoms and straight-chained C 10 20 alkenoyl having a double bond and an even number of carbon atoms.

Straight-chained C 10 20 alkanoyl RA and Rg having an even number of carbon atoms are, for example, n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octadecanoyl.

Straight-chained C 1 0 20 alkenoyl RA and Rg having a double bond and an even number of carbon atoms are, for example, 6-cis-, 6-trans-, 9-cis- or 9-trans-dodecenoyl, -tetradecencyl, -hexadecenoyl, -octadecenoyl or -icosenoyl, especially 9-cis-octadecenoyl (oleoyl).

In a phospholipid of formula A. n is an integer from two to four, preferably two. The group of the formula -(CnH 2 is unbranched or branched alkylene, for example 1,1ethylene, 1,2- or 1,3-propylene or 1,3- or 1,4-butylene. 1,2-Ethylene is preferred.

-82- Phospholipids of formula A are, for example, naturally occurring cephalins wherein Ra, Rb and RC are hydrogen, or naturally occurring lecithins wherein Ra, Rb and R e are methyl, for example cephalin or lecithin from soybeans, bovine brain, bovine liver or hen's eggs having different or identical acyl groups RA and Rg or mixtures thereof.

Synthetic, substantially pure phospholipids of formula A having different or identical acyl groups RA and Rg are preferred.

The term "synthetic" phospholipid of formula A defines phospholipids that have a uniform composition as regards RA and Rg. Such synthetic phospholipids are preferably the lecithins and cephalins defined below, the acyl groups RA and RB of which have a defined structure and are derived from a defined fatty acid having a degree of purity higher than approximately 95 RA and Rg may be identical or different and may be unsaturated or S, saturated. RA is preferably saturated, for example n-hexadecanoyl, and RB is preferably unsaturated, for example 9-cis-octadecenoyl oleoyl).

The term "naturally occurring" phospholipids of forml a A defines phospholipids that do not have a uniform composition as regards RA and Rg. Such natural phospholipids are likewise lecithins and cephalins the acyl groups RA and Rg of which are structurally undefinable and are derived from naturally occurring fatty acid mixtures.

The term "substantially pure" phospholipid defines a degree of purity of more than 70 (by weight) of the phospholipid of formula A, which can be established by suitable deter- S mination methods, for example by paper chromatography.

Special preference is given to synthetic, substantially pure phospholipids of formula A wherein RA is straight-chained Clo 20 alkanoyl having an even number of carbon atoms and RB is straight-chained Co 10 20 alkenoyl having a double bond and an even number of carbon atoms. Ra, Rb and R e are methyl and n is two.

In an especially preferred phospholipid of formula A, RA is n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl or n-octad-canoyl and Rg is 9-cis-dodec yl, 9-cis-tetradecenoyl, 9-cis-hexadecenoyl, 9-cis-octadecenoyl or 9-cis-icosenoyl. Ra, Rb and R e are methyl and n is two.

83- A very especially preferred phospholipid of formula A is synthetic 1-n-hexadecanoyl- 2-(9-cis-octadecenoyl)-3-sn-phosphatidyl choline having a purity of more than 95 Preferred natural, substantially pure phospholipids of formula A are especially lecithin (L-a-phosphatidyl choline) from soybeans or hen's eggs.

The names given in brackets are also customarily used for the acyl radicals in the phospholipids of formula A: 9-cis-dodecenoyl (lauroleoyl), -cis-tetradecenoyl (myristoleoyl), 9-cis-hexadecenoyl (palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl (petroselaidoyl), 9-cis-octadecenoyl (oleoyl), 9-trans-octadecenoyl (elaidoyl), 11-cis-octadecenoyl (vaccenoyl), 9-cis-icosenoyl (gadoleoyl), n-dodecanoyl (lauroyl), n-tetradecanoyl (myristoyl), n-hexadecanoyl (palmitoyl), n-octadecanoyl (stearoyl), n-icosanoyl (arachidoyl).

Other phospholipids are preferably esters of phosphatidic acid (3-sn-phosphatidic acid) with the mentioned acyl radicals, such as phosphatidyl serine and phosphatidyl ethanolamine.

Sparingly soluble active ingredients may also be present in the form of water-soluble, pharmaceutically acceptable salts, as defined above.

The carrier liquid d) comprises the components b) and c) or a) and c) as liposomes in such a manner that for a period of from several days up to several weeks no solids or solid aggregates, such as micelles, re-form and the liquid comprising the said components is administrable, preferably orally, if necessary after filtration.

The carrier liquid d) may comprise pharmaceutically acceptable, non-toxic excipients, for example water-soluble excipients that are suitable for producing isotonic conditions, for example ionic additives, such as sodium chloride, or non-ionic additives (structure formers), such as sorbitol, mannitol or glucose, or water-soluble stabilisers for the liposome dispersion, such as lactose, fructose or sucrose.

In addition to the water-soluble excipients, the carrier liquid may also comprise emulsifiers, wetting agents or surfactants that can be used for liquid pharmaceutical formulations, especially emulsifiers, such as oleic acid, non-ionic surfactants of the fatty acid polyhydroxy alcohol ester type, such as sorbitan monolaurate, monooleate, monostearate -84or monopalmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid polyhydroxy alcohol esters, such as polyoxyethylene sorbitan monolaurate, monooleate, monostearate, monopalinitate, trstearate or trioleate, polyethylene glycol fatty acid esters, such as polyoxyethyl stearate, polyethylene glycol-400-stearate, polyethylene glycol- 2000-stearate, especially ethylene oxide/propylene oxide block polymers of the Pluronic® type (Wyandotte Chem. Corp.) or the Synperonic® type (ICI).

Preferred preservatives are, for example, antioxidants, such as ascorbic acid, or microbicides, such as sorbic acid or benzoic acid.

Starting materials: The present invention relates also to novel starting materials and/or intermediates anu to processes for their preparation. The starting materials used and the reaction conditions selected are preferably those which result in the compounds described as being preferred.

All starting materials can preferably be prepared analogously to the processes mentioned in the Examples and Reference Examples.

In the preparation of all starting materials, free functional groups that are not intended to participate in the reaction in question, may be unprotected or may be in protected form, for example they may be protected by the protecting groups mentioned above under Process If necessary, the functional groups that are not intended to participate in the reaction are always in protected form (cf. for example the protection of compounds of formula XXI in the reaction, for example, to form compounds of formula XXII', see S below, at the carboxy group that is not to be reacted, in order to avoid lactonisation).

Those protecting groups can be removed at suitable times by the reactions described under Process The compounds having salt-forming groups can also be used in the form of S salts, and at any stage salts can be formed or converted into the free compounds again.

In the formulae, unless the stereochemistry of asymmetric carbon atoms is defined directly by the choice of corresponding bond symbols, the configuration of asymmetric carbon atoms is indicated by the configuration symbol which is selected from and The carboxylic or sulfonic acids of formula I1, or reactive derivatives thereof, are known and are commercially available or can be prepared in accordance with processes known e per se.

The compounds of formula III' are known or can be prepared in accordance with processes known per se. They can be obtained, for example, from compounds of formula .R COOH 2 (XII),

HN

Pa wherein R 2 is as defined for compounds of formula I' and Pa is an amino-protecting group, especially lower alkoxycarbonyl, such as tert-butoxycarbonyl, or phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, (or analogues thereof containing hydrogen in place of Pa, which can then be protected subsequently), by reduction to a compound of formula

RCHO

R2 HTS) (xm)

HN

Pa 0 (or the analogue having hydrogen in place of Pa) wherein the radicals are as last defined.

The reduction of amino acid derivatives of formula XII to the corresponding aldehydes XIII is effected, for example, by reduction to the corresponding alcohols and subsequent oxidation to the aldehydes of formula XIII.

The reduction to the alcohols is effected especially by hydrogenation of the corresponding acid halides or other activated carboxylic acid derivatives mentioned under Process or by reaction of activated carboxylic acid derivatives of compounds of formula XII, especially anhydrides with organic carboxylic acids, preferably those of haloformic acid esters, such as chloroformic acid isobutyl ester, (which are preferably obtained by reaction of compounds of formula XII in the presence of basic amines, for example tri-lower alkylamines, such as triethylamine, in organic solvents, such as cyclic ethers, for example -86dioxane, at temperatures of from -500 to 80 0 C, preferably from 0 to 50 0 C) with complex hydrides, such as alkali metal borohydrides, for example sodium borohydride, in aqueous solution in the presence or absence of the organic solvents last used, at temperatures of from -500 to 80 0 C, preferably from 00 to 50 0 C. The subsequent oxidation of the resulting alcohols is preferably effected with those oxidising agents which selectively convert the hydroxy group into an aldehyde group, for example chromic acid or derivatives thereof, such as pyridinium chromate or tert-butyl chromate, dichromate/sulfuric acid, sulfur trioxide in the presence of heterocyclic bases, such as pyridine/S0 3 (preferably dissolved in di-lower alkyl sulfoxides, such as dimethyl sulfoxide, aromatic solvents, such as toluene, or mixtures of those solvents), also nitric acid, pyrolusite or selenium dioxide, in water, aqueous or organic solvents, such as halogenated solvents, for example methylene chloride, carboxylic acid amides, such as dimethylformamide, and/or cyclic ethers, such as tetrahydrofuran, in the presence or absence of basic amines, for example tri-lower alkylamines, such as triethylamine, at temperatures of from -700 to 100 0 C, preferably from -700 to -50 0 C or from -100 to 50 0 C, for example as described in European Patent Application EP-A-0 236 734.

Direct reduction of the compounds of formula XII to the aldehydes is also possible, for example by hydrogenation in the presence of a partially poisoned palladium catalyst or by reduction of the corresponding amino acid esters, for example the lower alkyl esters, such as ethyl esters, with complex hydrides, for example boron hydrides, such as sodium borohydride, or preferably aluminium hydrides, for example lithium aluminium hydride, lithium tri(tert-butoxy)aluminium hydride or especially diisobutylaluminium hydride, in non-polar solvents, for example in hydrocarbons or aromatic solvents, such as toluene, at from -100 to 0°C, preferably from -70 to -30 0 C, and subsequent reaction to form the corresponding semicarbazones, for example with the corresponding acid salts of semicarbazones, such as semicarbazide hydrochloride, in aqueous solvent systems, such as i" alcohol/water, for example ethanol/water, at temperatures of from -20 to 60 0 C, preferably from 10 to 30 0 C, and reaction of the resulting semicarbazone with a reactive aldehyde, for example formaldehyde, in an inert solvent, for example a polar organic solvent, for example a carboxylic acid amide, such as dimethylformamide, at temperatures of from to 60 0 C, preferably from 0 to 30 0 C, and then with an acid, for example a strong mineral acid, such as a hydrogen halide, in aqueous solution, if desired in the presence of the solvent previously used, at temperatures of from -400 to 50 0 C, preferably from -100 to 0 C. The corresponding esters are obtained by reaction of the amino acids with the corresponding alcohols, for example ethanol, analogously to the conditions used in the -87condensation under Process for example by reaction with inorganic acid halides, such as thionyl chloride, in organic solvent mixtures, such as mixtures of aromatic and alcoholic solvents, for example toluene and ethanol, at temperatures of from -500 to 50 0

C,

preferably from -100 to 20 0

C.

The preparation of compounds of formula XIII is carried out in an especially preferred manner under conditions analogous to the reaction conditions mentioned in J. Org. Chem.

47, 3016 (1982), J. Org. Chem. 43, 3624 (1978) or J. Org. Chem. 51, 3921 (1986).

For the synthesis of a compound of formula III', a compound of formula XIII is then reacted with a reactive tetrealkylsilane, preferably a halomethyl-tri-lower alkylsilane, such as chloromethyltrimethylsilane, in an inert solvent, for example an ether, such as diethyl ether, a cyclic ether, such as dioxane, or an ester, such as ethyl acetate, at temperatures of from -100° to 50 0 C, preferably from -65° to 40 0 C, there being obtained compounds of formula

OH

IS) R8

(XIV)

HN

Pa wherein R 6

R

7 and R 8 are lower alkyl, for example methyl, and the remaining radicals are as last defined; the resulting compounds are converted in the presence of a Lewis acid, such as boron trifluoride ethyl etherate, in an inert solvent, especially a halogenated hydrocarbon, such as methylene chloride or chloroform, with subsequent aftertreatment with an aqueous base, for example sodium hydroxide solution, at temperatures of from -300 to 80 0 C, especially from 00 to 500C, with elimination and protecting group removal, into an olefinic compound of formula

R

2

~(XV)

H

2

N

-88wherein R 2 is as defined for compounds of formula an amino-protecting group Pa is re-introduced into the corresponding olefin, as described under Process a) for the introduction of amino-protecting groups, especially with the aid of an acid anhydride in a chlorinated hydrocarbon, such as methylene chloride or chloroform, at temperatures of from -500 to 80 0 C, especially from 0° to 35 0 C, there being obtained a protected aminoolefin of formula HN

(XVI)

Pa in which the radicals are as last defined; the double bond is converted into an oxirane, preferably stereoselectively using peroxides, especially peroxycarboxylic acids, for example haloperbenzoic acid, such as m-chloroperbenzoic acid, in an inert organic solvent, preferably a halogenated hydrocarbon, such as methylene chloride or chloroform, at temperatures of from -50° to 60 0 C, especially from -100 to 25 0 C, and, if necessary, diastereoisomers are separated, there being obtained an epoxide of formula 0 S) (XVII)

HN

Pa in which the radicals are as last defined; a suitable malonic acid diester, for example malonic acid dimethyl ester or malonic acid diethyl ester, is added to the olefins in question, for example by activation of the methylene group of the malonic acid diester by means of an alkali metal, for example sodium, in a polar anhydrous solvent, such as an alcohol, for example methanol or ethanol, at temperatures of from -500 to 80 0 C, especially from 00 to 35 0 C, and the solution is treated with an acid, such as a carboxylic acid, for example citric acid, there being obtained a lactone of formula -89- 0 R2" S) 0 (XVIII)

HN

I

Pa wherein R 9 is lower alkoxy, for example methoxy or ethoxy, and the remaining radicals are as last defined; if desired, in those compounds in which R 2 is phenyl that is unsubstituted or substituted as described for compounds of formula that radical is reduced to cyclohexyl, especially by hydrogenation, preferably in the presence of catalysts, such as noble metal oxides, for example mixtures of Rh(III)/Pt(VI) oxides (in accordance with Nishimura), preferably in polar solvents, such as alcohols, for example methanol, at normal pressure or at up to 5 bar, preferably at normal pressure, at temperatures of from to 50 0 C, preferably from 100 to 35 0 C; a compound of formula XVIII obtained directly or after hydrogenation is reacted with a reagent that introduces the radical R 3

-CH

2 for example of the formula R 3

-CH

2 -W wherein R 3 is as defined for compounds of formula I' and W is a nucleofugal leaving group selected from hydroxy esterified by a strong inorganic or organic acid, such as hydroxy esterified by a mineral acid, for example a hydrohalic acid, such as hydrochloric, hydrobromic or hydriodic acid, or by a strong organic sulfonic acid, such as an unsubstituted or substituted, for example halo-substi- S tuted, such as fluoro-substituted, lower alkanesulfonic acid or an aromatic sulfonic acid, for example benzenesulfonic acid that is unsubstituted or substituted by lower alkyl, such as methyl, halogen, such as bromine, and/or by nitro, for example a methanesulfonic, trimethanesulfonic or p-toluenesulfonic acid, and hydroxy esterified by hydrazoic acid, especially bromide, in an anhydrous polar solvent, for example an alcohol, such as ethanol, in the presence of an alkali metal, for example sodium, at temperatures of from -50° to 80 0

C,

S preferably from 00 to 35 0 C, yielding a compound of formula

R

3 0

(R,S)

(S)

R (S O (XIX)

HN

Pa wherein the radicals are as last defined; the compound of formula XIX is hydrolysed and decarboxylated, for example by hydrolysis by means of a base, such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, at temperatures of from -500 to 80 0 C, preferably approximately from 00 to 35 0 C, in an organic solvent, for example an ether, such as dimethoxyethane, or an alcohol, such as ethanol, and subsequent decarboxylation by heating in an inert solvent, preferably a hydrocarbon, for example an aromatic hydrocarbon, such as toluene, at temperatures of from 400 to 120 0 C, preferably from 700 to 120 0 C, there being obtained a compound of formula

R

3 R2 0

(XX)

HN

I

Pa wherein the radicals are as last defined; the resulting and (S,S,S)-isomers are separated by column chromatography, and the (R,S,S)-isomer is used further and, for the purpose of opening the lactone ring, is reacted with a base, such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide, in an inert solvent, such as an ether, for example dimethoxyethane, or an alcohol, such as ethanol, yielding a compound of foimula OH R 3

(R)

COOH

(XXI)

HN

Pa wherein the radicals are as last defined; there is introduced into the resulting compound a hydroxy-protecting group Py, for example one of the hydroxy-protecting groups mentioned under Process a) under the conditions mentioned therein, especially a tri-lower alkylsilyl group with the aid of the corresponding halo-tri-lower alkylsilane, for example tert-butyldimethylchlorosilane, in a polar solvent, such as a di-lower alkyl-lower alkanoylamide, such as dimethylformamide, in the presence of a sterically hindered amino -91 compound, such as a cyclic amine, for example imidazole, at temperatures of from -500 to 0 C, preferably from 00 to 35 0 C, yielding a compound of formula Py SR3

(XXII)

2

COOH

HN

Pa wherein the radicals are as last defined; or is acylated directly with a compound of formula XXV or with a reactive derivative thereof, as defined above, with the introduction of the radical T, as described above under Process there being obtained the corresponding compound of formula

T

I

R

2

(XXII')

COOH

HN

Pa which contains the radical T in place of Py and in which the remaining radicals are as defined; and a compound of formula III' having the radicals indicated under Process a) is prepared from a compound of formula XXII or XXII', for example by condensation with a compound of formula VII wherein the radicals are as defined under Process under the S conditions indicated for Process especially by in situ reaction in the presence of a condensation agent, such as benzotriazol-l-yl-oxy-tris(di-methylamino)phosphonium hexafluorophosphate or O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate, a sterically hindered amine, such as N-methylmorpholine, and a compound hindering racemisation, such as 1-hydroxybenzotriazole, in a polar solvent, preferably an acid amide, for example a di-lower alkylamino-lower alkanoylamide, such as dimethylformamide, at temperatures of from -500 to 80 0 C, especially from 00 to 35 0 C, and by subsequent protecting group removal of Pa, as described under Process provided Pa is not a radical corresponding to the residue H-B 1 as defined above for compounds of formula I' with the exception of a bond, condensation with a compound of the formula -92- H-B '-OH wherein B 1 is as defined under Process under the last-mentioned condensation conditions and finally removal of Py (only in the case of a compound of formula XXII) and/or further protecting groups, as described under Process and if nececssary (in the case of a compound having a free hydroxy group prepared from a compound of formula XXII) the introduction of T, as described under Process For the preparation of a compound of formula II' there is also possible successive condensation of a compound of formula XXII or XXII' with compounds that introduce the residues

-A

1

-A

2

-A

1

-A

2

A

2

-NR

4

R

5 and/or -NR 4

R

5 of the compound of formula VII, ui.der conditions analogous to those mentioned for Process and when a compound of formula XXII is used the protecting group Py is removed according to one of the methods described under Process f) and the radical T must then be introduced using a compound of formula XXV or a reactive derivative thereof under the reaction conditions mentioned for Process g).

The route from an above-mentioned compound of formula XVIII to a compound of formula XX may also be as follows: Hydrolysis of a racemic compound of formula XVIII (which can be prepared from the racemate of a compound of formula XVI via the corresponding racemate of a compound of formula XVII) and decarboxylation under conditions analogous to those employed for the hydrolysis and decarboxylation of compounds of formula XIX result in a compound which is analogous to the compound of formula XIX but in which the radicals R 3

-CH

2 and R 9 are absent and which is in the form of a racemate; that compound is then reacted with a compound of the formula R 3

-CH

2 as defined below of formula XVII, wherein W is one of the nucleofugal leaving groups mentioned there, especially halogen, such as bromine or chlorine, by deprotonation in the presence of a strong base, such as an alkali metal bis(tri-lower alkylsilyl)amide, for example lithium bis(trimethylsilyl)amide, followed by alkylation with the compound of the formula R 3

-CH

2 -W (preferably yielding the 3

-CH

2 and the 3 -CH2-),5(R)-compound of formula XX, that is to say a racemate).

The afore-mentioned compounds of formula XV can also be in the (R,S)-configuration at the carbon atom carrying the radical -NH 2 instead of in the (S)-configuration shown, and the compounds of formulae XII, XIII, XIV and especially those of formulae XVI, XVII, XVIII, XIX, XX, XXI and/or XXII can also be in the (R,S)-configuration at the carbon atom carrying the radical Pa-NH- instead of in the (S)-configuration. The afore-mentioned S93compounds of formulae XVI, XVII and XVIII can also be in the form of racemates, that is to say the optical antipodes of the formulae shown are also possible. It is possible to obtain from those racemates, for example, corresponding compounds of formula VI' (for example racemates if R 1 and T 1 do not contain centres of asymmetry) so that in this manner a compound of formula I' can be obtained wherein either the carbon atom carrying

R

2

-CH

2 is in the (S)-configuration, the carbon atom carrying T-O- is in the (S)-configuration and the carbon atom carrying R 3

-CH

2 is in the (R)-configuration (2R,4S,5S), or the mentioned carbon atoms have the opposite configuration (2S,4R,5R); or mixtures of compounds of formula VI' or I' having those two configurations may also be obtained.

Corresponding racemic mixtures or mixtures of diastereoisomers can (preferably) be separated into the individual isomers at any stage.

A compound of formula XX wherein the radicals are as defined is also prepared from a compound of formula XIII wherein the radicals are as defined, by reacting an aldehyde of formula XII with a 2-halopropionic acid ester, especially a 2-iodopropionic acid ester, such as 2-iodopropionic acid ethyl ester, there being obtained a compound of formula

(R,S)

(XX III

HN

Pa wherein the radicals are as defined and wherein the carbon atom carrying the radical Pa-NH- may alternatively also be in the (R,S)-configuration.

The reaction is carried out first with the formation of the homoenolate of the 2-halopropionic acid ester in the presence of a mixture of Zn/Cu in a di-lower alkyl-lower alkanoylamide, such as dimethylacetamide, at temperatures of from 00 to 100 0 C, especially from 200 to 80 0 C. In a further batch, preferably under protective gas, such as nitrogen or argon, a titanium tetrahalide, such as titanium tetrachloride, is added to a tetra-lower alkyl orthotitanate, such as tetraisopropyl orthotitanate, in an aromatic solvent, such as toluene or xylene, in the presence of a halogenated hydrocarbon, such as methylene chloride, and the mixture is stirred at from 00 to 50 0 C, especially from 200 to 0 C, there being formed the corresponding dihalotitanium di-lower alkanolate or prefer- -94ably the trihalotitanium lower alkanolate, especially trichlorotitanium diisopropanolate.

The zinc homo-enolate solution is added dropwise thereto at temperatures of from -500 to 0 0 C, especially from -40° to -25 0 C, and then the aldehyde of formula XIII in a halogenated hydrocarbon, for example methylene chloride, is added dropwie, the reaction taking place at from -500 to 30 0 C, preferably approximately from -20° to 5 0 C, with the formation of an ester, especially an ethyl ester, of the compound of formula XXIII. That ester is then hydro'ysed to form the compound of formula XIII, as defined above, preferably in an organic solvent, such as an aromatic compound, for example in toluene or xylene, in the presence of an acid, such as a carboxylic acid, for example acetic acid, at temperaturc of from 20 0 C to the boiling point of the reaction mixture, especially from 700 to 100 0 C. If necess ary, diastereoisomers are separated, for example by chromatography, for example on silica gel with an organic solvent mixture, such as a mixture of alkane and ester, such as lower alkane and lower alkyl-lower alkanoyl ester, such as hexane/ethyl acetate.

From the compound of formula XXIII, the corresponding compound of formula XX is Sthen obtained by deprotonation with a strong base, yielding the carbanion which is formed at the a-carbon atom adjacent to the oxo group of the lactone, and by subsequent nucleophilic substitution of the radical W of a compound of the formula R 3

-CH

2 -W wherein R 3 and W are as defined above for the preparation of compounds of formula XIX (W is especially bromo), the reaction preferably resulting stereoselectively in the (R)-configuration at the carbon atom carrying the radical R 3

-CH

2 in the compound of formula XX. The reaction with the strong base, especially with an alkali metal organosilicon amide .compound, for example an alkali metal bis(tri-lower alkylsilyl)amide, such as lithium bis- (trimethylsilyl)amide, or with an alkali metal di-lower alkylamide, such as lithium diisopropylamide, is preferably carried out in an inert organic solvent, especially an ether, for example a cyclic ether, such as tetrahydrofuran, or 1,3-dimethyl-3,4,5,6-tetrahydro- 2(lH)-pyrimidinone (DMPU), or mixtures of those solvents, at temperatures of from -100° to 0°C, preferably from -78° to -50 0 C, and the nucleophilic substitution is effected in situ S by the addition of the compound of the formula R 3

-CH

2 in the same solvent at temperatures of from -1.00 0 to 0°C, preferably from -60° to -40 0

C.

A compound of formula XV wherein the radicals are as defined and wherein preferably the carbon atom carrying the group -NH 2 is in the (R,S)-configuration can also be obtained by converting a formic acid ester, for example a formic acid lower alkyl ester, such as formic acid ethyl ester, by reaction with allylamine at temperatures of from 200 to 70 0

C,

especially from 500 to 60 0 C, into formic acid allylamide. That amide is then dehydrated under protective gas, such as nitrogen or argon, preferably with an acid halide, such as phosphorus oxychloride, phosgene or especially an organic sulfonic acid halide, for example an arylsulfonic acid chloride, such as toluenesulfonic acid chloride, in the presence of a base, for example a tri-lower alkylamine, such as triethylamine, or especially a mono- or bi-cyclic amine, such as pyridine or quinoline, at temperatures of from 500 to, 100 0 C, especially from arproximately 800 to approximately 100 0 C. An allyl isocyanide is formed which is converted by reaction with an organolithium salt, for example lower alkyllithium, such as n-butyllithium, into the corresponding lithium salt, the reaction preferably being carried out in an inert organic solvent, especially an ether, such as dioxane or dithyl ether, or an alkane, for example hexane, or a mixture of those solvents, at temperatures of from -120° to -50 0 C, especially approximately from -100 to -90 0 C. The lithium salt formed is then reacted in situ with a compound of the formula R 2

-CH

2

-W

wherein R 2 is as defined for compounds of formula I and W is as defined above for compounds of the formula R 3

-CH

2 especially bromine, preferably by the dropwise addition of R 2

-CH

2 -W in an organic solvent, for example an ether, such as tetrahydrofuran, at the temperatures last mentioned and with subsequent heating at from 00 to 50 0

C,

preferably from 200 to 30 0 C, yielding an isocyanide of formula

R,

(XXIV)

IC-EN

oe

E

wherein the radicals are as defined. The compound of formula XXIV is then hydrolysed, preferably in an aqueous solution to which an acid has been added, for example in an aqueous hydrohalic acid, such as hydrochloric acid, especially in concentrated hydro- S chloric acid, at temperatures of from -200 to 30 0 C, especially approximately from 00 to 0 C, yielding the compound of formula XV wherein the radicals are as last defined and wherein the carbon atom carrying the group -NH 2 is preferably in the (R,S)-configuration.

Compounds of formula IV are known or can be prepared in accordance with processes known per se, for example by condensation of carboxylic or sulfonic acids of formula II, or reactive derivatives thereof, with amino compounds of the formula H-B 1 '-OHI wherein B is as defined for compounds of formula IV, the condensation being carried out as last

I

-96described, or in the case of compounds of formula II wherein R 1 is N-(heterocyclyllower alkyl)-N-lower alkylaminocarbonyl, such as N-(2-pyridylmethyl)-N-methyl-aminocarbonyl, analogously to EP 0 402 646 of 19.12.1990, Example 218.

A compound of formula V' is prepared, for example, from a compound of formula XXII or XXII' by condensation with a compound of formula VII or successive condensation with compounds (for example H-A 1

H-A

2

H-A

1

-A

2 -OH or the compound of formula XI, wherein the residues are in each case as defined above) that correspond to fragments of the compound of formula VII. The condensation conditions are analogous to those described for the preparation of the compounds of formula III'; when a compound of formula XXII is used, T is then introduced by reaction with a compound of formula XXV or with a reactive derivative thereof, as defined under Process under the conditions mentioned for Process g).

A compound of formula VI' is prepared, for example, from an amino compound of Sformula XXII or XXII', for example by the introduction of a carboxy-protecting group, as Sdescribed under Process and removal of the protecting group Pa, as described under Process by condensation with a carboxylic acid of the formula R 1 -B -OH wherein the radicals are as defined for compounds of formula When a compound of formula XXII is used, T is then introduced by reaction with a compound of formula XXV or with a reactive derivative thereof, as defined under Process under the conditions mentioned for Process g).

A compound of formula VII is prepared, for example, from the corresponding amino acid H-Ai'-OH or H-A 2 '-OH or the peptide H-A 1

-A

2 -OH and the amine components of formula XI, wherein the radicals are in each case as defined above, by condensation analogously to the process described under Process For the prepaiation of a compound having a reduced peptide bond between A 1 and A 2 the peptide bond between A 1 and A 2 can be reduced, preferably at the dipeptide stage, for example with hydrogen in the presence of heavy metal or noble metal catalysts, 3uch as platinum or palladium, optionally on carriers, such as activated carbon, or by means of complex hydrides, preferably complex hydrides, for example lithium aluminium hydride or diisoamyl borane in polar solvents, such as alcohols, for example ethanol, or ethers, such as cyclic ethers, for example tetrahydrofuran, at temperatures of from 00 to 150 0 C, preferably from 20 0 C to the boiling point of the reaction mixture in question. The amine of formula XI is known or is prepared in accordance with methods known per se.

-97- A compound of formula VIII' can be prepared, for example, from a compound of formula VI' by condensation with an amino acid that introduces the residue A 1 The reaction is carried out analogously to the conditions described under Process a).

A compound of formula IX is prepared, for example, from an amino acid H-A 2

'-OH,

wherein A 2 is as defined under Process and an amine of formula XI wherein the radicals are as defined for compounds of formula I, by condensation.

A compound of formula X' is prepared, for example, from a compound of formula VI' and from the corresponding amino acid H-Al'-OH or H-A 2 '-OH or the peptide

H-A

1

-A

2 -OH wherein the residues are in each case as defined above, by condensation analogously to the process described under Process For the preparation of a compound having a reduced peptide bond between A 1 and A 2 the peptide bond between A 1 and A 2 is S.reduced, preferably at the dipeptide stage, for example with hydrogen in the presence of heavy metal or noble metal catalysts, such as platinum or palladium, optionally on carriers, such as activated carbon, or by means of complex hydrides, preferably complex hydrides, such as lithium aluminium hydride or diisoamyl borane in polar solvents, such S.as alcohols, for example ethanol, or ethers, such as cyclic ethers, for example tetrahydrofuran, at temperatures of from 0° to 150 0 C, preferably from 20 0 C to the boiling point of the reaction mixture.

The amine of formula XI is known and is commercially available or is prepared in accordance with methods known per se.

Compounds of formula XXV are known or can be prepared in accordance with processes known per se, or they are commercially available.

There may be mentioned by way of example the preparation of a compound of formula XXV wherein T is arylcarbonyl substituted by heterocyclyl-lower alkyl wherein heterocyclyl is bonded via a ring nitrogen atom, which is preferably effected by reaction of a halo-lower alkyl-substituted, such as chloro- or bromo-methyl-substituted, arylcarboxylic acid, such as chloromethylbenzoic acid or bromomethylbenzoic acid, with a corresponding heterocyclic nitrogen base, such as piperidine, piperazine, 1-lower alkylpiperazine or especially morpholine or thiomo;pholine, with nucleophilic substitution of the halogen atom.

-111 0 -98- Compounds of formula I can be prepared in accordance with the processes given in the European Patent Application having the publication number EP 0 532 466 (published on 17th March 1993; an English language equivalent has been applied for, for example, in South Africa). That European Patent Application is therefore included in this text by reference.

A compound of formula I can preferably be prepared analogously to a compound of formula I' in accordance with one of Processes a) up to and including by using in Process instead of a compound of formula III', a compound of formula III

H

RA

H-B i S; 0 R2 2 wherein the radicals are as defined for compounds of formula III', yielding the compound of formula Ib which contains a hydrogen atom in place of T in a compound of formula Ib' and in which the remaining radicals are as defined for compounds of formula Ib', (which can be prepared analogously to a compound of formula III' from a compound of formula XXII but omitting the acylation with a compound of formula XXV), or by using in Process instead of a compound of formula a compound of formula V

H

Sx, R3 *H R 4 N A. *N R 5 H

R

formula Ic which contains a hydrogen atom in place of T in a compound of formula Ic' and in which the remaining radicals are as defined for compounds of formula Ic', (which can be prepared anaiogously to a compound of fo-mula V' from a compound of formula XXII but omitting the acylation with a compound of formula XXV), or by using in Process instead of a compound of formula VI', a compound of formula VI I I -99-

H

R\ 3 H 0 I N OH

(VI),

B

1 0O

R,

wherein the radicals are as defined for compounds of formula VI', (which can be prepared analogously to a compound of formula VI' from a compound of formula XXII but omitting the acylation with a compound of formula XXV), or by using in Process d) for the preparation of a compound of formula Id which contains a hydrogen atom in place of T in a compound of formula Id' and in which the remaining radicals are as defined for compounds of formula Id', instead of a compound of formula VII', a compound of formula VIII

H

R3 H O R N

(VIII),

OH

R2 wherein the radicals are as defined for compounds of formula VIII', (which can be prepared analogously to a compound of formula VIII' from a compound of formula VI), or by using in Process instead of a compound of formula a compound of formula X

H

H 0 R3 R, N R N A 0H B A 2

B

1 R2 wherein the radicals are as defined for compounds of formula (which can be prepared analogously to a compound of formula X' from a compound of formula VI), or by using in Process instead of a compound of formula I' wherein at least one functional group is in protected form, a compound of formula I having at least one protected functional group, 100with removal of protecting groups.

The present invention relates also to the intermediates of formula I and their salts where salt-forming groups are present, if they are novel. They likewise have pharmaceutical activity, as described above for the compounds of formula I that can be freed from the compounds of formula and can be present in pharmaceutical compositions instead of compounds of formula the corresponding pharmaceutical compositions are obtained by using compounds of formula I instead of compounds of formula I' above in the description of the pharmaceutical compositions. The compounds can therefore be used in the treatment of diseases and, like the compounds of formula can be incorporated into pharmaceutical compositions and used for the treatment of retroviral diseases, such as AIDS, especially by inhibition of HIV-I- or HIV-II-protease.

They are preferably compounds of formula I O 3 H oH R" R 4 R N A 2 N

(I)

IR

0

SR

2 wherein

R

1 is hydrogen, lower alkoxycarbonyl, heterocyclylcarbonyl, benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals selected independently of one another from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, heterocyclyloxycarbonyl wherein heterocyclyl is bonded via a carbon atom, one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group, heterocyclylsulfonyl, lower alkylsulfonyl or N-(heterocyclyl-lower alkyl)-N-lower alkylaminocarbonyl, as defined for compounds of formula especially tert-butoxycarbonyl;

R

2 is phenyl, cyclohexyl, lower alkoxyphenyl, especially m- or p-methoxyphenyl, benzyloxyphenyl, especially p-benzyloxyphenyl, p-fluorophenyl, p-trifluoromethylphenyl or p-hydroxyphenyl,

R

3 is phenyl, lower alkoxyphenyl, especially m- or p-methoxyphenyl, p-trifluoromethylphenyl, m- or p-cyanophenyl, benzyloxyphenyl, especially p-benzyloxyphenyl, m- or p-fluorophenyl or hydroxyphenyl, -101- A, is the bivalent residue of the amino acid (L)-valine, (L)-isoleucine or glycine bonded N-terminally to the group -C=O and C-terminally to A 2

A

2 is the bivalent residue of the amino acid glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, cyclohexylalanine, p-lower alkoxyphenylalanine, such as p-methoxy-phenylalanine, p-benzyloxyphenylalanine or p-fluorophenylalanine bonded N-terminally to A, and C-terminally to the group NR 4

R

5 and

R

4 and R 5 together with the bonding nitrogen atom form unsubstituted or substituted thiomorpholino or morpholino, especially morpholino, with the proviso that at least either one of the radicals R 2 and R 3 is benzyloxyphenyl or A 2 is the bivalent residue of p-benzyloxyphenylalanine, while the remaining radicals are as defined, when either R 3 is other than o- or m-fluorophenyl, o- or m-cyanophenyl or o- or m-methoxyphenyl, or when A 2 is other than alanine or leucine; or salts of those compounds where salt-forming groups are present.

Of those compounds preference is given to the compounds of formula I wherein Ri is tert-butoxycarbonyl, R 2 is phenyl, p-benzyloxyphenyl or m- or p-methoxyphenyl, R 3 is phenyl, p-benzyloxyphenyl, m- or p-methoxyphenyl, m- or p-fluorophenyl or hydroxyphenyl, A, is the bivalent residue of the amino acid (L)-valine, (L)-isoleucine or glycine, especially of (L)-valine, bonded N-terminally to the group -C=O and C-terminally to A 2

A

2 is the bivalent residue of the amino acid glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, cyclohexylalanine, p-lower alkoxyphenylalanine, such as p-methoxy-phenylalanine, p-benzyloxyphenylalanine or p-fluorophenylalanine, especially of phenylalanine, tyrosine, p-methoxy-phenylalanine, p-benzyloxyphenylalanine or p-fluorophenylalanine, bonded N-terminally to A, and C-terminally to the group NR 4

R

5 S and R 4 and R 5 together with the bonding nitrogen atom form morpholino, with the proviso that at least either one of the radicals R 2 and R 3 is benzyloxyphenyl or A 2 is the bivalent residue of p-benzyloxyphenylalanine, while the remaining radicals are as defined.

Special preference is given also to the compounds of formula I wherein R 1 is tert-butoxycarbonyl, R 2 is phenyl, R 3 is o- or m-fluorophenyl, o- or m-cyanophenyl or 0o- or m-lower alkoxyphenyl, such as o- or m-methoxyphenyl, A 1 is the bivalent residue of the amino acid (L)-valine, (L)-isoleucine or glycine, especially of (L)-valine, bonded N-terminally to I EM -102the group -C=O and C-terminally to A 2

A

2 is the bivalent residue of the amino acid glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, cyclohexylalanine, p-lower alkoxyphenylalanine, such as p-methoxy-phenylalanine, p-benzyloxyphenylalanine or p-fluorophenylalanine, especially of phenylalanine, tyrosine, p-lower alkoxyphenylalanine, such as p-methoxy;-pheriylalanine, p-benzyloxyphenylalanine or p-fluorophenylalanine, bonded N-terminally to A, and C-ter minally to the group NR 4

R

5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino.

Special preference is given to a compound of formula I having the name: Boc-Phe[C] (o-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C] (m-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylami.de, Boc-Phe[C] (p-B zlO)Phe-(L)-Yal-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C] (p-B zlO)Phe-(L)-Val-(L)-(p-BzlOPhe)-morpholin-4-ylamide, Boc-(p-BzlO)PheIIC]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-BzlO)Phe[C]Phe-(L)- V'al-(L)-(p-BzlOPhe)-morpholin-4-ylamide, Boc-(p-BzlO)Phe[C] (p-BzlO)Phe-(L)-Val-(L)-Phe-morpholin-4-ylainide, Boc-(p-BzlO)PheIC] (p-BzlO)Phe-(L)-Val-,(L)-(p-BzlOPhie)-morpholin-4-ylahide, Boc-PheliC] (o-F)Phe-(L)-Val-(L)-Phe-morpho~lin-4-ylamide, Boc-Phe[C](o-F)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide, Boc-PheiC] (m-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylainlide, Boc-Phe[C] (m-F)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide, Boc-Phe[C]Phe-(L)-Val-(L)-L-eu-morpholin-4-ylamfide, Boc-Phe[C]Phe-(L)-Val-(L)-Ala-morpholin-4-ylamide, Bo-pC3)h[]pBI)h-L-Vl()Pemrhln4yaie Boc-(p-CH 3 O)PheIC](pB Boc-(p-CH 3 0)PheIC] (p-BzlO)Phe-(L)-Val-(L)-Tyr-morpholin-4-ylamide, Boc-(p-CH 3 O)Phe[C] (3-CH 3 O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-CH 3 O)Phe[C] (2-CH 3 O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C] (3-CH 3 OPh-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-PheliC] (2-CH 3 O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-Phe[C](3C3 H0Pe-orhln4yaie Boc-PheliC](2C3 h-L-al()(-H0Pe)mrhln4yamide or Boc-PheiC] (p-B zlO)Phe-(L)-Val-OL)-(p-CH 3 -Phe)-morpholin-4-ylamide or alternatively a compound having the name: -103- Boc-(p-CH 3 0)Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (very especially preferred), 3 0)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (very especially preferred), Boc-(p-CH30)Phe[C]Tyr-(L)-Val-(L)-Phe-morpholin-4-ylamide, Boc-(p-CH 3 0)Phe[CIPhe-(L)-Val-(L)-(p-CH 3 0-Phe)-morpholin-4-ylamide, Boc-(p-CH 3 O)Phe[C]Phe-(L)-Val-(L)-Tyr-morpholin-4-ylamide, Boc-(p-CH 3 0O)Phe[C] (p-CH 3 0)Phe-(L)-Val-(L)-(p-CH 3 0-Phe)-morpholin-4-ylamide, Boc-(p-CH 3 0O)Phe[C](p-CH 3 O)Phe-(L)-Val-(L)-Tyr-morpholin-4-ylamide, Boc-(p-CH 3 0)Phe[C]Tyr-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide or Boc-(p-CH30)Phe[C]Tyr-(L)-Val-(L)-Tyr-morpholin-4-ylamide.

Finally, the compound of formula I having the name: Boc-Phe[c](p-CH30)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide S. 5(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-2(R)-(p-methoxy-phenylmethyl)- 6-phenyl-hexanoyl-(L)-valyl-(L)-phenyl-alanyl-morpholin-4-ylamide) is very especially preferred.

A compound of formula XXVI can be prepared, for example, from a compound of formula I by reaction with a carboxylic acid of formula Wi-(CmH 2 m)COOH

(XXVII)

wherein the radicals are as defined for compounds of formula XXVI, or with a reactive acid derivative thereof that contains in place of the carboxy group a radical wherein Z 1 is as defined for compounds of formula XXV', under conditions analogous to those mentioned for Process g).

S The isocyanates of formula XXV" can be prepared, for example, from the corresponding amine precursors by conversion of the amino group into the isocyanato group, for example by reaction with phosgene at elevated temperature, for example under reflux conditions, or by the dropwise addition of the primary, secondary or tertiary amine, which is liquid or dissolved in a solvent, to an excess of phosgene in a suitable solvent (toluene, xylene, ligroin, chlorobenzene, c-chloronaphahalene etc.) with cooling (for example to -500 to 0 0 there being formed intermediately a mixture of carbamoyl chloride and amine -104hydrochloride, which is then phosgenated further at elevated temperature (for example at from 50 0 C to the reflux temperature) until completely dissolved, with HC1 being eliminated.

The remaining starting compounds are known, are prepared according to processes known per se and/or are commercially available.

The following applies generally to all the processes mentioned hereinabove and hereinbelow: As a result of the close relationship between the compounds of formula I' and their salts and starting materials (starting compounds and intermediates) in free form and in the form of their salts, hereinabove and hereinbelow any reference to the free compounds or their salts should be understood as including also the corresponding salts or free compounds, respectively, as appropriate and expedient.

All the above-mentioned process steps can be carried out under reaction conditions known per se, pre .erably the reaction conditions specifically mentioned, in the absence or, usually, in the presence of solvents or diluents, preferably those solvents or diluents which S. are inert towards the reagents used and are solvents therefor, in the absence or presence of catalysts, condensation agents or neutralising agents, for example ion exchangers, such as cation exchangers, for example in the H form, and depending upon the nature of the reaction and/or the reactants, at reduced, normal or elevated temperature, for example in a temperature range of from approximately -100°C to approximately 190 0 C, preferably from approximately -80 0 C to approximately 150 0 C, for example at from -80 to -60 0 C, at room temperature, from -20 to 40 0 C or at reflux temperature, under atmospheric pressure, or in a S* closed vessel, optionally under pressure and/or in an inert atmosphere, for example under an argon or nitrogen atmosphere.

At all stages of the reaction it is possible for any isomeric mixtures which may occur to be separated into the individual isomers, for example diastereoisomers or enantiomers, or into desired mixtures of isomers, for example racemates or diastereoisomeric mixtures, for example analogously to the methods described under "Additional Process Steps".

In certain cases, for example in the case of hydrogenation, it is possible to obtain stereoselective reactions, so that, for example, individual isomers can be obtained more easily.

-105- The solvents from which the solvents suitable for any particular reaction can be selected include, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example tetrahydrofuran, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as methylene chloride, acid amides, such as dimethylformamide, bases, such as heterocyclic nitrogen bases, for example pyridine, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or isopentane, or mixtures of those solvents, for example aqueous solutions, unless indicated to the contrary in the description of the processes. Such solvent mixtures can also be used in working-up, for example by chromatography or partition.

The compounds, including their salts, may also be obtained in the form of hydrates, or their crystals may include, for example, the solvent used for crystallisation.

The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for example in protected form or in the form of a salt, or a compound obtainable in accordance with the process of the invention is produced under the process conditions and is processed further in situ. In the process of S. the present invention it is preferable to use those starting materials which result in the compounds described at the beginning as being especially valuable. Reaction conditions i: analogous to those mentioned in the Examples are especially preferred.

Where necessary, protected starting compounds can be used at any stage of the process and the protecting groups can be removed at suitable stages of the reaction.

Protecting groups and the manner in which they are introduced and removed are as described under Processes a) and f).

The following Examples are intended to illustrate the invention but do not limit the scope thereof in any way. The Reference Examples listed at the beginning are starting compounds (of formula I) for the Examples (of formula listed thereafter.

I -106- Any reference to "Reference Examples" relates either to the "Reference Examples" specifically described hereinafter or to the Examples mentioned in European Patent Application EP 0 532 466 (published 17th March 1993, incorporated in the present text by reference) (the numbers of those Examples are thus identical to the "Reference Example" numbers given below).

Temperatures are given in degrees Celsius Where no temperature is specified, the reaction takes place at room temperature. The Rf values, which indicate the ratio of the seepage propagation of the substance in question to the seepage propagation of the eluant front, are determined on thin-layer silica gel plates by thin-layer chromatography (TLC) in the following solvent systems: TLC eluant systems: o o r

D

*0 0*40 hexane/ethyl acetate ethyl acetate hexane/ethyl acetate hexane/ethyl acetate hexane/ethyl acetate methylene chloride/methanol chloroform/methanol/water/glacial acetic acid ethyl acetate/methanol hexane/ethyl acetate chloroform/methanol/acetic acid/water ethyl acetate/acetic acid methylene chloride/methanol methylene chloride/ether methylene chloride/ether ethyl acetate/THF hexane/ethyl acetate methylene chloride/hexane/ether methanol ethyl acetate/hexane ethyl acetate/ethanol 1:1 4:1 2:1 3:1 9:1 85:13:1.5:0.5 9:1 1:2 75:27:5:0.5 19:1 7:3 49:1 3:1 9:1 8:1 10:10:1 3:1 97:3 -107- U THF/ethyl acetate 3:1 V methylene chloride/THF 2:1 W methylene chloride/propanol/methanol/triethylamine 8:3:3:1 X acetonitrile/ethyl acetate 1:1 Y ethyl acetate/ethanol 95:5 Z methylene chloride/methanol 12:1 A' methylene chloride/diethyl ether 1:1 B' methylene chloride/tetrahydrofuran 4:1 C' methylene chloride/tetrahydrofuran 1:1 The above-mentioned letter codes for TLC systems are also used in some cases to indicate the eluants in column chromatography.

The abbreviation for example, indicates that the Rf value was determined in solvent system A. The quantitative ratio of solvents to one another is always given in parts by volume The quantitae tio of the solvents used in the definition of the eluant systems for column chromatography are also given in parts by volume The ther shortened names and abbreviations used have the following meanings: abs. absolute Satm physical atmospheres Anal. elemental analysis Boc tert-butoxycarbonyl SBOP benzotriazol- 1-yloxy-tris(dimethylo. :amino)phosponium hexafluorophosphate brine saturated sodium chloride solution Scalc. calculated (unit of pressure) 1 atm corresponds to 1.013 bar DCC dicyclohexylcarbodiimide DEPC pyrocarboxylic acid diethyl ester DIPE diisopropyl ether DMAP 4-dimethylaminopyridine DMF dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro- 2(1H)-pyrimidinone i -108- DMSO dimethyl sulfoxide ethr diethyl ather Fj. i-MS Fast-Atom-Bombardment mass spectroscopy h hour(s) HBTU O-benzotriazol- 1-yl-N,N,N',N'tetramethyluronium hexafluorophosphate HOBt l-hydroxybenzotriazole HV high vacuum IR infrared spectroscopy min minute(s) m.p. melting point NMM N-methylmorpholine org. organic Pd/C palladium on activated carbon (catalyst) 'propanol isopropanol RE rotary evaporator RT room temperature oat. saturated TBAF tetrabutylammonium fluoride (trihydrate) TFA trifluoroacetic acid THF tetrahydrofuran TLC thin-layer chromatography Z benzyloxycarbonyl Mass spectroscopic data are obtained according to the "Fast-Atom-Bombardment" S(FAB-MS) method. The mass data relate to the protonatcd molecule ion The values for the IR spectra are given in with the solvent in question indicated in round brackets.

The abbreviations customary in peptide chemistry are used to denote divalent residues of natural a-amino acids. The configuration at the a-carbon atom is indicated by the prefix or -Cha- denotes cyclohexylalanyl, denotes phenylalanyl substituted in the p-position of the phenyl ring by fluorine, -(p-CH 3 O-Phe)- denotes phenylalanyl substituted in the p-position of the phenyl ring by a methoxy group, -(p-BzlOPhe)- denotes -109phenylalanyl substituted in the p-position by a benzyloxy group, -(p-CN-Phe)- denotes phenylalanyl substituted in the p-position of the phenyl ring by a cyano group, butyloxy-Phe)- denotes phenylalanyl substituted in the p-position of the phenyl ring by n-butoxy and -(4-isobutyloxy-Phe)- denotes phenylalanyl substituted in the p-position of the phenyl ring by isobutoxy.

HPLC-gradients: 1 20 100%a) in b)for H 20 -100 in b)for 35 min.

111 120% 10% a) in b)for 30 min.

IV 20 -100 inb) for 20 min and then 100 for 8min.

Eluant acetonitrile 0.05 TFA; eluant water 0.05 TFA. Column (250 x 4.6 mm) filled with "Reversed-Phase" material C 18 -Nucleosil® (5 gmi mean particle size, silica gel covalently derivatised with octadecylsilanes, Mach-_ey Nagel, Diiren, Federal Republic of Germany). Detection by UV absorption at 215 nm. The retention times (tlet) are given in minutes. Flow rate 1 mI/min.

T he following abbreviations for residues are defined by the corresponding formulae and names: The residue with the abbreviation -Phe[C]Phe- denotes the divalent residue of amino-2,(R)-benzyl-4(S)-hydroxy-6-phenylhexanoic acid and has the formula -110-

H

The residue with the abbreviation -Cha[C] (p-CN)Phe- denotes the divalent residue of 5(S)-amino-2(R)-(p-cyanophenylmethyl)-6-cyclohexyl-4(S)-hydroxyhexanoic acid and has the formula 0 9 0* 0* 0 0 0* 00 0 000 0 00 000 0 H OH The residue with the abbreviation -Cha[C]Cha- denotes the divalent residue of amino-6-cyclohexyl-2(R)-cyclohexylmethyl-4(S)-hydroxyhexanoic acid and has the formula 00 00 0 0 0000 0 ill The residue with the abbreviation -Cha[Clip-F)Phe- denotes the divalent residue of amino-6-cyclohexyl-2(R)-(p-fluorophenylmethylI)-4(S)-hydroxyhexanoic acid and has the formula

F

H

OH

N

0

C

The residue with 'the abbreviation -(p-F)Phe[C]Phe- denotes the divalent residue of amino-2(R)-benzyl-6-(p-fluorophenyl)-4(S)-hydroxyhexano,)ic acid and has the formula H OH

N

0

F

The further formulae of central building blocks shown below correspond to the following abbreviations, which are used in the Examples which follow.

C. 0

C

V.

112-

Y

NN

0 x xx I

Y

NN

Y

000 9 -Phe[C](p-F)Phe- -Phe[C](p-CN)Phe- -Phe[CI(P-CH 3 O)Phe- -Phe[C] (p-CF 3 )Phe- -(p-F)Phe (p-F)Phe- ?he[CI(p-CN)Phe- -Tyr[C]Tyr- -Tyr[C]Phe- -Phe[C]Tyr- -(P-BzIO)Phe[C] (p-BzIO)Phe-

H

F

OH

H

F

CN

CH

3 0

CFR

1

F

CN

OH

H

OH

-Cha[C] (p-CII 3 0)Phe- -Cha[iCI(p-CF 3 )Phe- CF 3 -Cha[,CJ(p-Bzlo)Phe-

C

6

H

5

-CH

2 -0 -Cha[C]Tyr- OH

CH

3 0

C

6

H

5

CH

2 0

C.

-(p-BzIO)PheIIC]Phe- C 6 H5C] -Phe[C](BzIO)Phe-H -(p-CH 3 0)Phe[C](p-CH 3 0)Phe-

CH

3

-O

CH

3 -0 H120

C

6

H

5

CH

2

O

H

C

6

H

5

CH

2

O

CH

3 -0

H

C

6

H

5

CH

2 0

OH

-(p-CH 3 0)Phe[C] (p-BzIO)Phe-

C

-(p-CH 3 0)PheIIC]Tyr- CH13-0 Accordingly, -Phe[C](p-F)Phe- corresponds to the divalent residue of 2(R)-(p-fluorophenylmethyl)-4(S)-hyclroxy-6-phenylhexanoic acid; -Phe[Cj (p-CN)Phecorresponds to the divalent residue of 5(S)-amino-2(R)-(p-cyanophelnylmethyl)-4(S)- 113hydroxy-6-phenylhexanoic acid; -Phe[C](p-CH 3 0)Phe- corresponds to the divalent residue of 5 (S )-amino-4(S)-hydlroxy-2(R)-(p-methoxyphenylmethyl)-6-phenylhexanoic acid; -Phe[C](p-CF 3 )Phe- corresponds to the divalent residue of 5(S)-amino-4(S)hydroxy-6-phenyl-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid; -(p-F)PheIIC](p-F)Phe- corresponds to the divalent residue of 5(S)-amino-6-(p-fluorophenyl) -2(R)-(p-fluorophenylniethyl)-4(S)-hydroxyhexanoic acid; -(p-F)Phe[C](p-CN)Phe- corresponds to the divalent residue of 5(S)-amino-2(R)-(p-cyanophenylmethyl)-6-(p-fluorophenyl)-4(S)-hydroxyhexanoic acid; -Cha[C](p-CH 3 O)Phecorresponds to the divalent residue of 5(S)-amino-2(R)-(p-methoxyphenylmethyl)-6cyclohexyl-4(S)-hydroxyhexanoic acid; -Cha[C] (p-CF 3 )Phe- corresponds to the divalent residue of 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(R)-(p-trifluoromethylphenylmethyl)hexanoic acid; -Tyr[C]Tyr- corresponds to the divalent residue of 5(S)-amino-4(S)hydroxy-6-(p-hydroxyphenyl)-2(R)-(p-hydroxyphenylmethyl)-hexanoic acid; -Phe[C]Tyrcorresponds to the divaleot residue of 5(S)-amino-4(S)-hydroxy-2(R)-(p-hydroxyphenylmethyl)-6-phenylhexanoic acid; -Tyr[C]Phe- corresponds to the divalent residue of amino-4(S)-hydroxy-6-(p-hydroxyphenyl)-2(R)-benzylhexanoic acid; -(p-zIOPheC] p-BIO)he-corespndsto he ivaentresidue of 5(S)-amino-6-(pbenzyloxyphenyl)-2(R)-(p-benzyloxyphenylmethyl)-4(S)-hydroxyhexanoic acid; -(p-BzlO)PheIIClPhe- corresponds to the divalent residue of 5(S)-amino-6-(p-benzyloxyphenyl)-4(S)-hydroxy-2(R)-benzylhexanoic acid; -PheIIC](p-BzlO)Phe- corresponds to the divalent residue of 5(S)-amino-2(R)-(p-benzyloxyphenylmethyl)-4(S)-hydroxy-6-phenylhexanoic acid; -(p-CH 3 O)Phe[C](p-GH 3 O)Phe- corresponds to the divalent residue of 5(S)-amino-4(S)-hydroxy-6-(p-mnethoxyphenyl)-2(R)-(p-methoxyphenylmethyl)-he-xanoic acid; -(p-CH 3 O)Phe[C]Phe- cc;responds to the divalent residue of 5(S)-amino-4(S)hydroxy-6-(p. rnethoxyphenyl)-2(R)-phenylmethylhexanoic acid; -(p-CH 3 O-)Phe[C](p-BzlO)Phe- corresponds to the divalent residue of 5(S)-amino-2(R)- (p-benzyloxyphenylmethyl)-4(S)-hydroxy-6-(p-methoxyphenyl)-hexanoic acid; and -(p-CH 3 O)Phe[C]Tyr- corresponds to the divalent residue of 5(S)amino-4(S)-hydroxy- 2(R)-(p-hydroxyphenvlmethyl)-6-(p-methoxyphenyl)-hexanoic acid.

-Cha[C] (p-B zlO)Phe- denotes the divalent residue of 5(S)-amino-2(R)-(P-benzyloxybenzyl)-6-cyclohexyl-2(R)-4(S)-hydroxyhexanoic acid; -Cha[G]Tyr- accordingly denotes the divalent residue of 5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(R)-(4-hydroxybenzyl)hexanoic acid.

-114- CF, Y HI OH H O

"NN

-0 0 F F C -(p-F)Phe[C](p-CF 3 )Phe-

-(CF

3 )Phe[C]Phe- H

-(CF

3 )Phe[C](p-F)Phe- F

-(CF

3 )Phe[CI(p-CF 3 )Phe- CF 3 The residue -(p-F)Phe[C](p-CF 3 )Phe- accordingly corresponds to the divalent residue of 3(S)-amino-4,(S)-hydroxy-6-(p-fluorophenyl)-2(R)-(p-trifluoromethylphenylmethyl)hexanoic acid.

The symbol is intended to indicate that the residues -(CF 3 )Phe[C]Phe-,

-(CF

3 )Phe[C](p-F)Phe- and -(CF 3 )Phe[C](p-CF 3 )Phe-, which correspond to the divalent residues of 5-arnino-2-phenyl-4-hydroxy-6-(p-trifluorometliylphenylmethyl)-hexanoic acid, 5-axino-2-(p-fluorophenylmethyl)-4-hydroxy-6-(p-trifluoromethylphenyl)-hexanoic acid and 5-amino-2-(p-trifluoromethylphenylmethyl)-4-hydroxy-6-(p-trifluoromethyphenyl)-hexanoic acid, may be present in the corresponding Examples in the form of a mixture of the 2(R),4(S),5(S)-isomer with the 2(S),4(R),5(R)-isomner.

Further meanings of corresponding divalent residues are as follows: -Phe[C](m-CN)Phe- denotes the divalent residue of 5(S)-amino-2(R)-(m-cyanophenylmethyl)-4(S)-hydroxy-6-phenylhexaloic acid; -Phe[C](o-CN)Phe- denotes the divalent residue of 5(S )-amino-2(R)-(m-cyaiw~phenylmethyl)-4(S)-hydroxy-6-phenylhexanoic acid; -Phe[CII(o-F)Phe- denotes the divalent residue of (S)-amino-2(R)-(o-fluorophenylmethyl)-4(S)-hydroxy-6-phenylhexanoic acid; -Phe[C](m-F)Phe- denotes the divalent residue of 115 5(S)-amino-2(R)-(m-fluorophenylmethyl)-4(S)-hydroxy-6-phenylhexanoic acid; -(p-CH 3 O)Phe[C](3-CH 3 O)Phe- denotes the divalent residue of 5(S)-amino-2(R)-(m-methoxyphenylmethyl)-4(S)-hydroxy-6-(p-methoxyphenyl)-hexanoic acid;

-(P-CH

3 O)Phe[C](2-0H 3 0)Phe- denotes the divalent residue of (S)-amino-2(R)-(o-methoxyphenylmethyl)-4(S)-hydroxy-6-(p-methoxyphenyl)-hexanoic acid; -Phe[C] (3-CH 3 O)Phe- denotes the divalent residue of (S)-amnino-2(R)-(m-methoxyphenylmethyl)-4(S)-hydroxy-6-phenylhexanoic acid; and -Phe[CI(2-CH3O)Phe- denotes the divalent residue of 5(S)-amino-2(R)-(o-methoxyphenylmethyl)-4(S)-hydroxy-6-phenylhexanoic acid.

Finally, -Phe[C] (p-isobutyloxy)Phe- corresponds to the divalent residue of (S)-amino-4(S)-hydroxy-2(R)-(p-isobutyloxybenzyl)-6-phenyl-hexanoic acid; -Phe[C](3,4-dimethoxy)Phe- corresponds to the divalent residue of 5(S)-amino-2(R)-(3,4-dimethoxybenzyl)-4(S)-hydroxy-6-phenyl-hexanoic acid; -Phe[iC](3,4,5-trimethoxy)Phe- corresponds to the divalent residue of 5(S)-amino-4(S)-hydroxy-6-phenyl-2(R)-(3,4,5-trimethoxybenzyl)-hexanoic acid; and -Phe[jC](2,3,4-trimethoxy)Phe- corresponds to the divalent residue of 5(S)-amino-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxybenzyl)-hexanoic acid.

Reference Examples (mentioned in the following with a description of the preparation only if an additional synthesis is described): Referen,;e Examples 1 to 41 and a description of the. preparation thereof (which may involve a novel synthesis) are to be f ound in the above-mentioned EP 0 532 466. They are as follows: Reeec Exml :.eCaC(-)h-L-a-L-h-opoi--lmd, Reference Example 1: Boc-Cha Phe-(L) -Val- -Phe-morpholin-4-ylamide ot, h (S)-[l1(S)-(Boc-amino)-2-phenylethyl]-3(R)-phenylmethyl-dihydrofuran-2-(3H)-one mentioned as first compound in Reference Example 2b) is prepared preferably as follows (method of preparation that is suitable also for larger amounts): 116i) 5(S)-fl(S)-(Boc-amino)-2-phenylethyll-dihydrofuran-2-(3H)-one DeCamp, A.T. Kawaguchi, R.P. Volante, and I. Shinkai, Tetrahedron Lett. 32, 1867 (1991)). Under a nitrogen atmosphere, 173 g of Zn/Cu (preparation: R.D. Smith, H.E.

Simmons, W.E. Parhqm, M.D. Bhavsar, Org. Synth., Coll. Vol 5, 855 (1973)) and 280 ml of dimethylacetamide are added to a solution of 375 g (1.65 mol) of 3-iodopropionic acid ethyl ester [Reference Example 21 in 1700 ml toluene and the mixture is stirred vigorously for 1 h at RT and then for 4 h at 80 0 C zinc homoenolate solution). In a second apparatus (nitrogen atmosphere), 127 ml (1.14 mol) of titanium tetrachloride are added to a solution of 122 ml (0.40 mol) of tetraisopropyl orthotitanate in 350 ml of toluene and 1900 ml of methylene chloride with slight cooling at an internal temperature of from 15 to 25 0 C, and the mixture is stirred for 15 min at RT yellow solution) and cooled to -40 0 C partial crystallisation of the trichlorotitanium isopropanolate). The zinc homoenolate solution, cooled to RT, is filtered under an argon atmosphere through a G3 glass frit and added dropwise to the trichlorotitanium isopropanolate, the temperature being maintained at from -30 0 C to -25 0 C deep red solution), and the mixture is stirred for 5 min at -25 0 C and cooled to -40°C. Subsequently a solution of 233 g (0.85 mol) of N-Boc-phenyialaninal (preparation: D.J. Kempf, J. Org. Chem. 51, 3921 (1986), then S crystallisation from hexane approximately 18 washing with cold hexane, drying) Sin 1500 ml of methylene chloride is added dropwise and the mixture is stirred for 15 h at from -22 to -18 0 C and finally for 1 h at 0 C. The reaction mixture is taken up in 101 of ice-water and 12 1 of tert-butyl methyl ether and stirred vigorously for from 7 to 10 min.

The aqueous phase is removed and extracted twice with 10 1 of ether each time; the organic ph.-jes are washed with 8 1 of water, 8 1 of sat. sodium hydrogen carbonate solution, 8 1 of water and 5 1 of brine, dried with sodium sulfate and concentrated by evaporation crystalline 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenylhexanoic acid ethyl ester).

The above intermediate is heated for 2.5 h at 100°C in 6500 ml of toluene and 230 ml of acetic acid under an argon atmosphere. The cooled reaction mixture is poured, with stirring, onto 6 1 of ice-water, the aqueous phase is removed and extracted twice with 2000 ml of toluene each time, and the organic phases are washed with 5 1 of sat. sodium hydrogen carbonate solution, 5 1 of 40 sodium hydrogen sulfite solution, 41 of water and 4 1 of brine and dried with sodium sulfate. Concentration of the organic phases by evaporation to a residue of approximately 300 g and the addition of 800 ml of hexane (stirred for several hours to complete the reaction) yields crystalline lactone, which according to HPLC contains approximately 10 of the (5R) epimer (TLC R(E)=0.08; tRet(n)=1 8 8 min). That material is used in the next step. The pure title compound may be 0 -117obtained by column chromatography (SiO 2 hexane/ethyl acetate 2: TLC RK(E)=0. 14; tRetPl)=l 9 2 min; [a]D=17.7O ethanol).

ii) 5(S)-fl (S )-(Boc-amino)-2-phenylethvll-3(R)-phenylmethyldihydrofuran-2-(3H)-one Ghosh, S.P. McKee, and W. J. Thompson, J. -Org. Chem. 56, 6506 (199 Under a nitrogen atmosphere, a solution of 1943 g (6.32 mol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -dihydrofuran-2- (3H)-one in 12.0 1 of THF and 1.9 1 of 1,3-dimethyl-3,4,5,6-tetrahydro-2( lH)-pyrimidinone is cooled to -751C, at an internal temperature of below -70 0

C

14000 ml of lithium bis(trimethylsilyl)amide (IM) in TBF (Aldrich) are added, and the mixture is then stirred for 20 min at -75 0 C. Over a period of 1 h, 835 ml (7.00 mol) of benzyl bromide are added thereto, the internal temperature not being allowed to exceed -701C, and the mixture is stirred for 30 mmI at -75 0 C to complete the reaction. There are then added to the clear solution at from -75 to -70 0 C 2320 ml of propionic acid (90 min) followed by 2320 ml of water (1 the temperature being allowed to rise to -10 0 C. The reaction mixture is poured onto 30 1 of ethyl acetate and 35 1 of 10 citric acid solution, *and the aqueous phase is removed and re-extracted twice with 10 1 of ethyl acetate each *time. The organic phases are washed three times with 12 1 of sat. sodium bicarbonate solution each time, with 20 1 of brine and twice with 20 1 of water each time, and concentrated, and the oily residue is taken up in 10 1 of toluene and concentrated by evaporation to a residual volume of approxim-q 'ly 5 1. Filtration of the evaporation residue through 4 kg of Merck silica gel (0.063-0.200 mm), subsequent washing with toluene and crystallisation of the crude product from hexane (4 1 of hexanelkg of crude product) yields the title compound: TLC Rf(D)=-0.54; FAB-MS Reference Example 3: Boc-Cha[C](p-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Reference Example 4: H-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, o Reference Example 5: 3-Benzofuranoyl-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, Reference Example 6: Nicotinoyl-Phie[C]Phe-(L)-Val-(L)-Phe-mnorpholin-4-ylamide, Reference Example 7: Morpholinocarbonyl-Val-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin- 4-ylamide, Reference Example 8: Boc-Cha[C]Cha-(L)-Val-(L)-Cha-morpholin-4-ylamide, Referenc Example 9: Boc-Cha[C] (p-F)Phe-(L)-Val-(L)-(p-F-Phie)-morpholin-4-ylamilde, Reference Example 10: Boc-Cha[C] (p-F)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4ylamide, Reference Example 11: Boc-Cha[C](p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Reference Example 12: 1,2,3 ,4-Tetrahydroisoquinoline-3 (S)-carbonyl-Val-Phe(C]Phe- -Val- (L)-Phe-morpholin-4-ylamide, Reference Example 13: Boc-Phie[C]Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, Reference Example 14: Boc-PheIICIPhe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide, Reference Example 15: Boc-Phe[CIJPhe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Reference Example 16: Boc-Phe[C]Phe-(L)-Ile-(L)-P'. -morpholin-4-ylamide, Reference Example 17: Boc-Phe[C]Phe-(L)-Val-Gly-morpholin-4-ylamide, Reference Example 18: Boc-Phe[C]Phe-(L)-Ile-Gly-morpholin-4-ylamide, Reference Example 19: Boc-Phe[C]Phe-(L)-Val-(L)-Val-morpholin-4-ylamide, Reference Example 20: Boc-Phe[C]Phe-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide, Reference Example 21: A) 1) one of the compounds mentioned under B) to J) below in which the radical -thiomorpholin-4-ylamide stands in place of -morphrlin-4-ylamide; B) 1) Boc-(p-F)Phe[C] (p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, 2) Boc-(p-F)Phe[C] (p-F)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide, 3) Boc-(p-F)Phe[C] (p-F)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4ylamide, 4) Boc-(p-F)Phe[C] (p-F)Phe-{L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-F)Phe[C] (p-F,)Phe--(L)-fle-(L)-Phe-morpholin-4-ylamide, C) 1) Boc-(p-F)Phe[C] (p-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide, 2) Boc-(p-F)Phe[C] (p-CN)Phe-(L)-Vai.-(L)-(p-F-Phe)-morpholin-4-ylamide, 3) Boc-(p-F)Phe[C] (p-CN)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin- 4-ylamide, 4) Boc-(p-F)Phe[C] (p-CN)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide, Boc-(p-F)Phe[C] (p-CN)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide, and D) 1) Boc-Phe[C] (p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide.

2) Boc-Phe[C1(p-F)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide Analogously to Reference Example 350 mg (0.395 mmol) of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenyl- -119methyl)-hexanoyl-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide are deprotected with 374 mg (1.19 mmol) of TBAF in 3 ml of DMF to yield the title compound: tR,#Il)= 23 3 min; FAB-MS (M+El)-(-765.

The starting material is prepared as follows: 2) a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-(p-F-Phe)-morpholin-4ylamide Analogously to Reference Example 9f), 265 mg (0.485 mmol) of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid, [Reference Example 21 D) and 188 mg (0.53 mmol) of H-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide (Reference Example 9e) in 4.6 ml of NMM/GH 3 CN 0.25M are reacted with 202.6 mg (0.53 mmol) of HBTU: TLC Rf(D)=0.28; 3 3 4 min.

3) Boc-Phe[CJ(p-F)Phe-(L)-Val-(L)-(p-CH 3 ,O-Phe)morpholin-4-ylamide Analogously to Reference Example 280 mg (0.31,2 mmol) of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-(p-CI-1 3 0-Phe)-morpholin-4-ylamide are deprotected with 295 mg (0.94 mm 01) of TBAF in 3 ml of DMF to yield the title compound. Column chromatography (SiO 2 ethyl acetate/hexane 4:1 ethyl acetate) yields the pure title compound: TLC Rf(B)=0.56; tRet(ll>= 2 3 .l min; FAB-MS (M+H)1=777.

The starting material is prepared as follows: 3) a) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxv)-6-phenyl-2(R)- (P-fluorophenylmethyl)-hexanovl-(L)-Val-(L)-(p-CH O-Phe)-morphlil-4ylamide Analogously to Reference Example 9f), 200 mg (0.366 mmol) of (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoic acid [Reference Example 21 D) and 146 mg (0.402 mmol) of 3 O-Phe)-mnorphiolin-4-ylamride (Reference Example l~e) in 3.6 ml of NMM/CH 3 CN 0.25M are reacted with 153 mg (0.402 mmol) of HIBTU: TLC RK(D)=0.

2 2 tR,#lI)=33.l min.

-120- 4) Boc-PherCi (p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide (described in EP 0 532 466) Boc-Phe[C1(p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 220 mg (0.251 mmol) of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Ile-(L)-Phe-morpholin-4-ylamide are deprotected with 2.40 mg (0.75 mmol) of 'EBAF in 3 ml of DMF to yield the title compound.

Column chromatography (SiO 2 ethyl acetateflTHF 9: 1) yields the pure title compound: TLC Rf(O)=0.3; tR~t(ll)= 2 3 9 min; FAB-MS (M+H)1=761.

The starting material is prepared as follows: a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)nf -fluorophenylmethyl)-hexanoyl-(L)-Ile-(L)-Phe-morphobin-4-ylamide Analogously to Reference Example 9f), 200 mg (0.366 mmol) of aino)-4(S)-(ter-butyldmethylsilyloxy)-6-phenyl-2(R)-(pfluorophen)'l- *::.methyl)-hexanoic acid [Reference Example 21 D) and 140 mg :(0.403 mmol) of 1H-(L)-Ile-(L)-Phe-morpholin-4-ylamide (Reference Example 16b) in 3.5 ml of NMM/CH 3 CN 0.25M are reacted with 153 mg (0.40 mmol) of HBTU: TLC Rf(D)=0. 16; tRat(MI= 34 4 min.

E) 1) Boc-Phe[Cl(P-CN'jPhe-(L)-Val-(L)-Phe-morpholin-4-ylamide (described in EP 0 532 466) 2) Boc-Phe[C] (p-CN)Phe-(L)-Val-(L)-(p-F-Phe)-moipholin-4-ylamide (described in EP 0 532 466) 3) Boc-Phe[C](pCN)Phe(L)-Val-(L)-(p-CH 3 -Phe)-morpholin-4-ylamide 4) Boc-Phe[C](p-CN)Phe-(L)-Val-(L)-Cha-morpholin-4- ylamide Boc-Phe[C1(p-CN)Phe-(L)-Ile-(L)-Phe-mcorpholin-4-ylamide (described in EP 0 532 466) F) 1) Boc-Phe[C](p-CH 3 0O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 417 mg (0.48 mmol) of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-.phenyl-2(R)-(p-methoxypheiiylmethyl)-hexanioyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are deprotected with 301 mg (0.95 mmol) of TBAF in 5 ml of DMF to yield the title 1 '21 t-mrpound: TLC R 1 tR~t()=lS.

8 min; FAB-MS (M+H)=759.

The starting material is prepared as follows: 1) a) p-Methoxybenzyl iodide A solution of 1.7 ml (12,8 mmol) of 4.methoxybenzyl chloride (Fluka; Buchs/Switzerland) in 25 ml of acetone is stirred at RT with 9.4 g (62.6 mmol) of sodium iodide. A gas chromatogram of the reaction mixture after 90 min indicates complete reaction, and the reaction mixture -is therefore pouted onto cther and washed with 10 sodium thiosulfate solution and brine. The organic phase is dried with Na 2

SO

4 and concentrated by evaporation to yield the title compound: 1H-NMR (200 MHz, CD 3 OD: 3.78 3 H), 4.54 211), 6.8-6.95 and 7.2-7.4 (2m, each 2 H).

1) b) 5(S)-ri (S)-(Boc-amino)-2-phenylethyl]-3(R)-(p-methoxyphenl- ::methyl)-dihydrofuran-2-(3H)-one Analogously to Reference Example 21 D) 2.98 g (9.74 of [1 (S)-(,3oc.>amino)-2-phenylethyl] -dihydrofuran-2-(3H)-oiie [Reference Example 21 D) dissolved in 40 ml of TI-IF are deprotonated at -759C with 19.5 ml of lithium bis(trimethylsilyl)amide 1M in JTF and alkylated with 2.9 g (11.7 mmol) of p-methoxybenzyl iodide in 20 ml of THF min). Column chromatography(SiO 2 hexane/ethyl acetate 2:1) and digestion from DIPE yields the pure title compound: TLC Rf(D)=0.32; tRet(I=1 6 7 min, 1) c) 5(S)-(Boc-amino)-4(S)7hydroxy-6-phenyl-2(R)-(p-methox(yphenvlmethyl)-hexanoic acid Analogously to Reference Example li), 1.7 g (3.99 mmol) of (Boc-ainino)-2-phenylethyl] -3(R)-(p-methoxyphenylmethyl)-dihydrofuran-2-(3H)-one in 43 ml of dimethoxyethane and 11 ml of water are hydrolysed with 16 ml of 1M lithium hydroxide solution. Stirring in ether yields the pure title compound: TLC Rf(F)=0.53; tR~t()=l 4 2 min; FAB-MS (M±Na)+=466.

-122- 1) d) 5(S)-(Boc amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- (p-methoxyphenylmethyl)-hexanoic acid Analogously to Reference Example lj), 0.93 g (2.10 mmol) of am-ino)-4(S)-hydroxy-6-phenyl-2(R)-(p-methoxyphenylmethyl)-hiexanoic acid in 20 ml of DMF are silylated with 1.4 g (9.64 mmol) of ter, -butyldimethyichiorosilane and 1.17 g (17.2 mmol) of imidazole. Tl- Jilvt :ster function is hydrolysed with 1.7 g of potassium carbonate in me _Ivj (23 ml)/THF (7 ml)Iwater (7 ml) and the crude product is stirred in hexane to yield the title compound: tRet()= 2

O.

6 min; FAB-MS (M+H)+=558.

1) e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenvl-2(R)- (p-methoxvphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 9f), 300 mg (0.537 mmol) of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-methoxyphenyl- ~*methyl)-hexanoic acid and 197 mg (0.59 mmol) of H-(L)-Val-a.,)-Phe- *morphoin-4i-ylamid (erne Example lo n52m of NNIC 3

'AN

0.25M are reacted with 224 mg (0.59 mmol) of HBTU: tRet(D 2 2 .l min; FAB-MS (M+H)+=873.

2) Boc-Phe[C](p-C-H 3 O)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Bo-PeC]-C Q)Phe- -CH O-Phe) -morpholin-4-ylamide Analogously to Reference Example 200 mg (0.22 mmol) of am-ino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2t(R)-(p-methoxyphenylmethyl)-hexanoyl-(L)-Val-(L)-(p-CH 3 O-Phe)-miorpholin-4-ylanide are ::::*deprotected with 210 mg (0.66 mmcl) of TBAF in 3 ml of DMF to yield the title compound. Column chromatography (SiO 2 methylene chloride/.methanol 19: 1) yields the pure title compound: TLC RK(F)=0.66; 0*00 tRWt(L)= 2 2 .5 mm~i; FAB-MS (M+H)+=789.

The starting material is prepared as follows: 3) a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsi yloxy)-6-phenyl-2(R)- (p-methoxyphenylmethyl)-hexanoyl-(L)-Val- O-Phe)-morpholin- 4-ylamide Analogously to Reference Example 90), 200 mg (0.358 mmol) of 123 amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-methoxyphenylmethyl)-hexanoic acid and 143 mg (0.39 mmol) of H-(L)-Val-(L)-(p-CH 3

O-

Phe)-morpholin-4-ylamide (Reference Example 10e) in, 3.6 ml of

NMM/CH

3 CN 0.25M are reacted with 149 mg (0.39 mmol) of HiBTU: tRt(ll)= 3 3 2 min.

4) Boc-Phe[C] (p-CH 3 Q)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamiAde Boc-Plhe[C](p.'CH 3 O)Phe-(L)-1le-(L)-Phe-morpholin-4-ylamide G) 1) Bo-hFIpC.)h-L-a-L-h-opoi--lmd An,.logously to Reference Example 120 mg (0.13 mmol) of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-trifluoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are deprotected with 124 mg (0.39, mmol) of TBAF in 3 ml of DNM to yield the title compound. Precipitation with DIPE from a concentrated solution in DMF yields the pure title compound: tR~t(ll)= 24 7 min; FAB-MS (MV+H)t-797.

The starting material is prepared as follows: 1) a) 5 (S)4 1 (S)-(Boc-amino)-2-phenyl-ethyll-3(R)-(p-trifluoromethvlphenylmethyl)-dihydrofuran-2-(3H)-one Analogously to Reference Example 21 D) 1.0 g (3.26 mmol) of [1 (S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Reference Example 21 D) dissolved in 20 ml of THE are deprotonated, at -751C with 6.5 ml of lithium bis(trimethylsilyl)amide 1iM in THE and alkylated o starting at -75 0 C with 0.93 g (3.91 mmol) of p-trifluoromethylbenzyl o: o. bromide (Fluki,; Buchs/Switzerland) (warniing up during 45 min up to 0 Column chromatography (Si0 2 hexane/ethyl acetate 2:1) yields the pure title compound: TLC R 4 tR~t(II)=27.O min; FAB-MS (M+H-butene) t =408.

1) b) 5 (S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-trifluoromethlphenylmethyl)-hexanoic acid Analogously to Reference Example 1i), 4.3 g (9.3 mmol) of (Boc-amino)-2-phenylethyl]-3(R)-(p-trifluoromethylphenylmethyl)-dihydrofuran-2-(3H)-one in 100 ml of dimethoxyethane und 25 ml of water are -124hydrolysed with 37 ml of 1M lithium hydroxide solution to yield the title compound: TLC RK(H)=O0.68;, 2 2 .5 min.

1) c) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)- (P-trifluoromethylphenylmethyl)-hexanoic acid Analogously to Reference Example 1j), 3.2 g (6.65 mmol) of amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-trifluoromethylphenylmethyl)hexanoic acid in 25 ml of DMF are silylated with 4.6 g (30.6 mmol) of tertbutyldimethylchlorosilane and 3.7 g (54.5 mmol) of imidazole. Hydrolysis of the silyl ester function with 5.5 g of potassium carbonate in methanol ml)fTHF (22 ml)/water (12 ml) yields the title -compound: tRet(ll1)= 3 2 7 min.

1) d) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethylsilyloxy)-6-phenyl-2(R)- (p-trifluoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4ylamide Analogously to Reference Example 9f), 200 mg (0.335 mmol) of 0* amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic and 123 mg (0.369 mmol) of H-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example lo) in 3.2 ml of NMM/CH 3

CN

0.25M are reacted with 140 mg (0.37 mmol.) of H-BTU: tRe(ID) 3 4 8 min.

2) Boc-Phe[C](p-CF 3 )Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 0 3) Boc-Phe[C](p-CF 3 )Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide 4) Boc-Phe[C] (p-CF, 3 )Phe-(L)-Val-(L)-Cha-mnorpholin-4-ylamide Boc-Phe[C](p-CF 3 )Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide H) 1) Boc-Cha[C] (p-CN)Phe-(L)-Val-(L)-(p-F-Phe)-morphoin-4-ylamide 2) Boc-Cha[C] (p-CN)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide 3) Boc-Cha[C](p-CN)Phe-(L)-Val-(L)-Ch-m,,rpholin-4-ylamide 4) Boc-Cnia[C] (p-CN)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide I) 1) Boc-Cha[CJ (p-CH 3 O)Phe-(L)-Val-(L)-Phe-moipholin-4-ylamide 2) Boc-Cha[C](p-CH 3 O)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-ChaiC] (p-CH 3 O)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4ylamide 125 4) Boc-Cha[C] (p-CH 3 O)Phe-(L)-Val-(L)-Ch.-a-morpholin-4-ylamide Boc-Cha[C](p-CH 3 O)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide J) 1) Boc-Cha[C] (p-CF 3 )Phe-(L).-Val-(L)-Phe-morpholin-4-ylamide 2) Boc-Cha[C] (p-CF- 3 )Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4-ylamide 3) Boc-Cha[C] (p-CF 3 )Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide 4) Boc-Cha[CJ (p-CF 3 )Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide Boc-Cha[C] (p-CF 3 )Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide Reference Example 22: Analogously to one of the above-mentionec, Reference Examples, or in the manner indicated. in detail in the case in question, the following are prepared by selcction of the corresponding starting compounds: Boc-(L)-Val-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide; B) H-(L)-Val-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide; C) Boc-CharCl(-p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide (described in EP 0 532 466) D) Boc-Cha[C](p-F)Phe-(L)-Val{L)-Cha-morpholin-4-yla~ide; E) Boc-Phe[C]Phe-(L)-Val-(D)-Phe-morpholin-4-ylamide; F) Boc-Phe[C]Phe-(L)-Val(red)-(L)-Phe-morpholin-4-ylamide; G) Isobutyloxycarbonyl-Phe[C]Phe-(L) -Val-(L)-Phe-morpholin-4-ylamide; H) Boc--Cha[C] (p-CN)Phe-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide; 1) Boc-CharCI(p)-F)Phle-(L)-Val-(L)-Phe-thiomorpholin-4-ylamide (described in EP 0 532 466) J) The compounds from Reference Example 22 A) to 22 in which the radical, -thiomorpholin-4-ylamide stands in place of -morpholin-4-ylamide.

-126- Note: Reference Examples 23 to 32 do not relate to compounds of formula I.

Reference Example 33: Boc-(p-F)Phe j~l(p-CF 3 )Phe-(L)-Val-(L)-Phe-morpholin-4ylamide (described in EP 0 532 466) Reference Example 34: Boc-(p-F)PherC1 (p-CF 3 -)Phe-(L)-Val-(L)-(p-F-Phe)-morpholin-4viamide (described in EP 0 532 466) Reference Example 35: Boc-(p-F)PheLC1 p-CF 9 )Phe-(IL)-Val-(L)-(p-CH O-Phe)-morpholin-4-ylamide (described in EP 0 532 466) *o Reference Example 36: Morpholinosulfonyl-(L)-Val-Phe[CIPhe-(L)-Val-(L)-Phe-mowpholin-4-ylamide *..*(described in EP 0 532 466) Reference Example 37: Morpholinosulfonyl-PherC]Phe-(L)-Val-(L)-Phe-morpholin-4ylamide o: (described in EP 0 532 466) Reference Example 38: N-(N-(2-P-vridylmethyl)-N-methyl-aminocarbonyl)-(L)-Val- .a PheCPhe)Val-()Phemorholin4lamide oo..o, (described in EP 0 532 466) 0. Reference Example 39: 5(S)-(Boc-amino)-4(S)-(acetoxy)-6-phenyl-2(R)-phenylmethvl- 00* hexanoy -(L)-Vai-(L)-Phe-morpholin-4-ylamide (described in EP 0 532 466) Reference Example The following compounds are obtained in a manner analogous to that described in one of the above-mentioned Reference Examples: A) Boc-(p-ICF 3 )Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide B) Boc-(p-CF 3 )Phe[C]Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide 127 C) Boc-(p-CF 3 )Phe[C]Phe-(L)-Val-(L)-(p-CH 3 O)Phe-morpholin-4-ylamide D) Boc-(p-CF 3 )Phe[C]Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide E) Boc-(p-CF 3 )Phe[C]Phe-(L)-fle-(L)-Phe-morpholin-4-ylamide F) Boc-(p-CF)Phe[C1 (p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 136 mg 146 mmol) of a mixture of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(R)-(p-fluorophenylmethyl)}-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and 4(R)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(S)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are deprotected with 92 mg (0.293 mmol) of TBAF in 1.5 ml of DMF to yield the title comnpound: tRetQI)= 26 .O min; FAB-MS (M+H)+=815.

The starting material is prepared as follows: a) rac. N-Boc-l-(p-trifluoromethylphenyl)-3-buten-2-amine Analogously to Reference Example 1d), 10.5 g (48.8 mmol) of rac. 1-(p-trifluoromethylphenyl)-3-buten-2-amine (Reference Example 40 P) and 13.8 g (63.4 mmol) of Boc anhydride are reacted in 100 ml of methylene chloride. The reaction mixture is washed with O.1N HCl and 2 portions of brine, and the aqueous phases are extracted with 2 portions of methylene chloride. The organic phases are dr-d with Na 2 S 04, concentrated by evaporation and precipitated with hexane from a concentrated solution in methylene chloride to yi-eld the title compound: TLC Rf(P)=0.27; tRet(II 2 5 .5 min; Anal.: calc. C 60.94 H 6.39 N 4.44 F 18.07 found C 61.15 H 6.43 N 4.27 F 18.09%.

b: 2(R)-fl (S)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl] -oxirane and 2(S)-fl (R'j-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl] -oxirane Analogously to Reference Example 1d), 13.5 g (42.8 mmol) of rac. N-Boc-1-(p-trifluoromethylphenyl)-3-buten-2-.amine and 36.8 g (214 mmol) of m-chloroperbenzoic acid are reacted in 284 ml of chloroform. The reaction mixture is partitioned between 3 portions of methylene chloride, 10 Na 2

SO

3 solution, sat. Na 2 C0 3 solution, water and brine, and column chromatography (Si0 2 hexane/ethyl acetate 4:1) of the crude product yields the racemnate of the title compounds: TLC Rf(C)=0.15; tRL(II)=22.9 min; Anal.: caic. C 58.00 H 6.08 N 4.23 F 17.20 found C 58.03 H 6.33 N 4.45 F 17.02 128c: 5(S)-ri (S)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl] -3(R,S)-carbethoxydihydrofuran-2-(3H)-one and 5(R)-rl1(R)-(Boc-amino)-2-(p-tiifluoromethylphenyl)-ethvjEi 3(S ,R)-carbethoxydihydrofuiran-2-(3H)-one Analogously to Reference Example le), 9.6 g (29.0 mmol) of a mixture of (Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl]-oxirane and 1(R)-(Boc-amino)-2- (p-trifluoromethylphenyl)-ethy]-oxrawc in 48 ml of ethanol and 5 ml of THF are reacted with sodium diethylmalonate (prepared from 153 ml of ethanol, 2 g (87 mm 01) of sodium und 15.4 ml (101 mmol) of inalonic acid diethyl ester). Crystallisation by the addition of hexane to a concentrated solution in ethyl acetate yields a mixture of the title compounds: TLC Rf(D)=O.4O; tR,,t(ll)= 24 .l min and 24.6 min; FAB-MS (M+Na)+=468.

d: 5(S)-ri (S)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyll-dihdrofuran-2-(3H)-one and 5(R)-ri (R)-(Boc-ainino)-2-(p-trifluoromethylphenyl)-ethyll-dihydrofuran-2-(3H)-one Analogously to Reference Example 1h), 9.0 g (20.2 mmol) of a mixture of (Boc-amino)-2-(p-trifluoromiethylphenyl)-ethyl] -3(R,S)-carbethoxydihydrofuran-2-(3H-)one and 5(R)-[l1(R)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl]-3Q( ,R)-carbethoxydihydrofuran-2-(3H)-one in 166 ml of dimethoxyethane are hydrolysed with 86.9 ml of iN aqueous LiOH solution. Decarboxylation of the resulting carboxylic acids in 350 ml of toluene (9 h 1201C) and crystallisation, of the crude product by the addition of hexane to a concentrated solution in ethyl acetate yields the title compound in the form of a racemate: tRt(l[)= 2 3 2 min; Anal.: calc. C 57.90 H 5.94 N 3.75 F 15.26 found C 57.70 5.78 N3.8261, F 15.42% e: 5 (S)-rl(S)-(Boc-amino)-2- (p-trfluoromethyphenyl)-ethyll-3(R)-(p-fluorophenyl S0 methyl)-dihydrofuran-2-(3H)-one and 5(R)-r 1(R)-(Boc-amirno)-2-(p-trifluoromethylphenyl)-ethyl]-3(S)-(p-fluorophenylmethyl)-dihydrofuran-2-(3H)-one Analogously to Reference Example 21 D) 700 mg (1.88 mmol) of a mixture of -00 [1(S)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl]-dihydrofuran-2-(3H)-one and 5(R)-[l1(R)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl] -dihydrofuran-2-(3H)-one dissolved in 3.4 ml of THE and 0.38 ml of i,3-dimethyl-3,4,5,6-tetrahydro-2(iH)-pyrimidinone are deprotonated at -75 0 C with 3.67 ml of lithium bis(trimethylsilyl)amide 1LM in THE, and alkylated at -75 0 C (40 min) with 0.242 ml (1.88 mmol) of 4-fluorobenzyl bromide (Fluka; Buchs/Switzerland). Column chromatography (SiO 2 hexane/ethyl acetate 2: 1) yields the title compound: TLC Rf(P)=0.59; tRet(II)= 2 6 6 min; FAB-MS (ML+H)=482.

129- 0) 5 -CBoc-amino)-4(S)-hydroxy-6-(p-trifuoromethylphenyl)-2(R)-(p-fluorophenvlmethyl)-hexanoic acid and 5 (R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoromethlphenyl)- 2(S)-(P-fluc)rophenylmethyl)-hexanoic acid Analogously to Reference Example ii), 1.1 g (2.28 mniol) of a mixture of (Boc-amino)-2-(p -trifluoromethylphenyl)-ethyl].3 (R)-(p-fluorophenylmethyl)-dihydrofuran-2-(3H)-one knd (R)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl]-3(S)- (p-fluorophenylmethyl)-dihydrofuran-2-(3H)-one in 37 ml of dimethoxyethane and 19 ml of water are hydrolysed with 9.1 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 112 ml of sat. NH 4 Cl solution 9.4 ml of 10 citric acid solution and 46 ml of methylene. chloride, and methanol is added until the precipitated solid has dissolved to give a clear solution in the 2 phases. The aqueous phase is extracted with 2 portions of methylene chloride/methanol approximately 9:1, and the organic phases are washed with brine, dried with Na 2

SO

4 and concentrated by evaporation: TLC Rf(D)=0O. 15; tRet(II)= 2 2 7 min.

g) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenl)-2(R)- (p-fluorophenylmethyl)-hexanoic acid andr5(R)-(Boc-amino)-4(R)-(tert-butyldimethyl- ;ilyloxy)-6-(p-trifluoromethylphenyl)-2(S)-(p-fluorophenylmethyl)- hqxa-oic acid Analogously to Reference Example lj), 1. 1 g (2.20 mmol) of a mixture of amino)-4(S)-hydroxy-6-(p-trifluoromethylphenyl)-2(R)-(p-fluorophenylmethyl)-hexanoic acid and 5(R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoromethylphenyl)-2(S)-(p-fluorophenylmethyl)-hexanoic acid in 2.4 ml of DMF are silylated with 1.52 g (10. 1 mmol) of tert-butyldimethylchlorosilane and 1.2 g (18.0 mmol) of imidazole. The silyl ester function is hydrolysed with 1.8 g of potassium carbonate in 50 ml of methanolfTHF/water 3: 1:1 and, after extraction and colum n chrom atography (S iO 2 hexane/ethyl acetate 2: 1), yields the title compound: TLC Rf(D)=0.16; tReLII) 32 7 min; FAB-MS (M+H)'=614.

h) 5(S )-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6-(p-tiifluoromethylphenyl)-2(R)- (P-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and amino)-4(R)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenl)-2(S)-(p-fluorophei~vlmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 9f), 200 mg (0.326 mmol) of a mixture of amino)-4(S)(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(R)-(p-luorophenylmethyl)-hexanoic acid and 5(R)-(Boc-amino)-4(R)-(tert-butyldimethiyisilyloxy)-6- (p-trifluoromethylphenyl)-2(S)-(p-fluorophenylmethyl)-hexanoic acid and 119 mg (0.358 mmol) of H-(L)-Yal-(L)-Phe-morpholin-4-ylamide (Reference Example lo) in -130- 3.1 ml of NMM/CH 3 CN 0.25M are reacted with 136 mg (0.36 mmol) of HBTU to yield the title compound: tR,.L(II)= 3 4 S min; FAB-MS (M+H)+=929.

G) Boc-(p-CF 3 )Phe[C] (p-F)Phe-(L)-Val-(.L)-(p-F)Phe-morpholin-4-ylamide H) Boc-(p-CF 3 )Phe[C] (p-F)Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide I) Boc-(p-CF 3 )Phe[CI (p-F)Phe-(L)-Val-(L)-(p-CH 3 O)Phe-morpholin-4-ylamide J) Boc-(p-CF 3 )Phe[C] (p-F)Phe-(L)-Ile-(L)-Phe-morpholin-4-ylamide K) Boc-(p-CF)Phe[CI (p-CF 3 )Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 110 mg 112 mmol) of a mixture of amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpho. x, 4-ylamnide and amino) -4(R)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(S)-(p-tifluoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are deprotected with 71 mg (0.225 mmol) of TBAF in 1.1 ml of DMF to yield the title compound: tRet()=l 8 .O and 18.6 min FAB-MS (M+H)-=865.

The starting material is prepared as follows: a: r 1(S)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyll -3(R)-(p-trifluoromnethylI phenylmethyl)-dihydrofuran-2-(3H)-one and 5(R)-ri (R)-(Boc-amino)-2-(-p-trifluoromethylphenyl)-ethyll-3(S)-(p-trifluoromethylphenylmethyl)-dihydrofuran-2-(3H)-one Analogously to Refe6rence Example 21 D) 1.5 g (4.02 mmol) of a mixture of [1 (S )-(Boc-amino)-2-(p-trifltioromethylphenyl)-ethyl]-dihydrofuran-2-(3H)-one and 1 (R)-(Boc-amino)-2-(p-trifluoromethylphenyl)-ethyl]-dihydrofuran-2-(3H)-one dissolved in 7.3 ml of THF and 0.81 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at -751C with 7.86 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated at -75'C (40 min) with 1.01 g (4.02 mmol) of 4-trifluoromethylbenzyl bromide (Fluka; Buchs/Switzerland). Column chromatography (SiO 2 methylene chloride/hexane/ether 10: 10: 1) yields the title compound: TLC Rt(Q)=O.23; 27 7 min; FAB-MS (M+H-Boc)+=432.

b) 5(5 )-(Boc-amino)-4(S)-hydroxy-6- (p-trifluoromethylphenyl)-2(R)-(p-tifluoromethvlI phenylmethyl)-hexanoic acid and 5 (R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoromethlphenyL)-2(S)-(p-trifluoi-omethylphenylmethyl)-hexarioic acid Analogously to Reference Example li), 1.43 g (2.69 mmol) of a mixture of -131 (Boc-ani no)-2-(p-trifluoromethylphenyl)-ethyl]-3(R)-(p-trifluoromethylphenylmethyl)dihydrofuran-2-(3H)-one and 5(R)-[l1(R)-(Boc-amino)-2-(p-trifluoromethylphenyl)ethyl] -3(S)-(p-trifluoromethylphenylmethyl)-dihydrofuran-2-(3H)-one in 43 ml of dimethoxyethane and 22 ml of water are hydrolysed with 10.7 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 132 ml of sat. NH 4 Cl solution, 11 ml of 10 citric acid solution and 54 ml of methylene chloride, and methanol is added until the precipitated solid has dissolved.

The aqueous phase is extracted with 2 portions of methylene chloride/methanol approximately 4: 1, and the organic phases are washed with brine, dried with Na 2

SO

4 and concentrated by evaporation: tRt(II)= 2 4 2 min; FAB-MS c) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(R)- (p-trifluoromethylphenylmethyl)-hexanoic acid and 5(R)-(Boc-amino)-4(R)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(S)-(p-trifluoromethylphenvlmethl)hexanoic acid Analogously to Reference Example 1j), 1.38 g (2.51 mmol) of a mixture of amino)-4(S)-hydroxy-6-(p-trifluoromethylphenyl)-2(R)-(p-trifluoromethylphenylmethyl)hexanoic acid and 5(R)-(Boc-amino)-4(R)-hydroxy-6-(p-trifluoromethylphenyl)-2(S)- (p-trifluoromethylphenylmethyl' ',exanoic acid in 5.7 ml of DMF are silylated with 1.74 g (11.6 mmol) of tert-butyldimethylchlorosilane and 1.4 g (20.6 mmol) of imidazole.

Hydrolysis of the silyl ester function with 2.1 g of potassium carbonate in 55 ml of methanol/THE/water 3: 1:1 yields the title compound: TLC Rf(A)=0.25; tR,#(D= 2 l.

8 min.

d) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(-trifluoromethlphenl)-2(R)- (p-trifluoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and (R)-(Boc-amino)-4(R)-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylphenl)-2(S1 (p-trifluoromethylphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-mopholin-4-Vlamide Analogously to Reference Example 9f), 200 mg (0.301 mmol) of a mixture of amiino)-4(S )-(tert-butyldimethylsilyloxy)-6-(p-trifluoromethylpheiyl)-2(R)-(p-trifluoromethylphenylmethyl)-hexanoic acid and 5(R)-(Boc-amino)-4(R)-(t i-t-butyldimethylsilyloxy)-6-(p-trifluoromethylphenyl)-2(S)-(p-trifluoromethylphenylmethyl)-hexanoic acid and mg (0.331 mmol) of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example in 2.8 ml of NMM/CH 3 CN 0.25M are reacted with 126 mg (0.33 mmol) of HBTU. In the course of the reaction, one of the diastereoisomers precipitates from the reaction mixture and can be filtered off By means of extraction (analogously to Reference Example 9f) of the mother liquor and column chromatography (SiO 2 132hexane/ethyl acetate 1: the other diastereoisomer can be isolated in a diastereoisomeric purity of approximately 90 (according to IH-NMR spectroscopy): TLC Rf(A)=0. 15; tRet()=23.O min (diastereoisomer not separated); IH-NMIR (300 MIHz,

CD

3 OD, after cristallisation inter alia 0.60 (dd, (H 3

C)

2

CH),

'H-NMR (300 MHz, CD 3 OD, after chromatography inter alia 0.91 (dd, (H 3

C)

2

CH).

L) Boc-(p-CF 3 )Phe[C] (p-CF 3 )Phe-(L)-Val-(L)-(p-F)Phe-morpholin-4-ylamide M) Boc-(p-CF 3 )Phe[C](p-CF 3 )Phe-(L)-Ile-(L)-Phe-morpholin-4-ylaniide N) Boc-(p-CF 3 )Phe[C] (p-CF 3 )Phe-(L)-Val-(L)-(p-CH 3 O)Phe-morpholin-4-ylamide 0) Boc-(p-GF 3 )Phe[C] (p-CF 3 )Phe-(L)-Val-(L)-Cha-morpholin-4-ylamide P) The compounds according to the above Reference Examples A) to in which the radical -morpholin-4-ylamide has been replaced by the radical -thiomorpholin-4-ylamide.

The starting material is prepared as follows: a) N-Allylformamide A solution of 300 ml of allylamine in 1288 ml of ethyl formate is heated for 8 h at 601C.

The reaction mixture is concentrated in a rotary evaporator and the residue is distilled over a Vigreux column (770C; 1 mbar): 1H-NMR (200 MHz, CDCl 3 8.2-7.95 (in, 1 H), 6.5-5.8 (sb, 1 5.9-5.7 (mn, 1 5.3-5.05 (in, 2 3.95-3.75 (in, 2 H).

b) Allyl isocyanide Schbllkopf, R. Jentsch, K. Madawinata and R. Harms, Liebigs Ann. Chemn., (1976) 2105). Under a nitrogen atmosphere, 517 g of quinoline and 286 g of p-toluenesulfonic acid chloride are placed in a vessel at 901C. A vacuum of 2-4 mbar is applied and 85 g of N-allylformamide are added dropwise, the resulting isocyanide being distilled off continuously at an internal temperature of 85-951C over a Vigreux column into a condensation trap (acetone/dry ice). When the reaction is complete, the distillate is immIediately distilled once more over a Vigreux columnn (nitrogen atmosphere, normal pressure; I 00'CQ: 'H-NMR (200 MHz, CDCI 3 5.9-5.7 (in, 1 5.45 16 Hz, 1 H), 5.32 i J Hz, 1 4.05 (in, 2 IR (CH 2 Cl 2 2150, 1650.

c) rac. 1-(p-Trifluoromethylphenyl)-3-buten-2-arnine Under a nitrogen atmosphere, 4.5 g of allyl isocyanide are dissolved in 100 ml of THF/ether/pentane abs. 4: 1:1 and cooled to -1001C. At from -100 to -901C, 42 ml of 133n-butyllithium (1.6M in hexane) are added dropwise, whereupon first of all a yellow colour forms and, shortly before the end of the addition, a solid is precipitated. The reaction mixture is allowed slowly to warm to -70 0 C and is then cooled again to -100 0

C.

At from -100 to -85 0 C, a solution of 16 g of p-trifluoromethylbenzyl bromide (Fluka; Buchs/Switzerland) in 10 ml of THF is added dropwise, and the mixture is slowly warmed to RT. The reaction mixture is concentrated by evaporation using a rotary evaporator mbar; 30°C), and the residue is poured onto 150 ml of ice-water and extracted 3 times with ether. The ethereal phases are concentrated by evaporation, 85 ml of methanol and 17 ml of concentrated hydrochloric acid are added to the brown residue at 0°C, and the mixture is left overnight in a refrigerator. The mixture is concentrated by evaporation using a rotary evaporator and the residue is partititioned between 2 x 150 ml of 2M hydrochloric acid and 2 x 200 ml of ether. The combined aqueous phases are rendered alkaline with solid sodium hydroxide, with cooling, and extracted with 3 portions of ethyl acetate.

The organic phases are washed with brine, dried with sodium sulfate, concentrated by evaporation and distilled in a bulb tube (0.1 mbar; 170 0 C) to yield the pure title compound: IH-NMR (200 MHz, CDCI 3 7.56 and 7.32 (2d, 8 Hz, each 2 5.96-5.78 1 5.19-5.02 2 3.68-3.55 1 2.87 and 2.71 (AB x d, Ji= 13 Hz, J 1 =6 Hz, J 2 8 Hz, 2 1.4 (sb, 2 H).

Further reaction analogously to Reference Examples 1 d) to 1 k) and 9 f) and 9, 10 f) and 10, 15 a) and 15 or 16 c) and 16 results in the compounds mentioned above under a) to o).

Reference Example 41: The following are prepared analogously to one of the above Reference Examples: S A) Boc-Phe[C1Phe-(L)-Val-(L)-Tyr-morpholin-4-vlamide Analogously to Reference Example 360 mg (0.418 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R,)-phenylmethylhexanoyl-(L)-Val-(L)-Tyrmorpholin-4-ylamide are deprotected with 263 mg (0.84 mmol) of TBAF in 7 ml of DMF to yield the title compound: TLC Rf(B)=0.28; tRet(II)= 2 0.1 min; FAB-MS (M+H)+=745.

The starting material is prepared as follows: 134a: Z-(L)-Tyr-morpholin-4-ylamide 9.08 g (44 mmol) of DCC are added to an ice-cooled suspension of 14.04 g (40 mmol) of Z-(L)-Tyr-OH in 750 ml of methylene chloride and the mixture is stirred for 20 min.

Subsequently, 10.81 g (80 mmol) of HOBT and a solution of 5.23 g (60 mmol) of morpholine in 50 ml of methylene chloride are added. The mixture is stirred for 18 h at RT and then filtered. The filtrate is washed with sat. NaHC0 3 solution, water and brine and the aqueous phases are extracted with 2 portions of methylene chloride. The organic phases are dried with Na 2

SO

4 concentrated by evaporation and subjected to column chromatography (SiO 2 ethyl acetate) to yield the title compound: TLC Rf(B)=0.39.

b: H-(L)-Tyr-morpholin-4-ylamide A solution of 2.05 g (5.3 mmol) of Z-(L)-Tyr-morpholin-4-ylamide in 91 ml of methanol is hydrogenated for 1.5 h at RT in the presence of 0.5 g of 10 Pd/C. Filtration through ®Celite (filter aid of diatomaceous earth, John-Manville Corp.) and concentration of the filtrate by evaporation yields the title compound: TLC Rf(R)=0.34.

Sc: Z-(L)-Val-(L)-Tvr-morpholin-4-ylamide At 0 C, 5.18 g (25 mmol) of DCC and 3.73 g (27.5 mmol) of HOBT are added to a solution of 6.3 g (25 mmol) of Z-(L)-Val-OH in 400 ml of methylene chloride and the mixture is then stirred for 20 min. A solution of 6.27 g (25 mmol) of H-(L)-Tyrmorpholin-4-ylamide in 600 ml of methylene chloride is subsequently added. After the S mixture has been stirred for 18 h at RT, working up is carried out as described in Reference Example 41 A) TLC Rf(B)=0.50.

e* d: H-(L)-Val-(L)-Tyr-morpholin-4-vlamide Hydrogenation in the presence of 1 g of 10 Pd/C for 1.5 h at RT of a solution of 4.83 g mmol) of Z-(L)-Val-(L)-Tyr-morpholin-4-ylamide in 182 ml of methanol, followed by filtration through ®Celite, concentration of the filtrate by evaporation and column chromatography (SiO 2 methylene chloride/methanol yields the title compound: TLC R(F)=0.30; FAB-MS (M+H)+=350.

e: 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-phenvlmethylhcxanoyl-(L)-Val-(L)-Tvr-morpholin-4-ylamide Analogously to Reference Example 1k), 300 mg (0.569 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-phenylmethylhexanoic acid (Reference Example 2d)) in 5 ml of DMF are activated with 277 mg (0.626 mmol) of BOP, 84.5 mg 135 (0.625 mmol) of HO)1T and 157 gI (1.42 mmol) of NMM, and reacted with 198.6 mg (0.568 mmol) of H-(L)-Val-(L)-Tyr-morpholin-4-ylamide in 2,mlofl (2 h.RT).

Column chromatography (Si0 2 ethyl acetate/hexane 2:1) yields the titl. .mpound: TLC tRet(fl= 3 2 2 min; FAB-MS (NM+H)+-=859.

B) Boc-Tvr[C1Phe-(L)-Val-(L)-Phe-mor,-holin-4-ylamide Hydrogenation in the presence of 82 mg of 10 Pd/C at RT of 165 mg 197 mmol) of Boc-(p-BzlO)Phe[C]Phe-(L-Val-(L)-Phe-morpholin-4-ylar,,de (Reference Example 46) dissolved in 12 ml of methanol, followed by filtration through ®Celite and concentration of the filtrate by evaporation, yi-lds the title comnpound: tRet(I)=l1 3 9 min; FAB-MS (M+kU)+=745.

C) Boc-TyrrClPhe-(L'i-Val-(L)-Tvr-moroholin-4-ylamide Exdrplenain in the presence of 120 mg of 10 Pd/C at RT of 235 mg (025mml) of Eape47) dissolved in 30 ml of methanol, followed by filtration through OCelite, concentration of the filtrate by evaporation and crystallisation from eti'A acetate/hexane, yields the title compound: TLC RK(B)=0.43; tRt(I)l1 2 .l min; FAB-M3 (M-iH)+=761.

D) Boc-PherC]Tvr-L)-Val-(L)-Phe-morpholin-4-ylamide Hydrogenation in the pre-sence of 70 mg of 10 Pd/C at RT of 140,mg 168 mmol) of Boc-Phe[.C](p-BzlO)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 44) disn-31ved in 10 ml of methanol, followed by filtration thr.Dugh ®Celite and concentration of the filtrate by evaporation, yields the title compound: tR, t(H)=l9.9 min; FAB-MS (M+H)+z-745.

E) Boc-PherC]Tyr-(L)-Val-(L)-Tvr-morpholin-4-ylamide Hydrogenation in the presence of 75 mg of 10 Pd/C at RT of 140 mg 159 mmol) of Boc-Phe[C] (p-BzlO)Phe-(L)-Vai-(L)-(p-BzlOPhe)-morpholin-4-ylamide (Reference Example 45) dissolved in 10 ml of methanol, followed by filtration through ®Celite and concentration of the filtrate by evaporation, yields the title compound: tR,#(I)=l 7 2 min; FAB-MS (M+H) t =761.

F) Boc-FrrC]Tvr-(L)-Val-L)-Phe-morpholin-4-ylamide Hydrogenation in the presence of 85 mg of 10 Pd/C at RT of 188 mg (0.178 mmol) of Boc-(p-BzlO)Phe[C] (B zlO)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference -136- Example 48) dissolved in 20 ml of methanol, followed by filtration through ®Celite and concentration of the filtrate by evaporation, yields the title compound: TLC tRcL(I)=l2. 1 min; FAB-MS (M+H)+=761.

G) Boc-Tyr[ClTyr-(L)-Val-(L)-Tyr-morpholin-4-ylamide Hydrogenation in the presence of 85 mg of 10% Pd/C at RT of 209 mg (0.20 mmol) of Boc-(p-BziO)Phe[CI (p-BzlO)Phe-(L)-Val-.(L)-(p-BzlOPhe)-morpholin-4-ylamide (Reference Example 49) dissolved in 20 ml of methanol, followed by filtration and concentration of the filtrate by evaporation, yields the_ title compound: TLC Rg(B)-=0.15; tRet(I)=lO.

6 min; FAB-MS H) The compounds according to the above Reference Examples A) to in which the radical -morpholin-4-ylamide has been replaced by the radical -thiomorpholin-4-ylamide.

The Reference Examples mentioned it, the following are not explicitly disclosed in EP 0 532466.

Reference Example 42: Boc-PherCi (o-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 145 mng 167 mmol) of 5(S)-(Boc-amino)-4(S)o(tert-butyldimethylsilyloxy )-6-phenyl-2(R)-(o-cyanophenylmethyl)-hexanoyl-(L)-Val- (L-Phe-iinor-pholin-4-ylamide are deprotected with 105 mng (0.334 mmol) of TBAF in 4 ml of DME. Precipitation with DIPE from a concentrated solution in DMF yields the pure title compound: tR, 1 (D=l5.7 min; FAB-MS (M+H)t--754.

The starting material is prepared as follows: a) 5(S)-r (S )-(Boc-amino)-2-rf'n-ylethyll-3(R)-(o-cyanophenylmethyl)-dihydrofuran-2 OM-J-one Analogously to Reference Example 21 D) 2.0 g (6.55 mmol) of amino)-2-phenylethyl]-dihydrofuiran-2-(3H)-one [Reference. Example 21 D) 1)b)] dissolved in 40 ml of THF are deprotonated with 13.1 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (75 min) with 1.4 g (7.2 mmol) of 2-bromomethylbenzonitrile (Fluka; Buchs!Switzerland). Column chromatography (SiO 2 hexane/ethyl acetate 2: 1) and stirring in hexane yields the pure title compound-, TLC Rf(D)=0.45; tR,(I)1 6 2 min.

137 b) 5 (S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(o-cyanophenylmethyl)-hexanloic acid Analogously to Reference Example li), 1.67 g (3.97 mmol) of 2.-phenylethyl] -3 (R)-(o-cyaniopheny] methyl)-dihydrofuran-2-(3H)-one in 37 ml of dimethoxyethane and 20 ml of water are hydrolysed with 16 ml of 1M lithium hydroxide solution to yield the title compound: tRCe()=l 3 .8-min.

c) 5().Bcaio-()(etbt~iehliyoy--hnl2R-ocaohnl methyl)-hexanoic acid Analogously to Reference Example 1j), 0.85 g (1.93 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-(o-cyanophenylmethiyl)-hexanoic acid in 10 ml of DM are silylated with 1.34 g (8.9 mmol) of tert-butyldimethylchlorosilane and 1.08 g (15.9 rnmol) of imidazole. Hydrolysis of the silyl ester function with 1.6 g of potassium carbonate in ml of methanol/THE/water 5:1:2, followed by column chromatography (SiO 2 ethyl jacetate/hexane 1: yields. the title compound: TLC Rf(A)=0.4; tRet(I)= 2 O.O min.

d) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenvl-2(R)-(o-cyanophenvlmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide At 51C, 41 mg (0.20 mmol) of DCC are added to 100 mg (0.18 mmol) of acid in 3 ml of THFf. After 10 min, 66 mg (0.20 mmol) of H-(L)-Val-(L)-Phe-morpholin- 4-ylamide (Reference Example lo) and 27 mg (0.20 mmol) of HOBT are added and the mixture is stirred for 17 h at RT. The reaction mixture is filtered and the filtrate is partitioned between 3 portions of ethyl acetate, 10 %l citric acid solution, water, sat. NaHCO 3 solution and brine. The organic phase is dried with Na 2

SO

4 concentrated by evaporation and digested in DIPE to yield the title compound: tRet(I)= 2 1 .8 min; FAB-MS Reference Example 43: Boc-PheECI (m-CN)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamidc, Analogously to Reference Example 131 mg (0.15 1 mmol) of 5(S)-(Boc-amino)-4(S)- (tr-uydmtysllx)6p ey-(R-mcaohnlehl-eaol()Vl (L)-Phe-morpholin-4-ylamide are deprotected with 95 mg (0.30 1 mmol) of TBAF in-4 ml of DMF. Precipitation with DIPE from a concentrated solution in DMF yields the pure title compound: taCe#)=l5.7 min; FAB-.MS (M+H)+=754.

The starting material is prepared as follows: 138 a) 5(S)-fl (S)-(Boc-amino)-2-phenylethyl]-3(R)-(m-cyanophenylmethyl)-dihydrofuran-2- (3H)-ore Analogously to Reference Example 21 D) 2.0 g (6.55 mmol) of (S)-(Bocamino)-2-phenylethyll-dihydrofuran-2-(3H)-one [Reference Example 21 D) 1)b)] dissolved in 40 ml of THF are deprotonated at -75 0 C with 13.1 ml of lithium bis(trimethylsilyl)amide 1M in TiIF and alkylated (60 min -601C) with 1.4 g (7.2 mmol) of 3-bromomethylbenzonitri le (Fluka; Buchs/Switzerland). Column chromatography (Si0 2 hexane/ethyl acetate 2: 1) and stirring in hexane yields the pure title compound: TLC

R

1 tRt()=l 6 .l min.

b) 5 (S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(m-cyanophenylmethyl)-hexanoic acid Analogously to Reference Example ii), 1.6 g (3.8 mmol) of 5(S)-[1l(S)-(Boc-aniino)- 2-phenylethyl]-3(R)-(m-cyanophenylmethyl)-dihydrofuran-2-(3H)-one in 37 m! of dimethoxyethane and 20 ml of water are hydrolysed with 15.2 ml of IM lithium hydroxide *solution to yi4-I the title compound: tR,-t(I)=1 3 8 min.

c) 5.(S)-Boc-ainino)-4(S)-(tert-butyldimethlsilloxy)-6-phenl-2(R)-(m-canohenymethyl)-hexanoic acid Analogously to Reference Example lj), 1.4 g (3.2 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-(m-cyanophenylmethyl)-hexanoic acid in 20 ml of DMF are silylated with 2.2 g (14.6 ramol.) of tert-butyldimethylchlorosilane and 1.8 g (26 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.6 g of potassium carbonate in ml of methanol/THF/water 8:1:2, followed by column chromatography (S ;32, ethyl acetate/hexane yields the title compound: TLC Rr(A)=0.39; tRet()=l 9 8 min.

d) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-cyanophenylmethyl)-hexanoyl-(J (L)-Phe-morpholin-4-ylamide Analogously to Reference Example 42 100 mg (0.18 mmol) of 4(S )-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-cyanophe.nylmethyl)-,hexanoic acid in 3 ml of THE are activated with 41 mg (0.20 mmol) of DCC and reacted with 66 mg (0.20 mmol) of H-(L)-Va1,-(L)-Phe-morpholin-4-ylamide (Reference Example 1o) and 27 mg (0.20 mmol) of HOBT to yield the title compound: tR,-t()=2l.5 min; FAB-MS 868.

Reference Example 44: Boc-PherCl (p-BzlO)Phe-(L)-Val-(L)-Phie-morpholin-4-ylamide Analogously to Reference Example 560 mg (0.59 mmol) of 5(S)-(Boc-amino)-4(S)- -139- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-benizyloxyphenylmethyl)-hexanoyl-(L)- Val- (L)-Phe-morpholin-4-ylamide are deprotected with 372 mg 18 mmol) of TBAF in 8.4 ml of DMF to yield the title compound: tRet(II= 2 6 .l min; F&B-MS (M+I-1)+=835.

The starting material is prepared as follows: a) p-Benzyloxybenzyl iodide A solution of 1.0 g (4.3 mmol) of 4-benzyloxybenzyl chloride (Fluka; Buchs/Switzerland) in 8 ml of acetone is stirred at RT with 3. 13 g (20.9 mmol) of sodium iodide. According to a gas chromatrogram, the reaction is complete after 90 min. Working up as described in.

Reference Example 21 F) 1) a) yields the title compound: 1H-NMR (200 M]Hz, CDC1 3 4.48 2 5.06 2 6.85-6.95 (in, 2 7.25-7.48 (in, 7 H).

b) 5 S)-[l(S)-(Boc-amino)-2-phenlethyl-3(R)- (p-benZyloxyphenylmethyl)-dihydro- Analogously to Reference Example 21 D) 1. 13 g i 3.70 mmol) of amin)-2pheylehyl-dihdroura-2-3H)one[Reference Example 21 D) 1)b)] inone are deprotonated at -75 0 C with 7.25 ml of lithium bis(trimethylsilyl)amide IM in THF, and alkylated (15 min) with 1.2 g (3.7 minol) of p-benzyloxybenzyl iodide in 2 ml of TI-F. Column chromatography (SiO 2 hexane/ethyl acetate 2: i) yields the pure title compound: TLC Rf(D)=0.30; tRetIl)= 28 2 min; FAB-MS (M+H)1-502.

c) 5(S)-(Boc-amino)-4(S)-hvdroxy-6-phenyl-2(R)-(p-benzvloxy-phenylmethyl)-hexanoic acid Analogously to Reference Example ii), 1.4 g (2.79 mmol) of 2-phenylethyl]-3(R)-(p-benzyloxyphenylmethyl)-dihydrofaran-2-(3H)-one in 45 ml of dimethoxyethane and 23 ml of water are hydrolysed with 11 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 137 ml of sat. NH 4 Cl solution, 11 ml of 10% citric acid solution and 56 MI of melthylene chloride, and methanol is added until the precipitated solid has dissolved.

The aqueous phase is extracted with 2 portions of methylene chloride/methanol approximately 10: 1, and the organic phases are washed with brine, dried with Na 2

SO

4 and concentrated by evaporation: tRet(H)= 2 4 .O min; FAB-MS (M+H)+-520.

-140d) (Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-benzyloxyphenylmethiyl)-hexanoic acid Analogously to Reference Example lj), 1.4 g (2.69 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-1 enyl-2(R)-(p-benzyloxyphenylmethyl)-hexanoic acid in 2.9 ml of DMF are silylated with 1.87 g (12.4 mmol) of tert-butyldimethylchlorosilane and 1.5 g (22 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.2 g of potassium carbonate in 63 ml of methanolfIHlF/water 3: 1:1 and column chromatography (SiO 2 hexane/ethyl acetate 2: 1) of the crude product yields the title compound: TLC 17; tR,,t(II)= 3 3 .7 min; FAB-MS (M+H)+=634.

e) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenl-2(R)-(-benzloxVphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 9f), 400 mg (0.63 1 mmol) of 5(S)-(Boc-amino)-4(S)- (ertbutldimethylsilyloxy)-6-phenyl-2(R)-(p bnyoyhnlehl-hexanoic acid and 231 mg (0.69 mmol) of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example lo) in 5.7 ml of NMM/CH 3 CN 0.25M are reacted with 263 mg (0.69 mmol) of HBTU: TLC R tRt(II)= 3 5 8 min; FAB-MS (M+H)t-=949.

Reference Example 45: Boc-Phe[C1 (p-BzlO)Phe-(L)-Val-(L)-(p-BzlOPhe)-morpholin-4ylamide Analogously to Reference Example 665 mg (0.63 mmol) of 5(S)-(Boc-amino)-4(S)- (tr-uydmtysl*oy)6pey-()(-ezlxyhnlehl-eaol() Val- (p-B zlOPhe)-morpholin-4-ylamide are deprotected with 398 mg (1.26 mmol) of TBAE in 9 ml of DMF. Precipitation with DIPE from a concentrated solution in .9..methylh ne chloride yield,, the pure title compound: t~et(ll)=28.7 min; FAB-MS (M+H)1=94l.

The starting material is prepared as follows: a: Boc-(L)-(P-BzlOPhe)-morpholin-4-ylamide 9.08 g (44 mmol) of DCC are added to an ice-cooled suspension of 14.84 g (40 mmol) of Boc-(L)-Tyr(Bzl)-OH (Bachem; Bubendorf/Switzerland) in 650 ml of methylene chloride and the mixture is stirred for 20 min. Subsequently, 10.81 g (80 mmol) of HOBT arid a solution of 5.23 g (60 mmol) of morpholine in 50 ml of methylene chloride are added.

After having been stirred for 18 h at RT the mixture is filtered. The filtrate is washed with sat. NaH-C0 3 solution, water and brine anid the aqueous phases are extracted with 2

I

141 portions of methylene chloride. The organic phases are concentrated by evaporation and again dissolved in a small amount of methylene chloride, the residual undissolved dicyclohexylurea is filtered off and the filtrate is concentrated by evaporation to yield. the title compound: TLC R (B)=O.69.

b: H-(L)-(P-BzlOPhe)-morpholin-4-ylamide At 0 0 C, 30 ml of TFA are added to a solution of 1.0 g (2.69 mmol) of Boc-(L)- (p-BzlOPhe)-morpholin-4-ylamide in 30 ml of methylene chloride. After 45 min, the solvent is evaporated off, and the residue is dissolved in ethyl acetate and washed with sat.

NaHCO 3 solution, 2x water and brine. The aqueous phases are extracted with 2 portions of ethyl acetate. The organic phases are dried with Na 2

SO

4 and concentrated by evaporation to yield the title compound: TLC Rf(F)=0.42.

c: Boc-(L)-Val-(L)-(p-BzlOPhe)-morpholin-4-ylamid9 At 0 0 C, 2.68 g (13 mmol) of DCC and 1.93 g (14.3 mmol) of HOBT are added to a solution of 2.8 g (13 mmol) of Boc-(L)-Val-OH in 350 ml of methylene chloride and the mixture is then stirred for 20 min. A solution of 4.41 g (13 mmol) of fl-(L)-(p-BzlOPhe)morpholin-4-ylamide and 1.8 ml (13 mmol) of triethylamine in 250 ml of methylene chloride is then added. After stirring for 18 h at RI, working up is carried out as described in Reference Example 41 A) This yields the pure title compound after column chromatography (SiO 2 ethyl acetate/hexane TLC Rf(S)=0.50.

d: Val- zlOPhe)-morpholin-4-ylamide a Analogously to Reference Example 45 5.7 g (10.6 mmol) of Boc-(L)-Val-(L)- (p-BzlOPhe)-morpholin-4-ylamide in 120 ml of methylene chloride are cleaved with 120 ml o'f TFA to yield the title compound: TLC R 1 (F)=0.42.

e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethlsillox)-6-phenyl-2(R)-(p-benzloxy phenylmethyl)-hexangyl-(L)-Val-(L)-(p-BzOPhe)-morpholin-4-ylamide Analogously to Reference Example 9f), 400 mg (0.631 mmol) of 5(S)-(Boc-amino)-4(S)- (t~tbtliehliyoy--hnl2()(-ezlxpeymty)hxni acid (Reference Example 44 and 305 mg (0.69 mmol) of H-(L)-Val.-(L)-(p-BzlOPhe)morpholin-4-ylamide in 5.7 ml of NMM/CH 3 CN 0.25M are reacted with 263 mg (0.69 mmol) of HBTU: TLC RK(A)=0.

3 1; tRt(II)= 37 .l min; FAB-MS (M+H)-1-055.

-142- Reference Example 46: Boc-(p-B zlO)Phe fClPhe-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 664 mg (0.70 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-(p-benzyloxyphienyl)-2(R)-(phenylmethyl)-hexanoyl-(L)- Val- (L)-Phe-morpholin-4-ylamide are deprotected with 440 mg (1.40 mmol) of TBAF in 7 mi of DMF. Crystallisation. from 'propanol/hexane yields the pure title compound: TLC Rf(D)=0.32; tRe(I)1 7 8 min; FAB-MS (M+H)=835.

The starting material is prepared as follows: a: N-Boc-(p-benzyloxyphenylalaninol) Analogously to Reference Example 21 B) 37.1 g (100 mmol) of Boc-(L)- (p-BzlOPhe)-OH (Bachem; Bubendorf/Switzerland) in 116 ml of TiMP are activated.at from -51C to -101C with 15.33 ml (110 mmol) of triethylamine and 14.36 ml (110 mmol) of chloroformic acid isobutyl ester in 70 ml of THF. The filtered reaction mixture is introduced dropwise into 7.57 g (200 mmol) of sodium borohydride, treatment with water and digestion in hexane yield the title compound: TLC Rf(A)=0.50; FAB-MS (M+H)+=358.

b: N-B oc-(P-benzyloxyphenylalaninal) Analogously to Reference Example 21 B) a solution of 3.5 ml of (49 mmol) of DMSO in 60 ml of methylene chloride is added at -60 0 C to 4.76 g (37.5 mmol) of oxalyl chloride in 33.6 ml of methylene chloride. The addition of 8.94 g (25 mmol) of N-Boc-(pben zylox-yphenylalaninol) in 150 ml of methylene chloride, 14 ml (100 mmol) of triethylamine in 30 ml of methylene chloride and aqueous working up (extraction of the aqueous phases with ethyl acetate) yields the crystalline title compound: TLC RK(A)=0.7 1; H-NMR (200 MHz, CDCl 3 1.44 9 3.06 J=6 Hz, 2 4.39 (in, 1 6.86-6.98 and 7.03-7.15 (2m, each 2 7.30-7.48 (in, 5 9.62 1 H).

c: 5(S)-fl (S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl] -dihydrofuran-2-(3H)-one Analogously to Reference Example 21 D) the zinc homoenolate is formed from 7.7 ml (57.1 minol) of 2-iodopropionic acid ethyl ester in 100 ml of toluene, 6.0 g (91.8 minol) of Zn/Cu and 9.69 ml of dimethylacetamide. The zinc homoenolate is transferred by means of cannula to trichiorotitanium isopropanolate (prepared from 4.17 ml (14.2 mmol) of tetraisopropyl orthotitanate and 4.41 ml (40.2 inmol) of titanium tetrachloride in 12 ml of toluene and 69 ml of methylene chloride) which has been cooled to from -401C to -25 0 C. The mixture is heated for 5 min at -25 0 C and cooled again to -143 0 C. A solution of 9.7 g (27 mmol) of N-Boc-(p-benzyloxyphenylalaninal) in 24.5 ml of methylene chloride is then added dropwise and the mixture is stirred for 15 h at approximately -20 0 C and then for 1 h at 0°C. The reaction mixture is poured onto 0.4 kg of ice-water and 0.5 1 of ether, and stirred vigorously for 10 min. The aqueous phase is removed and extracted with 2 portions of ether. The organic phases are washed with water, sat. sodium hydrogen carbonate solution, water and brine, dried with sodium sulfate and concentrated by evaporation crystalline 5(S)-(Boc-amino)-4(S)-hydroxy-6-(pbenzyloxyphenyl)-hexanoic acid ethyl ester).

The above intermediate is heated for 2.5 h at 100 0 C in 220 ml of toluene and 6.73 ml of acetic acid. 0.5 1 of water is added to the cooled reaction mixture, the aqueous phase is removed and extracted with 2 portions of ether, and the organic phases are washed with sat. sodium hydrogen carbonate solution, water and brine, dried with sodium sulfate and concentrated by evaporation. Crystallisation of the residue from ether/hexane yields the pure title compound: TLC Rf(E)=0.28; tRet(II)= 2 3 .5 min; 1 H-NMR (200 MHz, CDC13): 1.40 9 2.03-2.2 and 2.44-2.64 and 2.73-2.98 (3m, each 2 3.95 and 4.48 (2m, each 1 4.62 J=9 Hz, 1 6.87-6.97 and 7.09-7.21 (2m, each 2 7.27-7.48

H).

d: 5(S)-1 (S)-(Boc-amino)-2-(p-benzvloxyphenvl)-ethvll-3(R)-(phenylmethyl)-dihydro- S furan-2-(3H)-one -one--- Analogously to Reference Example 21 D) 2.47 g (6.0 mmol) of amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are deprotonated at 0 C with 11.73 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (75 min) with 0.713 ml (6.0 mmol) of benzyl bromide in 3 ml of THF. Column chromatography (SiO 2 hexane/ethyl acetate 4:1 2:1) and crystallisation from ether/hexane yields the pure title compound: TLC Rf(D)=0.36.

e) 5(S)-(Boc-amino)-4(S)-hydroxy-6-(p-benzvloxyphenvl)-2(R)-(phenvlmethyl)-hexanoic acid Analogously to Reference Example li), 0.502 g (1.00 mmol) of 5(S)-[1(S)-(Boc-amino)- 2-(p-benzyloxyphenyl)-ethyl]-3(R)-(phenylmethyl)-dihydrofuran-2-(3H)-one in 16 ml of dimethoxyethane and 8.6 ml of water are hydrolysed with 4 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 49 ml of sat. NH 4 Cl solution, 4,1 ml of 10 citric acid solution and methylene chloride, and ethanol is added until the precipitated solid has dissolved. The -144aqueous phase is extracted with 2 portions of methylene chloride/ethanol approximately 9: 1, and the organic phases are washed with brine, dried with Na 2

SO

4 and concentrated by evaporation: TLC Rf(A)=O.22.

f) 5 (S)-(Boc-arnino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)- (rphenylmethyl)-hexanoic acid Analogously to Reference Example lj), 1.04 g (2.00 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-(p-benzyloxyphenyl)-2(R)-(phenylrnethyl)-hexanoic acid in 7 ml of DMF are silvilated with 1.39 g (9.0 mmol) of tert-butyldimethyichiorosilane and 1. 12 g (16.4 mmol) of imidazole. Hydrolysis of the silyl ester function with 1.6 g of potassium carbonate in 46 ml of methanol[flTF/water 3: 1:1 and column chromatography (SiO 2 hexane/ethyl acetate 4:1 2:1 1:2) of the crude product yields the title compound: TLC Rg(A)=0.69.

g) 5(S)-(Boc-amino)-4(S)-(te-rz -tutyldimethylsilyloxy)-6-(p-benzyloxyphenl)-2(R)- (phenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 9f), 126.7 mg (0.200 mmol) of 4(S )-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(phenylmethyl)-h -xanoic acid and 73.3 mg (0.22 mmol) of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 1o) in 1.88 ml of NMM/CH 3 GN 0.25M are reacted with 83.4 mg (0.22 mmol) of HBTU: TLC RK(A)=0.33; FAB-MS (M+H)+=949.

Reference Example 47: Boc-(p-BzlO)Phe[ClPhe-(L)-Val-(L)-(p-BzlOPhe)-morpholin-4ylamide Analogously to Reference Example 788 mg (0.85 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsiyoy)6(penyopey)-R)phylty)-xay-L) Val- -(p-IBzlOPhe)-morpholin-4-ylamride are deprotected with 534 mg (1.70 mrimol) of TBAF in 8.5 ml of DMF. Crystallisation from ipropanollhexane yields the pure title ***compound: TLC Rg(B)=0.51; t~~e(I)=l9.O min; FAB-MS (M+H)--941.

The starting material is prepared as follows: a) 5(8 )-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)- (phenylmethyl)-hexanoyl-(L)-Val-(L)-(p-BzlOPhe)-morpholin-4-ylamide Analogously to Reference Example 9f), 560 mg (0.88 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldmethylsilyloxy)-6-(benzyloxyphenyl)-2(R)-(phenylmethyl)-hexanoic acid and 145 425 mg (0.968 mmol) of -Val- zlOPhe)-morpholin-4-ylamide (Reference Example 45 in 8.27 ml of NMM/CH 3 CN 0.25M are reacted with 366.9 mg (0.968 mmol) of HBTh: TLC Rf(A)=O.33; FAB-MS 1055.

Reference Example 48: Boc-(p-BzlO)Phe[C1(p)-BzlO)Phe-(L)-Val-(L)-Phe-riorpholin-4ylamide Analogously to Reference Example 1.10 g (1.0 mmol) of 5(S)-(Boc-a-minrc)-4(S)-(tertbutyldimethylsilyloxy)-6-(p-benizyloxyphenyl)-2(R)-(p-benzyloxyphenlinethyl)hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are deprotected with 628 mg (2.0 mmol) of TRAF in 10 ml of DMF. Crystallisation from hot 1 propanol yields the pure title compound: TLC RK(A)=-0.61; tRt(I)=1 9 .l min; FAB-MS (M+H)+=941.

The starting material is prepared as follows: a: 5(S)-ri (S)-(Boc-aiiiino)-2-(p-benzyloxvphenl)-ethyl]-3(R)-(p-benzyloxyphenyl methyl)-dihydrofuran-2-(3H)-one Analogously to Reference Example 21 D) 2.47 g (6.0 mmol) of amino)-2-(p-benzyloxyphenyl)ethyl]-dihydrofuran-2-(3H)-one (Reference Example 46 c)) dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydr---2(1H)-pyrimidinone are deprotonated at -701C with 11.73 ml of lithium bis(trimethylsilyl)axnide 1M in THFand alkylated (60 min) with 1.946 g (6.0 mmol) of p-benzyloxybenzyl iodide (Refrene Eampe 4a))in 3 ml of THF. Column chromatography (SiO 2 hexane/ethyl acetate 4: 1) and crystallisation from ethyl acetate/hexane yields the pure title compound: TLC RK(D)=0.45; tRC(I)=l 9 9 min; FAB-MS (M+I-I)+=608.

b) 5(S )-(Boc-amino)-4(S)-hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenyl methyl)-hetxanoic acid Analogously to Reference Example li), 2.7 g (4.43 mmol) of 5(S)-I[l(S)-(Boc-amino)-2oo. (p-benzyloxyphenyl)-ethyl]-3(R)-(p-benzyloxyphenylmethyl)-dihydrofuran-2-(3H)-one in 59 ml of dimethoxyethane and 31.8 ml of water are hydrolysed with 14.8 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 181 ml of sat. NH 4 CI solution, 16.2 ml of 10 citric acid solution and 400 ml of ethyl acetate, and THE is added until the precipitated solid has dissolved. The aqueous phase is extracted with 2 portions of ethyl acetate, and the organic phases are washed with brine, dried with Na 2

SO

4 concentrated by evaporation and digested in hexane: TLC Rf(A)=0.07.

-146c) 5 (S )-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)j (p-benzyloxyphenylmethyl)-hexanoic acid Analogously to Reference Example 1j), 2.44 g (3.90 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenylmethyl)-hexanoic acid in 14 ml of DMF are silylated with 2.70 g (17.6 mmol) of tert-butyldimethyichiorosilane and 2.18 g (32 mmol) of imidazole. Hydrolysis of the silyl ester function with 3.2 g of potassium carbonate in 90 ml of methanol/TEF/water 3:1:1 and column chromatography (SiO 2 hexane/ethyl acetate 2: 1 1: 1) of the crude product yields the title compound: TLC Rf(A)=0.53; FAB-MS (M+H)'=740.

d) 5 (S)-(Boc-ami no)-4(S)-(tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenl)-2(R)- (p-benzyloxyphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 9f), 740 mg (1.00 immol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-(p-benzyloxyphenyl)-2(R)-(p-benzyloxyphenylmethyl)hexanoic acid and 367 mg 10 mmol) of H-(L)-Val-(L)-Phe-morpholin-4-ylaxnide (Reference Example lo) in 9.39 ml of NMMICH 3 CN 0.25M are reacted with 417 mg (1.10 mmol) of HBTU: TLC Rf(A)=0.27; FAB-MS (M+H)+=1055.

Reference Example 49: Boc-(p-B3zlO)Phe (p-BzlO)Phe-(L)-Val-(L)-fr -BzlOPhe)- :morpholin-4-ylamide Analogously to Reference Example 0.85 g (0.73 mmol) of 5(S)-(Boc-Umino)-4(S)- (tr-uydmtysllx)6(-ezlxpey)2R-pbnyoy~eymty) hexanoyl-(L)-Val-(L)-(p-BzlOPhe)-morpholin-4-ylamide are deproteced with 460 mg (1.46 mmol) of TBAF in 7.3 ml of DMF. Digestion in ethyl acetate/hexane yields the pure title compound: TLC Rf(B)=0.66; tRt(I)= 2

O.

2 min; FAB-MS (M+H)+=1047.

The starting material is prepared as follows: a: 5(S)-(Boc-amino)-4(S)-(tert-butyldimethlsilyox)-6-(p-benzloxvphenyl)- 2 (p-benzyloxyphenylmethyl)-hexanoyl-(L)-Val-(L)-(p-B zlOPhe)-morpholin-4- ylamide *Analogously to Reference Example 9f), 740 mg (1.00 mmol) of 5(S)-(loc-,amino)-4(S)- (tr-uydmtysllx)6,pbnyoyhnl-()(-ezlxpinimty) hexanoic acid (Reference Example 48) and 483 mg (1.10 mmol) of (p-BzlOPhe)-morpholin-4-ylamide (Reference Example 45) in 9.39 ml of NMM/CH 3

CN

0.25M are reacted with 417 mg (1.10 mmol) of H-BTU: TLC R 1 (A)=0.19.

147 Ref -'rence E~.ample 50: Boc-%PherC] (o-F)Phe- L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 190 mg (0.219 mmol) of 5(S)-(Boc-amino)-4(S)- (tert- butyldimethylsilyloxy)-6-phenyl-2(R)- (o-fluorophenylmethyl)-hexanoyl-(!)-Va- (L)-Phe-morpholin-4-ylamide are deprotected, with 138 mg (0.438 mmol) of TBAF in 3 ml of DMF to yield the title compound: TLC Rf(A)=-0.23; tR~t(I)=l 6 .O min; FAB-MS 747.

The starting material is prepared as follows: a) 5 (S 1 (S)-(Boc-amino)-2-phenyl-ethylj-3(R)-(o-fluorophenylmethyl)-dihydrofuran-2- (3H)-one Analogously to Reference Example 21 D) 5.0 g (16.37 mmol) of amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Reference Example 21 1)b)] dissolved in 75 ml of TTL are deprotonated at -75'C with 32.7 ml of lithium bis(trirnethylsilyl)amide 1M in THE and alkylatp-d starting at -75 0 C with 2.1 ml (18.0 mmol) of o-fluorobenzyl bromide (Fluka; Buchs/Switzeriand) (warming up during 60 min up to max. -60 0 Column chromatography (SiO 2 hexane/ethyl acetate 3:1) yields the title compund:TLC Rf(D)=0.61.

b) 5 (S )-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(o-fluorophenylmethyl)-hexanoic acid Analogously to Reference Example 1i), 4.5 g (10.8 mmol) of 5(S)-[1(S)-(Boc-amino)- 2-phenylethyl] -3 (R)-(o-fluorophenylmethyl)-dihyclrofuran-2-(3H) -one in 170 ml of dimethoxyethane are hydrolysed with 43.5 ml of 1M lithium hydroxide solution. The evaporation residue of the ieaction mixture is poured onto a mixture of ice, 120 ml of sat.

ammonium chloride solution and 240 ml of 10 citric acid solution, and extracted with 3 portions of methylene chloride. The organic phases are washed with water and brine, dried over Na 2

SO

4 and concentrated by evaporation: tRet(I)=l 4 .5 min.

c) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluorophenyi methyl)-hexanoic acid Analogously to Reference Example lj), 1.5 g (3.47 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-(o-fluorophenylmethyl)-hexanoic acid in 15 ml of DMF are silylated with 2.4 g (16 mmol) of tert-butyldimethylchlorosilane and 1.95 g (28.5 mmol) of imidazole. Hydrolysis of the silyl ester function with 2.8 g of potassium carbonate in ml of methanol/TF/water 4: 1:1 yields the title compound after column chromato- 148 graphy (SiO 2 hexane/ethyl acetate 2: TLC Rf(D)=0.33; tRL(I)= 2

O.

7 min.

d) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fiuorophenylI methiyl)-hexanoyl-(L)-Val-(L)-Phe-inorpholin-4-ylamide Analogously to Reference Example 90); 150 mg (0.27 mmol) of 5(S)-(IBoc-amnino)-4(S)- (:e.rt-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluorophenylmethyl)-hexanioic acid and 101 mg (0.30 mmol) of H-(L)-Val-(L)-Plie-morphofin-4-ylamide (Reference Example 1o) in 2.6 ml of NMM/CH 3 CN 0.25M are reacted with 115 mg (0.30 mmol) of HBTU: tRet)= 2 2 3 min.

Reference Example 5 1: Boc-Phe[Cj (o-F)Phe-(L)-Val-()-(p-CH 3 0-Plie)-morpholin-4-y1amide Analogously to Reference Example 332 mg (0.37 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluorophenylmethyl)-hexanoyl-(L)-Val- (L)-(p-CH 3 O-Phc)-morpholin-4-ylamnide are deprotected with 350 mg 11 mmol) of TBAF in 3 ml of DNM. Digestion from DIPE and ether yields the title compound: TLC Rg(B)-=0.50; tRt(I)l1 6 .O min; FAB-MS (M+H)1=777.

The starting material is prepared as follows: a) 5(S )-(Boc-amino)-4(S)-(tert-butyldimethylsilylox)-6-phenl-2L)(ofluoropheny1 Analogously to Reference Example 9f), 205 mg (0.375 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(o-fluorophenylmethyl)-hexanoic acid (Refeec Example 50c) and 150 mg (0.412 mmol) of H-(L)-Val-(L)-(p-CH 3 O-Phe)o* *0*morpholin-4--ylamide (Reference Example 10e) in 3.6 ml of NMMICH 3 CN 0.25M are reacted with 156 mg (0.412 mmol) of HBTU. The crude product (foam) is stirred to yield the title compound: TLC Rf(A)=0.16; tRat(I= 22 6 min.

Reference Example 52: Boc-Phe[C1(m-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 181 mg (0.24 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoyl-(L)-Val- (L)-Phe-mnorpholin-4-ylamide are deprotected with 151 mg (0.478 mmol) of TBAF in 3 ml of DMF. Digestion in hexane yields the title compound: TLC Rf(A)=0.54; tRC()= 16.2 min; FAB-MS (M+H)=-747.

149 The starting material is prepared as follows: a) 5(S)-ri (S)-(Boc-axnino)-2-phenvlethyl'i-3(R)-(m-fluoro]phenylmethyl)-dihydrofuran-2k3H) -one Analogously to ReferenceExample 21 D) 5.0 g (16.37 mmol) of amino)-2-phenyletliyl-clihyclrofuran-2-(31H)-one [Reference Example 21 D) 1)b)] dissolved in 75 ml of THF are deprotonated at -751C with 32.7 ml of lithium bis(trimethylsilyl)amide iMin THF and alkylated starting at. -75 0 C with 3.4 g (18.0 mmol) of 3-fluorobenzyl b.-omide (Fluka; Buchs/Switzerland) (warming up during 60 min up to max. -501Q). Column chromatography (SiO?, hexane/ethyl acetate 3:1) yields the: title compound: TLC tRt(I)l1 7 2 min.

b) 5(S )-(Boc-amino)-4(S)-hvdroxy-6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoic acid Analogously to Reference Example ii), 3.7 g (8.95 mmol) of 5(S)-[1(S)-(Boc-amino)- 2-phenylethyl] -3(R)-(m-fluorophenylmethyl)-dihydrofuran-2-(3H)-one in 140 ml of dimethoxyethane are hydrolysed with 35.8 ml of 1M lithium hydroxide solution.

Extraction of the evaporation residue of the reaction mixture from a mixture of ice, 120,rtl of sat. amnmonium chloride solution and 240 ml of 10 citric acid solution with a large amount of methylene chloride (solubility!) yields the title compound: min.

a c) 5(S)-(Boc-amino)-4(S)-(tert-b-atyldimethylsilyloxy)-6-phenyl-2(R)-(m-fluorophenymethyl)-hexanoic acid Analogously to Reference Example lj), 2.7 g (6.25 mmol) of 5(S)-(Boc-amino)-4(S)hvdroxy-6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoic acid in 30 ml of DMF are a. silylated with 4.33 g (28.8 mmol) of tert-butyldimethylchlorosilane and 3.51 g (51.3 mmol) of imidazole. Hydrolysis of the silyl ester function with 5.1 g of potassalumn carbonate in 100 ml of methanol'TBEF/water 4: 1:1 yields the title compound after column a, chromatography hexane/ethyl acetate 2: tRe,()= 2

O.

8 min.

d) 5LS )-(Boc-amino)-4(S)-(tert-butyldimethiylsilyloxy)-6-phenyl-2(R)-(m-fluorohenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide C..Analogously to Reference Example 9f), 150 mg (0.27 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoic acid and 101 mug (0.30 mrnol) of H-(L)-Val-(L)-Phe-morpholin-4-ylamnide (Reference Example 1o) in 2.6 ml of NMM/CH 3 CN 0.25M are reacted with 115 mg (0.30 mmol) of HBTU.

Column chromatography (SiO 2 hexane/ethyl acetate 1:1) yields the title compound: TLC -150- Rf{A)=0.28; tRet()= 23 .O min.

Reference Example 53: Boc-Phe[GJ (m-F)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4ylqamide, .ilogously to Reference Example 336 mg (0.37 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoyl-(L)-Val- (L)-(p-CH 3 O-Phe)-morpholin-4-ylamnide are deprotected with 350 mg (1.12 mmol) of TBAF in 3 ml of DMF. Digestion from DIPE and ether yields the title compound: TLC RK(B)=-0.48; tRet()l1 6 .l min; FAB-MS =777.

The starting material is prepared as follows: a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-fluorophenylI methyl)-hexanoyl-(L)-Val-(L)-(p-CH 3 0-Phe)-morpholi -4-ylamide Analogously to Reference Example 9f), 205 mg (0.375 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(m-fluorophenylmethyl)-hexanoic acid (Reference Example 52c) and 150 mg (0,412 mmol) of.H-(L)-Val-(L)-(p-CH 3 O-Phe)-morphojlin-4-ylamide (Reference Example l~e) in 3.6 ml of NMM',ICH 3 CN (0.25M) are reacted with 156 mg (0.412 mmol) of HBTh. The crude product is stirred in an ultra-sound bath in hexane to yield the title compound: TLC Rf(A)=0. 16; tRt()= 22 .5 min.

Reference Example 54: Boc-!Phe[ClPhe-(L)-Val-(L)-Leu-morpholin-4-vlamide Analogously to Reference Example 1, 900 mg (1.1 1 rnmol) of 5(S)-Boc-amino-4(S)-(tertbutyldimethylsilyloxy)-65-phenyl-2(R)-phenylmethylhexanioyl-(L)-Val-(L)-Leu-morpholin-4-ylamide are deprotected with 608 mg (1 .93 mmol) of TBAF in 12 ml of DNF to yield the title compound: tRet MI 16 min; FAB-MS 695.

The starting materiai is prepared as follows: a) Z-(S)-Val-(L)-Leu -morpholin-4-ylamide Analogously to Reference Example 41 A) 3.98 g (10.9 rnmol) of Leu-OH1 (Bachem, Switzerland) are converted into the title compound with 0.87 ml mmol) of morpholine. TLC Rf (methylene, chloride/methanol 9:1) 0.6.

b) H- -Leu-morpholin- 1-ylamide Analogously to Reference Example 41 A) 4.7 g (10.9 mmol) of Z-(L)-Val-(L)-Leu- 151 morpholin-4-ylamide are converted into the title compound by hydrogenation in the presence of 1 g of 10 Pd/C. TLC Rf,(methylene chloride/methanol 9:1) 0.3: FAB-MS 300.

c) 5(S )-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-ohenyl-2(R)-phenylmethvlhexanoyl-(L)-Val-(L)-Leu-morpholin-4-ylamide Analogously to Reference Example 1 750 mg (1.42 mmol) of 5(S)-(Boc-amino-4(S)- (tert-butyldimethyl-silyloxy)-6-phenyl-2(R)-phenylmethylhexanoic acid and 508 mg (1.696 mmol) of H-(L)-Val-(L)-Leu-morpholin-4-ylamide are reacted in DMF: tRet(I)= 22.4 min; FAB-MS (M 809.

Reference Example 55: Boc-PherC]Phe-(L)-Val-(9A morpholin-4-ylamide Analogously to Reference Example 1, 623 mg (0.81 n.inol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(TL)-Val-(L)-Alamorpholin-4-ylamide are deprotected, with 456.5 mg (1.447 mmol) of TBAF in 11 ml of DMF to yild the title compound: tRe(II)= 19.6 min; FAB-MS 653.

The starting material is prepared as follows: a) Z-(L)-Val-(L)-Ala-morpholin-1-ylamide Analogously to Reference Example 41 A) 2 g (6.21 mmol) of Z-(L)-Val-(L)-Ala-OH (Bachem, Switzerland) are converted' into the title compound with 0.54 ml, (6.21 mmol) of morpholine. TLC Rg(methylene chloride/x.nethanol: 0.61.

b) H-(L)-Val-(L)-Ala-morpholii- 1-ylamide Analogously to Reference Example 41 A) 2.4 g (6.2 mmol) of Z-(L)-Val-(L)-Alamorpholin-1I-ylamide are converted into. the title compound by hydrogenation in the presence of 0.4 g of 10% Pd/C. TLC R~(methylene chloride/methanol: 0.53; PAB-MS 258.

c) 5 c-amino)-4(S)-(tert-butyl.dimethylsilyloxy)-6-phe yi-2(R)-phenylmethylhexranoyl-(L)-Val-(L)-Ala-morpholin- 1-ylamide Analogously to Reference Example 1k, 500 mg (0.947 mmnol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-phenylmethylhexanoic acid and 292.4 mg Y;6 mmol) of H-(L)-Val-(L)-Ala-morpholin-4-ylamide are reacted in DMF: tR~t(ll)=- 32.4 min; FAB-MS 767.

-152- Reference Example 56: The following compounds are prepared analogously to one of the above Reference Examples: A) Boc-(P-CH 3 O)PherClPhe-(L)-Val-(L)-Phe-morpholin-4-ylamide B) Boc-(p-CH3Q)PherCI (p-CHO)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide C) Boc-(p-CH 3 O)Phe[CIp-BzlO)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide D) Boc-(p-CH 3 O)PherClTvr-(L)-Val-(L)-Phe-morpholin-4-ylamide E) Boc-(p-CWO)PheCIPhe-T -Val-(L)-(p-CH,30-Piie)-morpholin-4-ylamide F) gocg(p-CH O)Phe[C]Phe-(L)-Val-(L)-Tyi'-morpholin-4-ylamide G) Boc-(p-CH O)Phe[CI (p-_CH 3 0)Phe-(L)-Val-(LY.(p- HO-Phe)-morpholin-4-ylamide Boc-(p-CH 3 O)Phe[C1 (p-CH 3 O)Phe-(L)-Val-(L)-Tyr-morpholin-4-ylamide Boc-(p-CH-40)PherC1 (p-BzlO)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide J) Boc-(p-CH 3 O)PherC1 (p-BzlO)Phe-(L)-Val-(L)-Tyr-morpholin-4-ylamide K) Boc-(p- HO)Phe[C]Tyr-(L)-Val-(L)-(p-(C-O-Phe)-morpholin-4-ylamide L) Boc-(p-CH 3 O)PherC]Tyr-(L)-Val-(L)-Tvr-morpholin-4-ylamide M) Boc-(p-CH-IO)PherCk(3-ChR 3 O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide N) Boc-(p-CH 3 O)PherC1(2-Cf{ 3 0)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide 0) Boc-Phe[C](2ICH O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide 101.6 g of TBAF are added to a solution of 140.3 mg of 5(S)-(Boc-amino)-4(S)-(tertbutyldimethiylsilyloxy)-6-phenyl-2(R)-(2-methoxyphtenylmethyl)-hexanoyl-(L)-Val-(L)- Phe-morpholin-4-ylamide in 3 ml of DMF, and the reaction mixture is stirred at RT for 153- 21 h. The faintly yellowish solution is diluted with approximately 30 ml of ethyl acetate, washed in succession once with water, once with saturated sodium bicarbonate solution and twice with brine until neutral, and dried over sodium sulfate. After removal of the solvent, the residue is purified on silica gel (eluant B) to yield the title compound. TLC Rf(B)=0.26. FAB-MS (M+H)+=759.

The starting material is prepared as follows: 56 0) a) 2-Methoxvbenzyl chloride 16.8 ml of thionyl chloride are added dropwise over a period of approximately 30 minutes to 10 ml of 2-methoxybenzyl alcohol (Fluka, Buchs, Switzerland) and 53.76 g of diisopropylaminomethylpolystyrene (Polyhiinig base; Fluka, Buchs, Switzerland; copolymer of 98 styrene and 2 divinylbenzene, diisopropylaminomethylated) in 200 ml of abs.

ether. After having been stirred for a further 1.5 h at 0°C, the mixture is filtered with suction and the filtrate is concentrated in a rotary evaporator and under a high vacuum.

The residue is purified by chromatography on silica gel (eluant: hexane/ethyl acetate 6:1).

TLC Rf(C)=0.5. H-NMR (200 MHz, CDCl 3 7.42-7.24 2H); 7.0-6.84 2H); 4.68 2H); 3.9 3H).

56 0) b) 2-Methoxybenzyl iodide 9.3 g of sodium iodide are added to 2 g of 2-methoxybenzyl chloride in 22 ml of abs.

acetone and the mixture is stirred overnight at RT. The reaction mixture is diluted with 250 ml of ether and washed with 10% sodium thiosulfate solution and brine. The title compound is obtained by drying over sodium sulfate and removing the solvent and is further processed without being purified. TLC Rf(C)=0.4 6 1H-NMR (200 MHz, CDC1 3 7.36-7.2 2H); 6.92-6.8 2H); 4.48 2H); 3.91 3H).

S 56 0) c) 5(S)-[1(S)-(Boc-amino)-2-phenvlethyll-3(R)-(2-methoxvphenvlmethvl)-dihydro-furan-2-(3H)-one Under a nitrogen atmosphere, a solution of 1 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [for preparation see under Reference Example 2 in 4 ml of abs. THF and 0.66 ml of DMPU is cooled to -75 0 C, 6.42 ml of lithium bis(trimethylsilyl)amide (1M) in THF (Aldrich, Steinhim, Federal Republic of Germany) are added at an internal temperature of below -70 0 C, and the mixture is then stirred for 20 min at -75 0

C.

812 mg of 2-methoxybenzyl iodide in 2 ml oY abs. THF are added dropwise to the reaction solution over a period of 10 min using a syring, during which the internal temperature -154must not exceed -70 0 C, and the mixture is stirred for 1 h at -75 0 C to complete the reaction.

1.22 ml of propionic acid followed by 1.22 ml of water are then added to the clear solution at from -75 0 C to -70 0 C using a syringe, the temperature rising to -30°C. The reaction mixture is subsequently diluted with 50 ml of ethyl acetate and stirred cold (ice/water cooling) for 5 min with 20"ml of 10% citric acid solution. The aqueous phase is removed, and the organic phase is washed in succession with brine, sat. sodium bicarbonate solution and again with brine. The combined aqueous phases are re-extracted twice with ethyl acetate. The combined organic ph.ases are dried over sodium sulfate and concentrated. The title compound is obtained in the form of a brownish oil. Purification is carried out by chromatography on silica gel. Chromatography on silica gel (eluant E) yields the pure title compound. TLC Rf(hexane/ethyl acetate 2.5:1)=0.54. MS M+=425.

56 0) d) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2-methoxyphenylmethyl)hexanoic acid 4.45 ml of a 1M lithium hydroxide solution are added dropwise at RT to a solution of 474 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-(2-methoxyphenylmethyl)- S dihydrofuran-2-(3H)-one in 18 ml of dimethoxyethane and 9.07 ml of water. The reaction mixture is then stirred for 3 h at RT, diluted with ethyl acetate and THF and washed in a separating funnel with a mixture of 54.78 ml of sat. ammonium chloride solution and *4.58 ml of 10% citric acid solution, followed by brine and water, until neutral. The title compound is obtained after drying over sodium sulfate and removing the solvent and is further processed without being further purified. TLC Rf(hexane/ethyl acetate 2.5:1)=0.15.

56 0) e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenv.-2(R)-(2-methoxyphenylmethyl)-hexanoic acid 614 mg of imidazole and 796 mg of tert-butyldimethylchlorosilane are added, with S* stirring, to a solution of 500 mg of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2methoxyphenylmethyl)-hexanoic acid in 5 ml of DMF. After having been stirred for 20 h at RT, the reaction solution is poured onto ice-water and extracted with ethyl acetate. The organic phase is washed with 10% citric acid solution and brine and dried over sodium o sulfate. The solvent is then concentrated by evaporation and the residue is chromatographed on silica gel (eluants E and A) to yield the title compound. R(hexane/ethyl acetate 2.5:1)=0.12. FAB-MS (M+H)+=558.

56 0) f) 5(S)-(Boc-amino)-4(S)-(tert-butvldimethvlsilvloxy)-6-phenyl-2(R)-(2methoxyphenylmethyl)-hexanoyl-0()-Val-(L)-Phe-morpholin-4-vlamide i -~e 155 A mixture of 100 mng of 5 (S)-(Boc-amnino)-4(S)-(tert-butyldimethylsilyloxy)-6-pheny- 2(R)-(2-methoxyphenyilmethyl)-hexanoic acid, 74 71 mg of HBTU and 65.68 mg of IH- -Val- (L)-Phe-morpholin-4-ylamide [for preparation see under Reference Example 1 o)] in 1.68 ml of a 0.25M solution of NMM in acetonitrile is stirred for 15 h1at RT under argon. The solution is concentrated to dryness, and the residue is taken up in ethyl acetate and washed in succesi-on with 10% citric acid, water, sat. sodium bicarbonate solution and brine. The title compound is obtained after drying over sodium sulfate and removing the solvent and is further processed without being purified. TLC Rf(A)=O.20. FAB-MS (M+H)+=873.

P) Boc-Phe[C1 (3-CH 3 O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide.

Analogously to Reference Example 56 356 mng of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3-methoxyphenylmethyl)-hexanoyl-(L)-Val-(L)-Phemorpholin-4-ylamide in 6.09 ml of DMF are desilylated with 206 mng of TBAF to yield the title compound: Purification is carried out by chromatography on silica gel (eluant B).

TLC Rf(B)=O.37. FAB-MS (M±H)+=759.

The starting material is prepared as follows: 56 P) a) 3-Methoxybenzyl iodide Analogously to Reference Example 56 0) the title compound is obtained from 2 ml of 3-methoxybenzyl chloride (Fluka, Buchs, Switzerland) and 9.72 g of sodium iodide in 23 ml of abs. acetone. IThIC Rfghexane/ethyl acetate 2.5: 1)=0.7 1. 1H NMR (200 Mvllz, CDCl 3 7.20 (in, 1H); 7.0-6.87 (in, 2H); 6.78 (dxd, 1Hi), 4.42 211); 3.8 3H).

56 P) b) 5(S)-ri (S )-(Boc-amino)-2-phenylethyl]-3(R)-(3-methoxx'phenylmethyl)-dihydrofuran-2-(3H)-one Analogously to Reference Example 56 0) 1.5 g of 5(S)-[l(S)-(Boc-amino)-2-phenylethyl] -dihydrofuran-2-(3H)-one [prepared according to Reference Example 2i)] in 3 ml of a abs. TI-F are deprotonated (-75 0 C) with 9.62 ml of lithium bis(trimethylsilyl)amide (IM in THF) and with the addition of 0.998 ml of DMPU, and alkylated with 1.22 g of 3-methoxybenzyl iodide. Chromatography on silica gel (eluant E) yields the pure title compound. TLC Rf (hexane/ethyl acetate 2.5: 1)=0.32. FAB-MS (M+H)+=426.

56 P) c) 5( )-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(3-methoxyphienylniethvl)hexanoic acid -156- Analogously to Reference Example 56 0) 1.315 g of 5(S)-[1(S)-(Boc-amino)-2phenylethyll-3(R)-(3-methoxyphenylmethyl)-dihydrofuran2(3H)-one in 49.9 ml of dimethoxyethane and 25.16 ml .of water are hydrolysed with 12.36 ml of lithium hydroxide solution 1M to yield the title compound which is directly further processed.

TLC Rf(A)=O.09. FAB-MS =444.

56 P) d) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxv)-6-phenyl-2(R)-(3-methoxy phenylmethyl)-hexanoic acid Analogously to Reference Example 56 0) 1.3 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6phenyl-2(R)-(3-methoxyphenylmethyl)-hexanoic acid in 13 ml of DMF are silylated with 1.987 g of tert-butyldimethylchlorosilane and 1.646 g of imidazole. Chromatography on silica gel (eluants E, D and A) yields the pure title compound. TLC Rf(D)=-0.O6. FAB-MS (M+Ti)+=558.

56 P) e) 5 (S)-(Boc-amino)-4(S)-(tert-butvldimethylsilyloxy)-6-phenyl-2(R)-(3-methoxy phenylmethyl)-hexanoyl-(L)-Vaql-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 56 0) 192.2 mg of 5(S)-(Boc-amino)-4(S)-(tertbuty:,iimethylsilyloxy)-6-phenyl-2(R)-(3-methoxyphenylmethyl)-hexanoic acid and 126.4 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide [prepared according to Reference Example 1o)] in 3.23 ml of NMM/CH 3 CN 0.25M are reacted with 143.7 mg of HBTU to yield the title compound. TLC Rf(A)=0.25. FAB-MS (M+H)+=873.

Q) Boc-PhefC] (3-C11 3 )Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide R) Boc-Phe[CJ (2-CH {O)Phe-(L)-Val-(L)-(P-CH 3 O-Phe)-morpholip-4-ylamide S) Boc-Phe[CJ (p-BzlO)Phe-(L)-Val-(L)-(p-CH 3 (DIPhe)-morpholin-4-ylamide Analogously to Reference Example 345 mg (0.352 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(p-benzyloxyphenyl)methyl]-hexanoyl-(L)- .Val- -(p-CH 3 O-Phe)-morpholin-4-ylamide are deprotected with 222 mg (0.704 mmol) of TBAF in 5 ml of DMI. Dig stion. from DIPE in an ultrasound bath yields the titl compound: TLC Rf(B)=-0.28; tR~t(I)=l7.6 min; FAB-MS -865.

The starting material is prepared as follows: 157 a) 5 (S )-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-plienyl-2(Ry [r(p-benzyloxyphenyl)methyllhexanoyl-(L)-Val-(L)-(p-CHI,3-Phe)morpholin4ylamide Analogously to Reference Example 9f), 263 mg (0.415 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-[(p-benzyloxyphenyl)methyl]phexanoic acid (Reference Example-44d) and 137 mg (0.377 mmol) of H-(L)-Val-(L)-(p-CH 3 O-Phe)morpholin-4-ylamide (Reference Example lOe) In 3.6 ml of NMM/CH 3 CN 0.25M are reacted with 157 mg (0.415 mmol) of HBTU to yield the title compound: tR't()= 23 .5 min.

Reference Example 57: Boc-Phe[C] Tyr- (L)-Val-(L)-(p-CIH-3-Phe)-morpholin-4-ylamide Hydrogenation of 70 mg (0.081 mmol) of Boc-Phe[C](p-BzlO)Pbe-(L)-Val-(L)- (p-CH 3 O-Phe)-morpholin-4-ylamide (Reference Example 56S)) in 8 ml of methanol in the presence of 35 mg of 10% Pd/C yields the title compound after filtration through Celite and concentration by evaporation: TLC Rf(B)=0.17; tRct()=l 4 .l min; FAB-MS (M+H)+=775.

Reference Example 58: Boc-Phe[C1 HO-Phe)-morpholin-4ylamide Analogously to Reference Example 322 mg (0.36 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-cyao~u-)henylmethyl)-hexanoy-(L)-Val" (L)-(p-CH 3 O-Phe)-morpholin-4-ylamide are deprotected with 340 mng (1.08 mmol) of TBAF in 3 ml of DMF over a period of 19 h. Digestion of the crude product from DIPE in an ultrasound bath yields the title compound: TLC Rf(Y)=0.41; 15.4 min, FAB-MS (M+H)+=784.

The starting material is prepared as follows: a) 5(5 )-(Boc-aniino)-4(S )-(tert-butvldimethylsilyloxy)-6-phenyl-2(R)-(P-cyanophenvl- *0methyl)-hexanoyl-(L)-Val-(L)-(p-CH30-Phe)-morpholin-4-ylamide Under a nitrogen atmosphere, 200 mg (0.362 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(p-cyanophenylmethyl)-hexanoic acid [Reference Example 21 E) are dissolved in 6 ml of abs. THF and, at 5 0 C, 82 mg (0.398 mmol) of DCC are added. After 10 min 145 mg (0.398 mmol) of H-(L)-Val-(L)-(p-CH 3 O-Phe)morpholin-4-ylamide (Reference Example 10e) and 54 mg (0.398 mmol) of I3OBT are added and the mixture is stirred for 17 h at RT. The reaction mixture is filtered, and the filtrate is taken up in ethyl acetate and washed with 10 citric acid solution, water, sat.

NaHCO 3 solution and brine. The aqueous phases are extracted twice with ethyl acetate, 158and the organic phases are dried with Na 2

SO

4 concentrated by evaporation and digested in DIPE to yield the title compound: 2 l.

8 min; FAB-MS =898.

Reference Example 59: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-r(2,4-difluorophenyl)-methyl]-hexanoyl-(L)-Val-(L)-Phe-morpholin4ylamide Analogously to Reference Example 264 mg (0.30 mmol) of 5(S)-(Boc-amino)-4(S)- (tr-uydmtysllx)6pey-()-(,-iloohnl-ehl-eaol (L)-Val-(L)-Phe-morpholin-4-ylaxnide are deprotected with 190 mg (0.60 mmol) of TBAF in 5 ml of DMF for 17 h. Digestion of the crude product from a small amount of methylene chloride and DIPE/hexane 3:1 in an ultrasound bath yields the title compound: TLC tRt()=l 6 .l min; FAB-MS (M+H)1-765.

The starting material is prepared as follows: a) 5(S)-ri (S)-.(Boc-amino)-2-phenylethyll-3(R)-[(2,4-difluorophenyl)methyll-dihydro furan-2-(3H)-one :1:::Analogously to Reference Example 21 D) 5.0 g (16.37 mmol) of amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Reference Example 21 D) 1)b)] dissolved in 100 ml of IHF are deprotonated at -751C with 32.7 ml of lithium bis(trimethylsilyl)amide IM in THE, and alkylated starting at -751C with 2.51 ml (19.6 mmol) of 2,4-difluoitobenzyl bromide (Aldrich; Milwaukee/USA) (warming up during 2 h up to 0 Column chromatography (SiO 2 hexane/ethyl acetate 2:1) yields the title compound: TLC Rf(D)=0.5; 7 2 min.

b) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-r(2,4-difluorophenyl)methylj-hexanoic acid Analogously to Reference Example ii), 3.1 g (7.18 mmol) of 5(S)-[1(S)-(Boc-amino)-2phenylethyl]-3(R)-[(2,4-difluorophenyl)methyl]-dihydrofuran-2-(3H)-one in 77 ml of dimethoxyethane and 19 ml of water are hydrolysed with 28.7 ml of 1M lithium hydroxide solution (19 h RT): tRet()l1 4 7 min.

c) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilvloxy)-6-phenyl-2(R)-[(2,4-difluorophenyl)methyll-hexanoic acid Analogously to Reference Example 1j), 3.2 g (7.12 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-[(2,4-diflucrophenyl)methyl]-hexanoic acid in 67 ml of DM13 are silylated with 4.93 g (32.7 mmol) of tert-butyldimethylchlorosilane and 3.97 g -159- (58.4 mmol) of imidazole. Hydrolysis of the silyl ester function with 5.9 g of potassium carbonate in 77 ml of methanol,, 20 ml of THE and 20 ml of water yields the title compound after column chromatography (SiO 2 hexane/ethyl acetate 2: TLC Rf(D)=O.22; tRct(I)= 2

O.

8 min.

d) 5(5 )-(Boc-amino)-4(S )-(tert-butyldimethvylsilyloxy)-6--phenyl-2(R)-r(2,4-difluorophenyl)-methyl] -hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 9f), 200 mg (0.35 mmol) of 5(S)-(Boc-ar.ino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,4-difiuorophenyl)methyl]hexanoic acid and 130 mg (0.39 mmol) of H-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example.

1o) in 3.4 ml of NMM/CH 3 CN 0.25M are reacted with 148 mg (0.39 mmol) of HBT.U to yield the title compound: t~et(I)=22.4 min.

Reference Example 60: Boc-PherC]Phe-(L,)-Val-(L)-Phe-trans-(2,6)-dimethylmorpholin- 4-ylamide: Analogously to Reference Example 1, 770 mg (0.89 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)-hexanoyl.(L)wVal-(L)-Phe.

trans-(2,6)-dimethylmorpholin-4-ylamide are deprotected with 280 mg (0.89 mmol) of TBAF in 10 ml of DMF. Digestion from DIPE and ether yields the title compound: TLC Rf(D')=0.26; tR~t()=l 7 .l min.; FAB-MS(M+H)+=757.

The starting compound is prepared as follows: a) 5 (S )-(Boc-amino)-4(S )-tert-butvldimethylsilyloxy)-6-phenyl-2(R)-(phenylmethyl)hexanoyl-(L)-Val-(L)-Phe-tranis-(2,6)-dimethylmorpholin-4-ylamide: Analogously to Reference Example 9f),420 mg (0.97 mmol) of 5(S)-(Boc-amino)-4(S)kLer-butyimthII.1yyliuoy-6-pI1Iyl- 2(R)-(phenylmethyl)-hexanoic acid (Reference Example 50c) and 512 mg (0.97 mmol) of H-(L)-Val-(L)-Phe-trans-(2,6)-dimethylmorpholin-4-ylamide in 10 ml of NMM/CH 3 CN 0.25M are reacted with 405 mg of HBTU. Chromatography on silica gel with ethyl acetate/hexane 1) yields the title **compound: tR,.t(I)= 22 9 min.

b) H-(L)-Val-(L)-Phe-trans-(2,6)-dimethylmorpholin-4-ylamide: 402 mg (1.1 mmol) of HBTU are added to a solution of 400 ing (1 mmol) of Z-(L)-Phe- (L)-Val-OH and 120 mg (1 mmol) of trans-(2,6)-dimethylmorpholiiie in 10 ml of

NMNL/CH

3 CN 0.25M and the mixture is stirred for 96 h at RT. The reaction mixture is -160diluted with ether and washed in succession with water, 10 citric acid, sat. sodium bicarbonate solution, water and sat. sodium chloride solution. The organic phases are dried over sodium sulfate and concentrated by evaporation. The residue is hydrogenated as described in Reference Example 1 m) with Pd/C in methanol and yields the title compound in the form of an amorphous solid.

Reference Example 61: Boc-Phe[C1 (p-isobutyloxy)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide: 233 mg (0.7 mmol) of caesium carbonate are added to a solution of 155 mg (0.2 mmol) of Bor-PheC]Tyr-(L)-Val-(L)-Phe-morpholin-4-ylamide from Reference Example 41D in 18 ml of dioxane and the mixture is stirred for 12 h. 1.1 ml (9.4 mmol) of isobutyl iodide are added to the milky suspension and the reaction mixture is scirred for 2 h at RT and then heated for 6 h at 80 OC. The reaction mixture is cooled and diluted with methylene chloride, solids are removed by filtration and the filtrate is concentrated by evaporation.

The title compound is obtained after purification by chromatography on silica gel with ethyl acetate/hexane TLC Rf(C')=0.56; tRet(I)=1 8 .1 min.; FAB-MS (M+H)1=801.

Reference Example 62: Boc-PherC1(P-isobutyloxy)Phe-(L)-Val-(L)-(p-isobutyloxy-Phe)morpholin-4-ylamide: Analogously to Reference Example 61, the title compound is obtained from 114 mg (0.14 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-hydroxyphenylmchyl)-hexanoyl-(L)-Val-(L)-(p-isobutyloxy-Phe)-morpholin-4-ylamide, 163 mg mmol) of caesium carbonate and 0.4 ml (3.4 mmol) of isobutyl iodide after purifica- S tion by chromatography on silica gel with ethyl acetate: TLC R(C')=0.55 tRC(I)= 2 0. 1.;FAB-MS (M+H)f=873.

The starting material is prepared as follows: a) 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(4-hydroxyphenylmethyl)-hexanoyl- (L)-Val-(L)-(p-isobutvloxv-Phe)-morpholin-4-vlamide: A solution of 408 mg (0.4 mmol) of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)- 6 -phenyl-2(R)-(4-benzyloxyphenylmethyl)-hexanoyl-(L)-Val-(L)-(p-isobutyloxy-Phe)morpholin-4-ylamide in 6 ml of methanol is hydrogenated for 5 h with 76 mg of Pd/C 5 in the presence of 1 atm hydrogen pressure. The catalyst is removed by filtration, the filtrate is concentrated by evaporation, and the residue is chromatographed on silica gel with ethyl acetate/methanol In addition to 5(S)-(Boc-amino)-4(S)-(tert-butyl- 161 dimethylsilyloxy)-6-phenyl-2(R)-(4-hydroxyphenylmethyl)-hexanoyl-(L)-Val-(L)-(pisobutyloxy-Phe)-morpholin-4-ylamide obtairi: d as a by-product, the title compound is obtained: TLC Rf(C')=0.37.

b) 5 (S )-(Boc-amino)-4(S)-(tert-butvldimethylsilyloxy)-6-phenyl-2-(R)-(4-benzyloxyphenylmethyl)-hexanoyl-(L',-Val-(L)-(p-isobutyloxy-Phe)-morpholin-4-ylamide: Analogously to Reference Example 9f, 291 mg (0.45 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phe,,.nyl-2(R)-(4-benzyloxyphenylmethyl)-hexanoic acid (Reference Example 44d) and 203 mg (0.5 mmoi) of IH-(L)-Val-(L)-(p-isobutyloxy-Phie)morpholin-4-ylamide (Reference Example 70b) in 4.6 ml of NMMICH 3 CN 0.25M are reacted with 193 mg of HBTU: TLC Rg')=0.39; FAB-MS =1021.

Reference Example 63: 5(S)-[4-(Tetrahydropyranyl)oxycarbonylaminol-4(S)-hydroxy-6phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4.ylamide 0.331 ml (2.38 mmol) of triethylamine are added to 500 mg (0.795 mmol) of (amino)-4(S)-hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4- ,..*ylamide and reacted, with cooling to 5'C, with 262 mg (1.59 mmol) of chloroformic acid 4-tetrahydropyranyl ester (Chemical Abstracts Registry No. 89641-80-5). After having o.been stirred for a further hour at RT, the reaction mixture is poured onto water and extracted 3 times with ethyl acetate. The combined organic phases are washed with water, ~.saturated sodium bicarbonate solution and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The title compound is purified by column chromatography (SiO 2 methylene chloride/methanol); TLC Rf 0.3; tRet(I) 14.28 min; FAB-MS (M+HW) 757.

Reference Example 64: [3(S)-(Tetrahydrofuranyl)oxycarbonylaminol-4(S)-hydroxy- 6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 63, 500 mg (0.795 mmol) of 5(S)-(amino)-4(S)hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are reacted with 363 mg (2.41 mmol) of chloroformic acid 3(S)-tetrahydrofuranyl ester. The title compound is purified by precipitation with ether; TLC Rf 0.25; tRt(I)= 13.86 min; FAB-MS 743.

The starting material is prepared as follows: -162a) Chioroformic acid 3(S)-tetrahydrofuranyl estcr 14.1 ml (27.24 mmol) of a 20 solution of phosgene in toluene are added dropwise to 14 ml of toluene. After the mixture has been cooled in an ice-bath, solution of 2 g (22:.7 unmol) of (S)-(+)-3?-hydroxy-tetrahydrof-aran (JPS CHINIE, Bevaix, Switzerland) in a small amount of toluene is added, the mixture is then stirred for 1 h at'RT, and the excess phosgene is expelled with argon. After concentration in a rotary evaporator at reduced pressure, distillation is carried out for the purpose of purification. Boiling point at 12 torr 130'C.

Reference Example 65: [3(R)-(Tetrahydrofuranyl)oxycarboniylamino]-4(S)-hydroxy- 6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamnide Analogously to Reference Example 63, 500 mg (0.795 mmol) of 5(S)-(amino)-4(S)hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are reacted with 363 mg (2.41 mmol) of chioroformic acid 3(R)-tetrahydrofuranyl ester. The title compoun~d iAs purified by column chromatography (SiO 2 ethyl acetate to ethyl acetate/acetone: 9/1 TLC Rfgethyl acetate/acetone: 0.62; tRet(V)= 14.06 min; FABrMS 743.

The starting m,-terial is prepared as follows: a) Chloroformic acid 3(R)-tetrahydrofuranyl ester 12.5 ml (24.15 mmol) of a 20 solution of phosgene in toluene are cooled in an ice-bath, a solution of 1.06 g (12.03 mmol) of (R)-(+)-3-hydroxytetrahydrofuran (JPS CHIMIE, Bevaix, Switzerland) in, a small amount of toluene is then added dropwise and, after the mixture has been stirred at RT for 2 h, the excess phosgene is expelled with argon. After concentration by evaporation in a rotary evaporator under ieduced pressure, the crude title compound is further processed without being further purified.

Reference Example 66: 5 (S)-Ethoxycaxbonylamino-4(.S)-hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 63, 500 mg (0.795 mmol) of 5(S)-(amino)-4(S)hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are reacted with 0.15 1 ml (1.585 mmol) of chioroformic acid ethyl ester (Fluka, Buchs, Switzerland).

The title compound is purified by crystallisation (ethyl acetate/ether); TLC Rf(B)= 0.4; tRet(IV)= 14.51 min; FAB-MS 701.

163 Reference Example 67: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-benzyloxyphenylmethyl)-hexanovl '(L2-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 1, 1.45 g (1.517 mmol) of 5(S)-(Boc-a~rino)-4(S)- (ter-t-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-benzyloxybenzyl)-hexanoyl..(L)-Val- (L)-Phe-morpholin-4-ylamide in 12 ml of DMF are reacted with 0.950'g' (3.03 mmol) of TBAF trihydrate to yield the title compound. The title compound is purified by crystallisation (hexane). TLC Rf 0.5; tRet(IV)= 18.99 min; FAB-MS 841.

The starting compounds are prepared as follows: a) 5(S 1(S)-(Boc-amino)-2-cvcrlohexylethll-dihydrofuran-2-(3H)-one A solution of 5 g (16.37 mmol) of 5(S)-[1(S)-(BEoc-a,r.-i,)-2-phenylethyl]-dihydrofuran- 2-(3H)-one in 50 ml of methanol is hydrogenated for 2 0 ni' .T under normal pressure in the presence of 0.5 g of Nishimura catalyst. The catalyst is removed by filtration and the filtrate is then concentrated in a rotary evaporator and dried under a high vacuum. TLC Rf 0.5; FAB-.MS 312.

b) 5(S)-ri (S )-(Boc-amino)-2-cyclohexylethyl]-3(R)-(4-benzyloxybenzvl)-dihydrofuran-2- (3H)-one Analogously to Reference Example 21 D) 1) 30.9 g (99.26 mmol) of ~:amino)-2-cyclohexylethyl]-dihydrofuran-2-(3H)-one are reacted with 200 ml (200 mmol) of lithium bis Itrimethylsilyl)amide 1M in THF and 34 g (104.8 mmol) of 4-benzyloxybenzyl iodide to yield the title compound. The title compound is purified by column chromatography (Si0 2 hexane/ethyl acetate: 4/1 to 1/1) and crystallisation (hexane/ethyl acetate); TLC Rf 0.33; tR~t(IV)= 20.41 min; FAB-MS 08.

c) 5 (S )-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-(4-benzyloxybenzyl)-hcxanoic acid Analogously to Reference Example I 2.4 g (4.728 mmol) of 5(S)-[1(S)-(Boc-amino)- 2-cyclohexylethyl]-3(R)-(4-benzyloxybenzyl)-dihydrofuran-2-(3H)-one in 10 ml of 1,2-di- .methoxyethane are reacted with 9.45 ml of 1M LiOH solution to yiel d the tit'z, compound, which is purified by crystallisation. from hexane. TLC Rf 0.33; tRL(IV)= 18 min; FAB-MS 526.

d) 5(5 )-(Boc-amino)-4(S)-(tert-butyldimhethyl)silyloxy-6-cyclohexyl-2(R)-(4-benzyoxy benzyl)-hexanoic acid Analogously to Reference Example 1ij), 28.8 g (54.8 mmol) of 5(S)-(Boc-amino)-4(S)- 164hydroxy-6-cyclohexyl-2(R)-(4-benzyloxybenzyl)-hexanoic acid in 288 ml of DMF are converted into the title compound with 35.8 g (237.6 mmol) of tert-butyldirn~ethyichiorosilane and 30 g (237.6 mmol) of imidazole. The title compound is purified by column chromatography (Si0 2 hexane/othyl acetate: 4/1 to TLC Rf 0.33; tR 0

(IV)=

23.72 min; e) 5 (S )-(Boc-amiiuo)-4(S )-(tert-butyldimethyl)silyloxy-6-cyclohexyl-2(R)-(4-hydroxyphenylmethiyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide 3 g (4.69 mmol) of 5 (S)-(Boc-amino)-4(S)-(tert-butyldim ethyl silyloxy)-6-cyclobexy1- 2(R)-(4-benzyloxybenzyl)-hexanoic acid in 40 ml of DMF are cooled in an ice-bath to 51C with 1.91 g (5.16 mmol) of H-(L)-Val-(L)-Phe-morpholin-4-ylamide, and 0.783 ml (5.16 mmol) of DEPC and 2.3 ml (16.41 mmol) of triethylamine are added. After the mixture has been sturred for 1.5 h at RT it is poured onto water and extracted three times with ethyl acetate. The combined organic phases are washed with water, saturated sodium bicarbonate solution (twice) and brine, dried over sodium sulfate and then concentrated under reduced pressure. The title compound is purified by column chromatography (SiO 2 hexane/ethyl acetate: TLC Rf 0.3; tRet(JV) 25.3 min; FAB-MS 955.

Reference Example 68: 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohtexyl-2(R)-(4-hydroxyphenylmethyl)-hexanoyl-(L)-Val-(L)- he-morpoi-ylmd Analogously to Reference Example 1, 0.69 g (0.797 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-hydroxyphenylmethyl)-hexanoyl-(L)- Val- (L-Phie-morpholin-4-ylamide in 5 ml of DMF are reacted with 0.5 g (1.59 mmol) of TBAF trihydrate to yield the tidle compound. The title compound is purified by crystallisation (ether). tRet(IV)= 15.52 min; FAB-MS 75 1.

The starting compound is prepared as follows: a) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethvl)silyloxy-6-cyclohexyl-2(R)-(4-hydroxy pnen i-.h Lhyl)-hexanol-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 45, 19.5 g (20. 41 mmol) of 5 (S)-(Boc-amnino)-4(S)hydroxy-6-cyclohexyl-2(R)-(4-benzyloxyphenylmethyl)-hexanoyl-(L)-Val-(L)-Phemorpholin-4-ylamide (Refeil.'nce EXample 67 e) in 400 ml of methanol are hydrogenated in the presence of 4 g of 10% Pd/C. The title compound obtained after working up is further reacted without additional purification; TLC Rf. 0.28; tRW 1 IV) =21.99 min; FAB-MS 866.

165 Reference Example 69: 5(S)-(Boc-amino)-4(S)-hiydroxy-6-cyclohiexyl-2(R)-(4-methoxyphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholirn 4 -11amide Analogously to Reference Example 1, 3.93 g (4.469 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-cyclohexyl-2(R)-(4-methoxyphenylmethyl)hexanoy[-(L).

Val -(L)-Phe-morpholin-4-ylamide in 15 ml of DIVF are reacted with 2.82 g (8.94 mmol) of TBAF trihydrate to yield the title compound. The title compound is purified by precipitation (hexane). TLC Rf 0.64; tR,-t(IV)= 17.34 min; FAB-MS 765.

The starting compound is prepared as follows: a) 5 (S)-(Boc-amino)-4(S)-(tert-bu.tyldiniethyl)silyloxy-6-cyclohexyl-2(R)-(4-methoxy plienylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 70 a solution of 4 g (4.623 mmol) of amnino)- 4 (S)-(tert-butyldimethyl)-silyloxy-6-cyclohexyl-2(R)-(4-hydroxyphenylmethyl)hexanoyl-(L)-Val-(L)-Phe-morp~ili.,1--4-ylamride in 70 ml of dioxane is reacted with 6.02 g (18.49 mmol) of caesiumn carbonate and 9.1 ml (92.46 mmol) of methyl iodide. The title compound obtained after working up is further processed without being further purified.

TLC Rf 0.36; t et(IV)= 24min; FAB-MS 880.

Reference Example 70: 5(S)-(Boc-amino)-4(S)-hydroxy-6-p henlyl-2(R) -benzvlhexanovl- UL-Val-(L)-(4-isobutyloxy-Phe)-morpholin-4-ylamide Analogously to Reference Example 1, 201 mg (0.22 mmol) of 5(S)-(Boc-amino)-4(S)- ~(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-benz;ylhexanoyl-(L)-Val-(L)-(4-isobutyioxy- Phie)-morpholin-4-yiamide are deprotected with 139 mg (0.44 mmol) of TBAF in 5 ml of DMF over a period of 18.5 h. Column chromatography (Si0 2 ethyl acetate/hexane: 4/1) yields the title compound: TLC Rf(B)= 0.38; tRet(I)= 18.3 min; FAB-MS 801.

The starting compounds are prepared as follows: a) N-(Benzyloxycarbonyl)-(L)-Val-(L)-(4-isobutyloxy-Phe)-morpholin-4-ylamide A solution of 1.93 g (4 mmol) of N- (benzyloxycarbonyl)-(L) -Val- L)-Tyr-morpholin-4-ylamide (Reference Example 41 A) in 3 ml of 1/1 DMF/dioxar. i~s treated with 2.6 g (8 mmol) of caesium carbonate and 2.31 ml (20 mmol) of isobutyl iodide and then heated to 50'C. After 1.25 h, 2.6 g (8 mmol) of caesium carbonate and 2.31 ml (20 mmol) of ;sobutyl iodide are again added, followed by a further 2.31 ml (20 mmol) of isobutyl -166iodide after 2.15 h and after 4 h. After having been stirred for a total of 5.75 h at 50 0 C, the reaction mixture is poured onto ice/water and extracted three times with methylene chloride. Drying over sodium sulfate is followed by concentration in a rotary evaporator.

Column chromatograph'y (SiO 2 ethyl acetate/hexane 4/1) yields the title compound: TLC Rf 0.43.

b) H-L-a-L-4iouyoyPe-opoi--lmd Analogously to Reference Example 10 1.5 g (2.78 nrnol) of N-(benzyloxycarbonyl)- (L)-Val-(L.)(4-isobutyloxy-Phe)-morpholin.4-ylamide in 40 ml of methanol are hydrogenated in the presence of 0.2 g of 10% Pd/C. The title compound is further used without being further purified: 'TLC Rf 0.44.

c) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimnethylsilyloxy)-6-1Pheuvl-2(R)-benzylhexanoyl- (L)-Val-(L)-(4-isobutyloxy-Phe)-morpholin-4-ylamide Analogously to Reference Example 10 118 mg (0.22 mmol) of 5(S)-(Boc:-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-benzylhexanoic acid and 100 mng (0.25 mmol) of H-(L)-Val-(L)-(4-isobutyloxy-Phe)-imopholin-4-ylamide in 2.19 ml of NMM/CH 3

CN

*0.25M are reacted with 94.8 mg (0.24 minol) of HBTU to give the t~le compound.

Column chromatography (SiO 2 ethyl acetate/hexane: 4/1) yields the title compound: TLC Rf 0.54.

Reference Example 71: 5(S)7(Boc--amino)-4(S)-hydroxy-6-phenyl-2(R)-benzylhexanoyl- (L)-Leu-CL)-(p-CI1 3 -Phe)-morpholin-4-ylamide Analogously to Reference Example 1, 189 mug (0.22 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-benzylhexanoyl-(L)-Leu-(L)-(p-C 3 O-Phe)morpholin-4-ylamide are deprotected with 139 mug (0.44 ,nmol) of 'PBAF in 5 ml of DMF over a period of 18 h. Column chromatography (SiO 2 ethyl acetate/hexane: 4/1) yields the title compound: TIC Rf(B)= 0.37; tRet(I)= 16.6 min; FAB-MS 773.

The starting compounds are prepared as follows: a) N-(Benzyloxycarbonyl)-(L)-Leui-(L)-(p -CH O-Phe)-morpholinylamide 0.45 g (1.68 tumol) of (L)-N-benzyloxycarbonyl-leucine (Fluka, Buchs, Switzerland) and~ 0.444 g (1.68 mmol) of H-(L)-(p-CH 3 O-Phe)-morpholinylamide in 70 ml of methyli.ne chloride are reacted with 0.347 g (1.68 tumol) of DCC and 0.25 g of HOBT to give the title compound. Column chromatography (SiO 2 ethyl acetate/hexane: 4/1) yields the tidle -167compound: TLC Rr 0.28.

b) -he-opoi--lmd Analogously to Reference Example 10 0.73 g (1.43 mmol) of N-(benzyloxycarbonyl)-

CH

3 O-Phe)-morpholin-4-ylamide in 20 ml of methanol is- hydrogenated in the presence of 0. 1 g of 10% Pd/C. The title compound is further used without being further purified: TLC Rr 0.47.

c) 5(S)-(Boc.-amino)-4(S)-(tert-h tuyIdimethylsilyloxy)-6-phenyl-2(R)-benzylheranoyl- (L)-Leu-(L)-(p-CHO-Phe)-morpholin-4-ylamide An~alogously to Reference Example 10 fi), 118 mg (0.22 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-benzylhexanoic acid and 91 mg (0.25 mmol) of H-(L)-Leu-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide in 2.19 ml of NMMICH 3 I~N 0.25M are reacted with 94.8 mg (0.24 mmol) of HBTU to give the title compound. Column chromatography (SiO 2 ethyl acetate/hexane: 4/1) yields the title compound: TLC Rf 0.57.

d) Z-(L)-(p-CH30-Phe)-morpholin-4-ylamide Analogously to Reference Example 70 a solution of 2 g (5.2 mmol) of Z-(L)-Tyrfe*: morpholin-4-ylamide (Reference Example 70 in 100 ml of 1: 1 DME/dioxane is reacted with 3.38 g (10.4 mmol) of caesium carbonate and 0.324 ml (5.2 mmol) of methyl iodide.

Column chromatography (S'0 2 ethyl acetate/hexane: 4/1) yields the title compound: TLC Rf (ethyl acetate/hexane: 0.34.

0 4 e) 3 O-Phe)-morpholin-4-ylamide.

Analogously to Example 70 a solution of 3.9 g (9.8 mmol) of Z-(L)-(p-CH 3 O-Phe)- 'eo 0 morpholin-4-ylamide in 150 ml. of methanol is hydrogenated in the presence of 1.2 g of 0000 0 10% Pd/C. After working up, the title compound is further used without additional purification. TLC Rf 0.32.

so. Reference Example 72: 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-benzylhexanoyl- (L)-Valr(L)-(4-n-butyloxy-Phe)-morpholin-4-ylamide Analogously to Reference, Example 1, 201 mg (0.22 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-(4-n-butyloxy Phe)-morpholin-4-ylamide are deprotectcd with 139 mg (0.44 mmol) of TBAF in 5 ml of DMF over a period of 16.5 h. Column chromatography (SiO 2 ethyl acetate/hexane: 4/1) -168yields the title compound: TLC Rf(B)= 0.39; tR~t(I)= 18.2 min; FAB-MS 801.

The starting compounds are prepared as follows: a) Nf-(Benzvloxvcarbonyl)-(L)-'Val-(L)-(4-n-butyloxy-Phe)-morpholin-4-ylamide Analogously to Reference Example 70 a solution of 0.48 g 1 mmol) of N-(benzylcxycarbonyl)-(L)-Val-(L)-Tyr-morpholin-4-ylamide in 0.2 ml of 1/1 DMF/dioxane is treated with 65 mg (0.2 mmol) of caesiumn carbonate and 11.9 gi (0.1 mmol) of n-butyl iodide. Column chromatography M0~ 2 ethyl acetate/hexane 4/1) yields the title compound: TLC Rf 0.47.

b) H-(L)-Val-(L)-(4-n-butyloxy-Phe)-morpholin-4-ylamide Analogously to Reference Example 10 1.38 g (2.6 mmol) of N-(benzyloxycarbontyl)- Val- (4-n-butyloxy-Phe)-morpholin-4-ylamide in 40 ml of methanol are hydrogenated in the presence of 0.2 g of 10% Pd/C. The title compound is further used without being further purified: TLC Rf 0.45.

c) 5(S)-(Boc-amino)-4(S)-(ter-t-butLyldimethylsilyloxy)-6-phenyl-2(R)-benzylhexanoyl- Val- (4-n-butyloxy-Phe)-morpholin-4-ylIamide Analogously to Reference Example 10 118 mng (0.22 mmol) of 5(S)-(Boc-arnino)-4(S)- (tert-butyldimethylsilyloxy-6-phenyl-2(R)-benzylhexanoic acid and 98 mg (0.25 mmol) of H-(L)-Val-(L)-(4-n-butyloxy-Phe)-morpholin-4-ylamide in 2.19 ml of NMM/CH 3

CN

0.25M are reacted with 94.8 mng (0.24 mmol) of HBTU to yield the title compound. The ::::title compound, 17LC Rf 0.57, is further used without additional purification.

Reference Example 73: 5(S)-(Boc-a mino)-4(S)-hydroxy-6-phenyl-2(R)-benzylhexanoyl- (L)-phenylglycyl-(L)-(p-CH 3 O-Phe)-mor hoi4-amd Analogously to Reference Example 1, 380 mg (0.41 mmol) of 5(S)-(Boc-amino)-4(S)- (tert-butyldimethylsilyloxy)-6-phenyl-2(R)-benzylhexanoyl-(L)-phenylglycyl-(L)- (p-CH 3 O-Plie)-morpholin-4-ylamide are deprotected with 265 mg (0.82 mmol) of TBAF in 10 ml of DMF over a period of 17 h. Column chromatography (Si0 2 ethyl acetate!hexane: 2/1 to 4/1) yields the title compound: TLC RK(B= 0.47; 16.4 min; FAB-MS 793.

The starting compounds are prepared as follows: -169a) L-t-utlox cabnl-L-hnlgv -L-r-HO-Phe)-morpholin-4-ylamide 0.44 g (2 ramol) of N-tert-butyloxycarbonyl-(L)-phenylglycine and 0.53 g (2 mmol) of H-(L)-(p-CH 3 O-Phe)-morpholinylamide in 80 ml of methylene chloride are reacted with 0.413 g (2 mmol) of DCC and 0.297 g of HOBT to give the title compound. Column chi omatography (SiO 2 ethyl acetate/hexane: 4/1) yields the title compound: TLC Rf (ethyl acetate/hexane: 411)= 0.31.

b) H-(L)-Phenylglycyl-(L)-(p.CH30-Phe)-morpholin-4-ylamide A solution of 900 mg (1.81 mmol) of N-(t-butyloxycarbonyl)-(L)-phcnylglycyl-(L)- (p-CH 3 O-Phe)-morpholin-4-ylamide in 19 ml of formic acid is stirred for 2 h and then concentrated in a rotary evaporator and dissolved in ethyl acetate. The solution is washed in succession 4 times with sodium bicarbonate, once with water and once wvith brine, dried over Na 2

,SO

4 and then concentrated. The title compound is further used without being further purified. TLC Rf 0.12.

c) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-benzylhexanoyl- (L)-phenylglycyl-(L)-(p-CH O-Phe)-morpholin-4-ylamide Analogously to Reference Example 10 118 mg (0.22 mmol) of 5(S)-(Boc-amino)-4(S)o. o. (tert-butyldimethylsilyloxy)-6-phenyl2(R)-benzylhexanoic acid and 96 mg (0.25 mmol) of H-(L)-phenylglycyl-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide in 2.19 ml of

NMM/CH

3 CN 0.25M are reacted with 94.8 mg (0.24 mmol) of HBTh to give the title o: compound. Column chromatography (Si0 2 ethyl acetate/hexane: 4/1) yields the title compound: TLC Rf 0.57.

rReference Example 74: Boc-Phe [C](3,4-dimethoxy)Phe- -Val- -Phe-morpholin-4-yl- 0' amnide Analogously to Reference Example 56 141 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyl- .:oo dimethylsilyloxy)-6-phenyl-2(R)-(3,4-dimethoxyphenylmethyl)-hexanoyl-(L)-Val-(L)- Phe-morpholin-4-ylamide in 3 ml of DMF are desilylated with 100.4 mg of TBAF to yield the title compound. Purification is carried out by chromatography twice on silica gel (eluants ethyl acetate/hexane 4:1 and ThC Rf(B)=0.21. FAB-MS (M+H)=-789.

The starting material is prepared as follows: 74 a) 3,4-Dimethoxybenzyl chloride Analogously to Reference Example 56 0) the title compound is obtained from 10 g of -170- 3,4-dimethoxybenzyl alcohol (Fluka, Buchs, Switzerland), 46.2 g of diisopropylaminomethylpolystyrene (poly-Hilnig base) and 4.62 ml of thionyl chloride in 200 ml of abs.

ether. TLC Rf(C)=.3l1. 1H-NMR (200 MHz, CDCI 3 7.0-6.87 (in, 2H); 6.82 1H); 4.56 2H); 3.9 3H); 3.87 3H1).

74 b) 3,4-Dimethoxybenzyl iodide Analogously to Reference Example 56 0) the title compound is obtained from 6.185 g of 3,4-dimethoxybenzyl chloride and 24.19 g of sodium iodide in 62 ml of abs. acetone.

TLC Rf-).40. IH-NMR (200 MHz, CDCI 3 6.95 (dxd, 1H); 6.88 1H); 6.75 1H1); 4.47 2H); 3.87 311); 3.86 311).

74 c) (S)-(Boc-amino)-2-phenylethyll-3(R)-(3,4-dimethoxyphenlmethyl)-dihvdrofuran-2-(3H)-one Analogously to Reference Example 56 0) 1 g of 5(S)-Il(S)-(Boc-amino)-2-phenylethyl] -dihydrofuran-2-(3H)-one [prepared according to Reference Example 2i)] in 4 ml of abs. THE is deprotonated (-75 0 C) with 6.42 ml of lithium bis(nimethylsilyl)amide (1M in THF) and with the addition of 0.66 ml of DMPU, and alkylated with 911 mg of 3,4-dimethoxybenzyl iodide. Chromatography on silica gel (eluants D, A and hexane/ethyl acetate 1:2) yields the pure title compound. TLC Rf(A)=0.42. MS M+=455.

74 d) 5(S )-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(3,4-dimethoxyphenylmethyl) hexanoic acid Analogously to Reference Example 56 0) 778 mg of 5(S)-[1(S)-(Boc-amino)-2phenylethyl]-3(R)-(3,4-dimethoxyphenylmethyl)-dihydrofuran-2-(3H)-one in 27.67 ml of dimethoxyethane and 13.91 ml of water are hydrolysed with 6.83 ml of lithium hydroxide solution 1M to yield the title compound which is directly further processed. TLC Rf(A)=0.07.

74 e) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-dimethoxyphenylmethyl)-hexanoic acid Analogously to Reference Example 56 0) 804 mg of 5(S)-(Boc-amino)-4(S)-hydroxy- 6-phenyl-2(R)-(3,4-dimethoxyphenylmethyl)-hexanoic acid in 5.94 ml of DM13 aresilylated with 1. 162 g of tert-butyldimethylchlorosilane and 946.6 mg of imidazole.

Purification of the title compound is carried out by chromatography twice on silica gel (eluants D, A, ethyl acetate/hexane 2:1 and TLC R 1 MS Mt-=557.

171 74 f) 5(S )-(Boc-amino)-4(S)-(tert-butyldimethyisilyloxy)-6-phenyl-2 ,4-dimethoxyphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 56 0) 100 mg of 5(S)-(Boc-amino)-4(S)-(tertbutyldimethylsilyloxy)-6-phenyl-2(R)-(3,4-dimethoxyphenylmethyl)-hexanoic acid and 62.3 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide [prepared according to Reference Example 1o)] in 1.59 ml of NMM/CH 3 CN 0.25M are reacted with 70.9 mg of HBTU to yield the title compound. TLC Rf (ethyl acetate/hexane 2: 19. FAB-MS (M+H)1-903.

Reference Example 75: Boc-PherCI (3,4,5-trimethoxy)Phe-(L)-Val-(L)-Phe-morpholin-4ylamide Analogously to Reference Example 56 511 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4,5-trimethoxyphenylmethyl)-hexanoyl-(L)-Val-(L-)- Phe-morpholin-4-ylamide in 9.36 ml of DMF are desilylated with 323.5 mg of TBAF to yield the title compound. Purification is carried out by chromatography on silica gel (eluants B and TLC Rf(B)=0.13. FAB-MS 4819.

The starting material is prepared as follows: 75 a) 3,4,5-TimethoxybenzyI iodide Analogously to Reference Example 56 0) the title compound is obtained from 5 g of 3,4,5-trimethoxybenzyl chloride (Fluka, Buchs, Switzerland) and 16.89 g of sodium ioclid-.

in 40 ml of abs. acetone. TLC Rf(C)=0.27. 1 H NMR (360 MHz, CDCl 3 6.60 2H);, 4.44 2H); 3.86 6H); 3.83 3H).

75 b) 5(S)-fl (S)-(Boc-amino)-2-phenylethyll-3(R)-(3,4,5-trimethoxyphenylmethyl)dihydrofuran-2-(3H)-cne Analogously to Reference Example 56 0) 1 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -dihydrofuran-2-(3H)-one [prepared according to Reference Example 2i)] in 4 ml of abs. THE is deprotonated (-75 0 C) with 6.4.2 ml of lithium bis(trimethylsilyl)amide (iM in THE) and with the addition of 0.66 ml of DMPU, and alkylated with 1.008 g of 3,4,5-trimethoxybenzyl iodide. Chromatography on silica gel (eluants hexane/acetone 3: 1) yields the title compound. TLC Rf(hexane/acetone 3:1)=0.22. FAB-MS MI=485.

c) 5 (S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(3 .4,5-trimethoxyphenylmethy1)hexanoic acid Analogously to Reference Example 56 0) 1.097 g of 5(S)-[1(S)-(Boc-amino)- -172- 2-phenylethyl]-3(R)-(3,4,5-trimethoxyphenylmethyl)-dihydrofuran-2-(3H)-one in 36.48 ml of dimethoxyethane and 18.39 ml of water are hydrolysed with 9.03 ml of lithium hydroxide solution iM to yield the title compound, which is further processed without being purified.

d) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4,5-timethoxyphenylmethylI)-hexanoic acid Analogously to Reference Example 56 0) 1.526 g of 5(S)-(Boc-amino)-4(S)-hydroxy- 6-phenyl-2(R)-(3,4,5-trimethoxyphenylmethyl)-hexanoic acid in 15.16 ml of DMF- are silylated with 2.11 g of tert-butYldimethylchlorosilane and 1.683 g of imidazole. Purification of the title compound is carried out by chromatography twice on silica gel (solvents: hexane, A, ethyl acetate/hexane 2: 'TLC Rf(B)=0.39. FAB-MS (M+H)+=618.

e) 5 (S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(3,4,5-trimethoxyphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Reference Example 56 0) 316.5 mg of 5(S)-(Boc:-amino)-4(S)-(tertbutyldimethylsilyloxy)-6-phenyl-2(R)-(3,4,5-trimethoxyphenylmethyl)-hexanoic acid and 171 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide [prepared according to Reference Example lo)] in 4.82 ml of NMM/CI{ 3 CN 0.25M are reacted with 213.39 mg of HBTU to yield the title compound. TLC R 1 FAB.-MS (M+I-I)1=933.

Reference Example 76: Boc-PheECI (2.3.4-trimethoxy)Phe-(L)-Val-(L)-Phe-morpholin-4yamide Analigously to Reference Example 56 407 mg of 5(S)-(Boc-amino)-4(S)-(tert-butyldi- *methylsilyloxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenylmethyl)-hexanoyl-(L)-Val-(L)- Phe-morpholin-4-ylamide in 7.41 ml of DMF are desilylated with 256 mg of FBAF to yield the title compound. Purification is carried out by chromatography on silica gel (eluant: TLC Rf(B)=0.12. FAB-MS 19.

The starting material is prepared as follows: 76 a) 2,3,4-Trimethoxybenzyl chloride Analogously to Reference Example 56 0) the title compound is obtained from 10.22 g of 2,3,4-trimethoxybenzyl alcohol (Aldrich, Steinheim, Federal Republic of Germany), 3 3.75 g of diisopropylaminomethylpolystyrene (poly-Hinig base) and 10.6 ml of thionyl chloride in 200 ml of abs. ether. Purification is carried out by chromatography on silica gel 173 (eluant: TLC Rf(E)=O.47. 'H-NMR (360 Mffz, CDCI 3 7.05 1H); 6.65 111); 4.61 2H); 3.98 3H); 3.86 3H1); 3.85 3H).

76 b) 2,3,4-Trimethoxybenzyl iodide The title compound is obtained from 2.34 g of 2,3,4-trimethoxybenzyl chloride and 7.87 gof sodium iodide in 18.6 ml of abs. acetone analogously to Reference Example 56 0) b), and is further processed without being purified. TLC Rfghexane/ethyl acetate 2.5:1)--0.44.

1 H-NMR (200 MI-z, CDCl 3 7.03 1H); 6.60 1H1); 4.50 21-1); 4.05 3H); 3.85 (2xs, 6H).

76 c) r 1(S)-(Boc-amino).-2-phenylethyll-3(R)-(2,3 ,4-trimethoxyphenylmethyl)dihydrofuran-2-(3H)-one Analogously to Reference Example 56 0) 1.5 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl] -dihydrofuran-2-(3H)-one [prepared according to Reference Example 2i)] in 6 ml of abs. THF are deprotonated. (775 0 C) with 9.62 ml of lithium bis (trim ethylsilyl)amide (IM in TITF) and with the addition of 0.998 ml of DMPU, and alkylated with 1.51 g of 2,3,4trimethoxybenzyl iodide. Chromatography on silica gel (eluants: hexane/ethyl acetate 1:2) o yields the pure title compound. TLC Rf(A)=O0.53. FAB-MS MI=485.

76 d) 5 (S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxyphenylmethyl)hexanoic acid Analogously to Reference Example 56 0) 1.354 g of 5(S)-[1(S)-(Boc-amino)-2phenylethyl] -3 (R)-(2,3,4-trimethoxyphuiiylmethyl)-dihydrofuran-2-(3H.)-one in 43.36 ml of dimethoxyethane and 21.86 ml of water are hydrolysed with 10.74 ml of lithium :0 hydroxide solution IM to yield the title compound, which is further processed without being purified. TLC Rf(A)=0.03. MS MW-H 2 0 485.

76 e) 5 (S)-(Boc-amirio)-4(S)-(tert-butyldimethylsilyloxy)-6-henyl-2(R',-(2,3,4-trimethoxyphenylmethyl)-hexanoic acid Analogously to Reference Example 56 0) 1.308 g of 5(S)-(Boc-amino)-4(S)-hydroxy- 6-phenyl-2(R)-(2,3,4-trimethoxyphenylmethyl)-hexanoic acid in 13 ml of DMF are silylated with 1.8 16 g of tert-butyldimethylchlorosilane and 1.443 g of imidazole. Purifica-~ tion of the title compound is carried out by chromatography twice on silica gel (solvents: A and ethyl acetate/hexane 1.5: TLC Rf(ethyl acetate/he,'xane 2: 1)=0.02. FAB-MS 18.

174 76 f) 5(S)-(Boc-amino)-4(S)-(tert-butyldimethylsilyloxy)-6-phenyl-2(R)-(2,3,4-tri- Methioxyphenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylanmide Analogously to Reference Example 56 0) 250 mg of 5(S)-(I300-amino)-4(S)-(tertbutyldimethylsilyioxy)-6-phenyl-2(R)-(2,3,4-trimethoxyphenylmethyl)-hexanoic acid and 148.4 mg of H-(L)-Val-(L)-Phe-morpholin-4-ylamide [prepared according to Reference Example 1o)] in 3.807 ml of NMM/CH 3 CN 0.25M are reacted with 168.8 mg of HBTU to yield the title compound. TLC R 1 (B)=0.64.

Examples of compounds of formula I': Example 1: 5 (S)-(Boc-amino)-4(S)-(2-furanylcarboxy)-6--phenyl-2(R)-phenylmethvlhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 74 p.1 (0.75 mmol) of 2-furancarboxylic acid chloride (Fluka; Buchs/Switzerland) are added to a solution of 365 mg (0.50 mmol) of Doc-Phe[C]Phe-{L)-Val-(L)-Phe-morpholin-4-ylamide (Example 2) and 10 mg of DMAP in 3 ml of dioxane and 0.6 ml of pyridine and the mixture is stirred for 44 h at RT. Since, according to HPLC, there is still some starting material present, a further 0. 1 ml of 2-furanecarboxylic acid chloride and 1 nil of pyridine are added. After a further 2 days, the reaction mixture is diluted with ethyl acetate and washed with sat. NaHCO 3 Solution, water and brine. The aqueous phases are extracted with 2 portions of ethyl acetate and the combined organic phases are dried with Na 2

SO

4 and concentrated by evaporation.

Precipitation with DIPE/hexane 1:2 from a concentrated solution in methylene chloride yields the pure title compound: TLC Rf(I)=0.23; tRet(I)=1 7 .5 min; FAB-MS =823.

Example 2: S a- Boc-amino)-(S-NN-dimethylaminoacetyloxy)-6-phenyl-2(R)phenylmethylh, xanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 130 mg (0.82 mmol) of N,N'-dimethylacetyl chloride (in the formn of the hydrochloride salt) [preparation: N.H. Kramer and H.F.G. Linde, Arch. Pharm.

(Weinheim) 324, 433 (1991)] are added to a solution of 300 mg (0.41 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and a small amount of DMAP in 1 ml of pyridine, and the mixture is stirred for 9 h at 60 0 C. Since, according to HPLC, there is still some starting material present, a further 130 mg of N,N-dimethylacetyl chloride hydrochloride is added. After a further 2 h at 60 0 C, the reaction mixture is diluted with ethyl acetate and washed with sat. NaHCO 3 Solution, 2x water and brine. The aqueous phases are extracted with 2 portions of ethyl acetate, and the 175comnbined organic phases are dried with Na 2

SO

4 and concentrated by evaporation. Column chromatography (Si02, ethyl acetate/ethanol 97:3 95:5) and digestion in DIPE in an ultrasound bath yields the crystalline title compound: TLC R(T)=0.11; tRet(II)=1 9 .5 min; FAB-MS (M+H)*=814.

Example 3: 5(S)-(Boc-amino)-4(S)-4-(dimethylamino)-butyrvloxyl -6-phenyl-2(R)phenylmethylhexanovyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 200 mg (0.27 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example 2) and a small amount of DMAP in 5 ml of dioxane/acetonitrile 4:1 and 372 gl (2.2 mmol) of N-ethyldiisopropylamine are reacted with 161 mg (0.87 mmol) of 3-(dimethylamino)butyryl chloride (in the form of the hydrochloride salt). Digestion of the crude product from DIPE yields the title compound: tRet(I)=13.8 min; FAB-MS (M+H)+=842.

The starting material is prepared as follows: a: 4-(Dimethylamino)butyrvl chloride hydrochloride g (60 mmol) of 4-dimethylaminobutyric acid hydrochloride (Janssen; Briiggen/- S Germany) are heated for approximately 3 h at 65 0 C in 30 ml of SOC1 2

SOC

2 is evaporated off and the residue is stirred to yield the title compound: TLC of a sample dissolved in methanol, Rf(U)=0.67; TLC of 4-dimethylaminobutyric acid hydrochloride, R(U)=0.50.

i Example 4: 5(S)-(Boc-amino)-4(S)-(N-Z-N-methylaminoacetyloxy)-6-phenyl-2(R)phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 339 p1 (2.4 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine Haveaux, A. Dekoker, M. Rens, A.R. Sidani, J. Toye, L. Ghosez, M. Murakami, M. Yoshioka, and W. Nagata, Organic Syntheses 59, 26 (1980)1 are added at 0 0 C to 446 mg (2.00 mmol) of Z-sarcosine (Bachem; Bubendorf/Switzerland) in 10 ml of methylene chloride. After 2 h at 0 0 C, the mixture is concentrated by evaporation under HV. The residue is taken up in 2 ml of dioxane and, with ice-cooling, a solution of 1.093 g mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) in 1.3 ml of pyridine and 10 ml of dioxane is added. Since, according to HPLC, there is still some starting material present after 60 h at RT, 17 mg of DMAP and an additional mmol of Z-sarcosyl chloride (preparation analogous to above) in 2 ml of dioxane are added. After 18 h at RT, the mixture is concentrated by evaporation and chromatographed -176- (Si0 2 ethyl acetate/hexane, 3: Digestion in hexane yields the pure title compound: TL'C RK(B)=0.74; tR~()=l8.6 min; FAI3-MS (M+H)1=934; Anal: caic. C 68.15 H 7.23 N 7.50 found C 68.15 H 7,54 N 7.50 Example 5: 5(S)-(oc-amino)-4(S)-(methylminoaceylox)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide 200 mg (0.21 rnrnol) of 5(S)-(Boc-amino)-4(S)-(N-Z-N-methylaminoacetyloxy)-6phenyl-2(R)-phenylrnethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 4) dissolved in 10 ml of ethyl acetate are hydrogenated at RT in the presence of 0.20 g of Pd/C (approxim ately 3 the mixture is filtered through ®Celite, the filtrate is concentrated by evaporation and the oil obtained is crystallised f rom hexane (ultrasound bath) to yield the title compound: TLC Rf(B)=0.45; tRet,(I)=1 3 3 min; FAB-MS (M+H)t-=800.

~:*Example 6: 5(s>,(Boc-amino)-4(S)-[N-(imidazol-4-methyl)-N-methlyaminoacetloxy1-6nheriyl-2(R)-p'-ienylmethylhexanoy1-(L)-Val-(L)-Phe-morpholin-4-ylamide A solution of 160mig (0.20 mmol) of 5(S)-(Boc-amino)-4(S)-(meth.ylaminoacetyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 5) and 23 mg (0.24 mmol) of imidazole-4-carbaldehyde (Ph.D. Stein and St.E.

Hall, US-Patent 4 977 174, 11lth Dec. 1990) in 2 ml of methanol and 26 mg (0.44 mmol) of acetic acid is hydrogenated in the presence of 20 mg of 5 Pd/C at RT for approximately 3 h. The mixture is filtered through ®Celite, and the filtrate is concentrated by evaporation and partitioned between 3 portions of ethyl acetate, sat. NaHCO 3 solution, water and brine, subjected to column chromatography (Si0 2 ethyl acetateflHF 3:1 1:3) and crystallised from acetonitrile/DIPE/h-xane to yield the title compound: TLC Rf(U)=0.13; tR~t(I)=l 2 2 min; FAB-MS (M+H)'=880.

Example 7: 5(S)-(Poc-amino)-4(S)-rN-(pyridine-2-methyl)-N-methylaminoacetyloxyl-6- 0000 phenyl-2RM-vhenylniethlhexano -(L)-Val-(L)-Phe-morpholin-4-ylamide A solution of 80 mg 10 mmol) of 5(S)-(Boc-amino)-4(S)-(methylaminoacetyloxy)-6phenyl-2(R)-phenylmiethylhexanoyl-(.L)-Val-(L)-Phe-morpholin-4-ylar-nide (Example and 12.9 mag 12 ramol) of freshly distilled pyridine-2-carbaldehyde (Fluka; Buchs/- Switzerland) in 1.5 ml of methanol and 13 mg (0.22 mmol) of acetic acid. is hydrogenated at RT in the presence of 15 mg of 5 Pd/C. Filtration through ®Celite and column III chromatography (Si0 2 ethyl acetate ethyl acetate/ethanol/triethylamine 90: 10: 1) yields the title compound: TLC t~et()=14.3 min; FAB-MS =891.

177- Example 8: 5(S)-(Boc-amino)-4(S)-[3-(1-triphenylmethvlimidazol-4-vl)-propionyloxyl- 6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 2.0 g (5.2 mmol) of 3-(1-triphnylmethylimidazol-4-yl)propionic acid dissolved in 20 ml of methylene chloride are converted into the acid chloride with 1.1 mi (7.8 mmol) of 1-chloro-N,N,2-trimethyl-l-propenamine. The evaporation residue is dissolved in 12 ml of dioxane and added to a solution of 1.23 g (1.7 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin .4-ylamide (Reference Example 2) in 4 ml of pyridine. According to HPLC, there is still a large amount of starting material present after 18 h at RT, and therefore 50 mg of DMAP and a further 3 mmol of 3-(1-tripL.enylmethylimidazol-4-yl)-propionic acid chloride (preparation as described above) are added. After a further 24 h at RT, the reaction mixture is concentrated by evaporation, and the residue is dissolved in ethyl acetate and washed with 3x water and brine. The aqueous phases are extracted with 2 portions of ethyl acetate. Column chromatography (SiO 2 methylene chloride/THF 9:1 methylene chloride/THF/triethylamine 90:10:1) yields the title compound: tRet(I)=17.

7 min; FAB-MS (M+H)+=1093.

o• The starting material is prepared as follows: a: Imidazol-4-ylpropionic acid (sodium salt) 1.38 g (10 mmol) of urocanic acid (Aldrich) are dissolved in 10 ml of 1N aqueous NaOH solution. The solution is diluted with 10 ml of methanol, 80 mg of 5 Pd/C catalyst are added and the mixture is hydrogenated for approximately 1 h at RT. Filtration through ®Celite and concentration by evaporation yields the title compound: IH-NMR (200 MHz,

C

2 2.40 and 2.73 (2t, J=7 Hz, each 2 6.77 and 7.56 (2s, each 1 H).

b: 3-(l-Triphenylmethyliiidazol-4-yl)-propionic acid With stirring, 3.4 g (12.2 mmol) of triphenylchloromethane are added in portions over a period of 4 h to a 2-phase mixture of 10 mmol of imidazol-4-ylpropionic acid (in the form of the sodium salt), 4 ml of water, 4.6 ml (33 mmol) of triethylamine and 8 ml of 'propanol. After the reaction mixture has been stirred for a further 4 h, 10 g of silica gel are added and the mixture is concentrated to dryness and applied in the form of a powder to a silica gel column (methylene chloride). Elution with methylene chloride/propanol/methanol/triethylamine 8:3:3:1 yields the title compound: TLC R(W)=0.77; tRe(I)=l 1.8 min; FAB-MS (M+H)+=383.

178- Example 9: 5(S)-(Boc-amino)-4(S)-r3-(4-imidazolyl)-propionyloxyl-6-phenyl-2(R)phenylmethylhexanoyl-(L)-Val (L)-Phe-morpholin-4-ylamide 0.50 mmol of 5(S)-(Boc-amino)-4(S)-[3-(1 -triphenylmethylimidazol-4-yl)-propionyloxyl-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 8) dissolved in 20 ml of ethyl acetate are hydrogenated for 8 days at 601C and at a hydrogen pressure approximately 4 atmn (approximately 4.052 bar or 0.4052 MPa) in the presence of 0.3 g of 20 palladium hydroxide on carbon. Removal of the catalyst by filtration, concentratIon of the filtrate by evaporation, and column chromatography (SiC) 2 acetonitrile/ethyl acetate/triethylartrie 50:50:1) yields the title compound: TLC Rf(X)=0.'39; tRet()= 1 3 3 min; FAB-MS Example 10: 5(S)-(Boc-amino)-4(S)-(niethoxyacetyloxv)-6-(p-fl uorophenyl)-2(R)- (p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 100 mg (0.13 mmol) of Boc-(p-F)Phe[C](p-F)Phe-(L)- (L-Phe-morpholin-4-ylamnide [Reference Example 21 B) and a small amount of DMAP in 1 ml of dioxane and 0.16 ml of pyridine are reacted with 36 p1 (0.39 mmol) of methoxyacetic acid chloride. (Fluka; Buchs/Switzerland). Digestion in DIPE yields the title compound: TLC Rf(B)=0.38; tRet()=lG.

9 min; FAB-MS =837.

Example 11: 5(S)-(Boc-amino)-4(S)-(2-picolinoyl)-6-(p-fluorophenyl)-2(R)-(p-fluoro phenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 32.2 mng (0.26 mmol) of 2-picolinic acid (Fluka;:Buchs/- Switzerland) in 0.5 ml of methylene chloride are converted into the acid chloride at 0 0

C

*with 22 gI 157 mmol) of 1 -chloro-N,N,2-trimethyl- 1-propenamine Haveaux, A.

Dekoker, M. Rens, A.R. Sidani, J. Toye, L. Ghosez, M. Murakani, M. Yoshioka, and W.

Nagata, Organic Syntheses 59, 26 (1980)]. After 45 min, 1 ml of dioxane, 0.26 ml of pyridine, 100 mg 13 mmol) of Boc-(p-F)Phe[C](p-F)Phe-(L)-Val-(.L,)-Phe-morpholin- 4 4-ylamide [Reference Example 21 B) and 0.3 mg of DMAP are added. Since, according to HPLC, the reaction is not complete after 18 h at RT, further acid chloride is added until complete conversion has taken place. The dark reaction mixture is diluted with methylene chloride and washed twice with sat. NaHCO 3 solution, water and brine. The aqueous phases are extracted with 2 portions of methylene chloride, and the organic phases are dried with Na 2

SO

4 concentrated by evaporation and chromatographed (SiC) 2 ethyl acetate). Decolouration of the red-coloured solution of the product in ethyl acetate using activated carbon yields the title compound: TLC Rf(B)=0.16; tR~t()=l6.9 min; FAB-MS (M-iH)+=870.

-179- Example 12: 5(S)-(Boc-amino)-4(S)-(pyridine-2-carboxyl)-6-phenyl-2(R)-(p-fluoropheniylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 11), 49 mg (0.40 mmol) of 2-picolinic acid in 3 ml of methylene chloride are converted into the acid chloride at RT with 62 41 (0.44 mmol) of 1-chioro- N,N,2-trimethyl-l-propenamine (17 A solution of 150 mg (0.20 mmol) of Boc- Phe[C] (p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide [Reference Example 21 D) and mg of DMAP in 2.3 ml of pyridine is added thereto. Since, according to HPLC, there is still some starting material present after 17 h at RT, a further 0.6 mmol of 2-picolinic acid chloride is added. After a further 17 h, the reaction mixture is poured onto sat.

NaHCO 3 solution and extracted with 3 portions of methylene chloride. The organic phases are washed with water and brine, dried with Na 2

SO

4 and concentrated by evaporation. The dark-red product is dissolved in ethyl acetate, treated with activated carbon, filtered, arid concentrated by evaporation again. Digestion in an ultrasound bath in DIPE yields the title ***compound: TLC Rf(B)=0.52; tRt(I)l1 8 8 min; FAB-MS (M+H)t-852.

Example 13: 5(S)-(Boc-amino)-4(S)-(methoxyacetyloxy)-6-phenyl-2(R)-(p-fluorophenyI.

methyl )-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 150 mg (0.20 mmol) of Boc-Phe[C](p-F)Phe-(L)-Val-(L)- Phe-morpholin-4-ylamide [Reference Example 21 D) and 1.2 mg of DMAP in 1.5 ml of dioxane and 0.24 ml of pyridine are reacted with 27 R1 (0.30 mmol) of methoxyacetic acid chloride (Fluka; Buchs/Switzerland). Extraction with ethyl acetate yields the title compound: TLC Rf(B)=0.7; tRt()=l 6 9 min; FAB-MS 19.

Example 14: 5(S)-(Boc-amino)-4(S)-(benzyloxyacetyloxy)-6-phenyl-2(R)-(p-fluoro- ]phenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 150 mg (0.20 mmol) of.Boc-Phe[C] p-F)Phe-(L)-Val-(L)- Phe-morpholin-4-ylamide [Reference Example 21 D) and 12 mg of DMAP in 1.5 ml of dioxane and 0.24 ml of pyridine are reacted with 2 portions each of 47.5 g1 (0.30 ramol.) of benzyloxyacetyl chloride (Fluka; Buchs/Svitzerland). Digestion in hexane/DIPE 1:4 yields the title compound in the form of a foam: TLC R 1 8 7 min; FAB-MS Example 15: 5(S)-(Boc-amino)-4(S)-[(S)-a-methoxy--phenylacetyloxyI-6-pihenyl-2(R)- (p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 66.5 mg (0.40 mmol) of (S)-c-methoxy-ax-phenylacetic acid -180- (Fluka; Buchs/Switzerland) in 3 ml of methylene chloride are converted at RT into the acid chloride with 62 p.1 (0.44 mmol) of 1-chloro-N,N,2-trimethyl-l-propenamine [B.

Haveaux, A. Dekoker, M. Rens, A.R. Sidani, J. Toye, L. Ghosez, M. Murakami, M.

Yoshioka, and W. Nagata, Organic Syntheses 59, 26 (1980)]. After 30 min, a solution of 150 mg (0.20 mmol) of Boc-Phe[C](pzF)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamnide [Reference Example 21 D) and 1.5 mg of DMAP in 2.3 ml of pyridine is added and the mixture is then stirred for 3 h. The reaction mixture is then poured onto NaHCO 3 solution and extracted with 3 portions of methylene chloride. The organic phases are washed with water anL dried with Na 2

SO

4 and concentrated by evaporation. Digestion in DIPE yields the title compound in the form of a foam: TLC Rg(B)=O0.73; tRt(I)=l 8 6 min; FAB-MS (M+H) t '=895.

Example 16: 5(S)-(Boc-amino)-4(S)-(R)-or.-methoxy-ca-phenlacetyloxy -6-phenyl-2( (p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 15), 66.5 mg (0.40 mmol) of (R)-a-methoxy-a-phenylacetic acid (Fluka; Buchs/Switzerland) in 3 ml of methylene chloride are converted into the acid chloride with 62 gI1(0.44 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine, and reacted with a so'tution of 150 mg (0.20 mmol) of Boc-Phe[C](p-F)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide [Example 21 D) and 1.5 mg of DMA4P in 2.3 ml of pyridine to yield the title compound: TLC Rf(A)=O0.30; tR~t(I)=lS.

4 min; FAB-MS Example 17: 5(S) -(Boc-aminco)-4(S)-(l-pvrazolylacetyloxy)-6-phenyl-2(R)-phenylmethyhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, 340 p.1(2.4 mmol) of 1 -chloro-N,N,2-trimethyl- 17propenamine Haveaux, A. Dekoker, M. Rens, A.R. Sidani, J. Toye, L. Ghosez, M. Murakami, M.

Yoshioka and W. Nagata, Organic Syntheses 59, 26, (1980)] are added at 0 0 C, under a nitrogen atmosphere, to 252-mg (2 mmol) of 1-pyrazeilylacetic acid (Jones et al., J. Org.

Chem. 19, 1428-32 (1954)) in 15 ml of methylene chloride. After the mixture has been stirred for 30 minutes at room temperature, a solution of 729 mg (1 mmol) of Boo- Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 2) and mg of 4-dimethylaminopyridine in 5 ml of pyridine is added. After 155 minutes at room temperature, the mixture is stirred for a further 2 hours at,40 0 C. Since, according to TLC, there is still some starting material present, an additional 2 mmol of 1-pyrazolylacetic acid chloride (for preparation see above) is added. Aft-r -a further 1.5 hours, the reaction mixture is poured onto 150 ml of a 2:1 mixture (vlv) of water./saturated aqueous sodium bicarbonate solution and extracted three tines with methylene chloride. The combined organic phases are 181 washed in succession with water and brine, dried over sodium sulfate, and then concentrated. Drying under HV is followed by chromatography (SiO 2 methylene chloride/methanol from 100:0 to 97:3). Digestion in diisopropyl ether and a brief treatment in an ultrasound bath yields the pure title compound: TLC Rfgethyl acetate)= 0.34. 16.8 min.

Example 18: 5(S)-(Boc-amino)-4(S'j-(isoguinoline-3-carbonyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholi-4-,.vlamide Analogously to Example 4, the corresponding acid chloride is prepared from 173 mg (1 mmol) of isoquinoline-3-carboxylic acid (Aldrich, Federal Republic of Germany) with 250 p1l of 1-chloro-N,N,2-trimethyl-l-propenamine. In the subsequent step, a solution of 365 mg (0.5 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 5 mg of 4-dim ethylaminopyridine in 3 ml of pyridine is added to the acid ****chloride. After working up analogously to Example 17, the product is chromatographed (SiC 2 ethyl acetate/hexane from 4:1 to 100:0). Digestion in diisopropyl ether yields the pure title compound: TLC Rfgethyl acetate)= 0.28; tRet()= 17.2 min.

Example 19: 5(S)-(Boc-amino)-4(S)-(pyrazinecarbonyloxy)-6-phenyl-2(R)-phenylmethvlhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, the corresponding acid chloride is prepared from 248 mg (2 mmol) of pyrazinecarboxylic acid (Fluka, Switzerland) with 340 Al of 1-chloro-N,N,2- *trimethyl-1-propenamine. In the subsequent step, a solution of 729 mg of Boc- Phe[C]Phe-(L)-Val-(L)-Plhe-rnorpholin-4-ylamide (Reference Example 2) and 5 mg 4-dimethylaruinopyridine in 5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, the product is chromatographed (Si0 2 ethyl acetate/hexane from 4:1 to 100:0). Digestion in diisopropyl ether yields the pure title conmpound: TLC Rf(ethyl acetate)= 0.31; tRt(I)= 16.4 min.

Example 20: 5 (S)-(Boc-amino)-4(S)-(4-ax-chloromethylW nzoyloxy)-6-phenyl-2(R)phenylriethylhexanoyl-(L)-Val-(L)-Phe-morpholirn-4-ylamide Analogously to Example 4, the corresponding acid chloride is prepared from 680 mg (4 mmol) of ax-choro-p-toluic acid (Fluka, Switzerland) with 800 .tl of 1-chloro-N,N,2-trimethyl-lI-propenamine. In the subsequent step, a solution of 729 mg (1 mmol) of BoC.- Phe[C]Phe-(L)-Val. (L)-Phe-morpholin-4-ylarnide (Reference Example 2) in 5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, the product is chromatographed (SiC 2 ethyl, acetate). Digestion in diisopropyl ether yields the 182pure title compound: TLC Rg(ethyl acetate) 0.5; tR,,t(lJ)= 28.2 min.

Example 21: 5(S)-(Boc-amino)-4(S)-[4-(4-morpholino)methylbenzoyloxyl -6-phenyl- 2(R)-phenylmethylhexanoyl-(L)-Val4(L)-Phe-morpholin-4-ylamide Analogously to Example 4, the corresponding acid chloride is prepared from 258 mg (1 mmol) of a-(4-morpholino)-p-toluic, acid (p-(morpholin-4-ylmethyl)benzoic acid; preparation according to US-Patent 4 623 486 dated 18.11.1986 (Lombardino et with 350 41t of l-chloro-N,N,2-trimethyl-1-propenamine. In the subsequent step, a solution of 365 mg (0.5 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylainide (Reference Example 2) in 2.5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, column chromatography (SiO 2 ethyl acetate then methylene chloride/methanol 100:0 to 96:4) yields the pure title compound: TLC Rf (ethyl acetate)= 0.28; tRet(ll)= 20.1 min; a ****Example 22: 5(S)-(Boc-amino)-4(S)-(isonicotinoyloxy)-6-phenyl-2(R)-phenylmethyhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide a Analogously to Example 4, the corresponding acid chloride is prepared from 260 mg ia:~ (2 mmol) of isonicotinic acid (Fluka, Switzerland) with 340 R1d of 1-chloro-N,N,2-trimethyl-l-propenamine. A solution of 729 mg (1 mmol) of IBoc-Phe[C]Phe-(L)-Val-(L)- Phe-morpholin-4-ylamide (Reference Exrample 2) and 5 mg of 4-N,N-dimethylaminopyridine in 5 ml. of pyridine is then added. After working up analogously to Example 17, column chromatography (Si0 2 ethyl acetate) yields the pure title compound: TLC Rf (ethyl acetate)= 0.27; tRet(I)= 15.3 min; FAB-MS 834.

Example 23: 5(S)-(Boc-amino)-4(S)-(nicotinoyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-inorpholin-4-ylamide *a Analogously to Example 4, the corresponding acid chloride is prepared from 740 mg (6 mmol) of nicotinic acid (Fluka, Switzerland) with 1200 R1l of 1-chloro-N,N,2-trimethyl-lI-propenamine. In the subsequent step, a solution of 1100 mg (1.5 mmol) of Boc- Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 10 mg of 4-N,N-dimethylaniinopyridine in 5.5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, column chromatography (Si0 2 ethyl acetate) yields the pure title compound: TLC Rf(ethyl acetate)= 0.33; tRW1(I)= 22.4 min.

183- Example 24: 5(S )-(Boc-aminG)-4(S)-(2-picolinoyloxy)-6-phenyl-2(R)-phenylmethylI hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 41, the corresponding acid chloride is prepared from 985 mg (8 mmol) of 2-picolinic acid (Fluka, Switzerland) with 1600 p.1 of 1-chloro-N,N,2-trimethyl-1I-propenamine. In the subsequent step, a solution of 1450 mg (2 mmol) of Boc- PhejjC]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 10 mg of 4-N,N-dimethylaminopyridine in 7.5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, column chromatography (SiO 2 herane/ethyl acetate 1/1 to ethyl acetate) yields the pure title compound: TLC R.Kethyl acetate)= 0.23; tReP(I)= 28.4 min.

Example 25: 5 (S)-(Boc-amino)-4(S)-(3-methoxypropanoyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, the corresponding acid chloride is prepared from 387 p1 (4 mmol) of 3-methoxypropionic acid (Fluka, Switzerland) with 680 p1 of 1-chloro- *:N,N,2-!rim ethyl- 1-propenamnine. In the subsequent step, a solution of 1450 mg (2 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and mg of 4-N,N-dimethylaminopyridine in 10 ml of pyridine is added to the acid chloride.

After working up analogously to Example 17, column chromatography (SiO 2 ethyl acetate) yields the pure title compound: TJLC R~(ethyl acetate)= 0.37; tRet(J)= 17.3 min; FAB-MS 815.

Example 26: 5(S )-(Boc-amino)-4(S)-[(4-chloroplhenoxy)methoxyacetylox)1-6-phenyl- 2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe--,norpholin-4-ylamide Analogously to Example 4, the corresponding acid chloride is prepared from 217 rng (I mmol) of (4-chlorophenoxy)methoxyacetic acid (Cretin et al., Phytochemistry 22(12), 2661-64 (1983)) with 170 g! of 1-chloro-N,N,2-trimethyl-1-propenamine. In the subsequent step, a solution of 365 mg (0.5 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example 2) and 5 mg of 4-N,N-dimethylamninopyridine in 2.5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, column chromatography (Si0 2 ethyl acetate) yields the pure title compound: TLC R~(ethyl acetate)= 0.5; tRet(I)= 19.1 min; FAB-MS 927.

Example 27: 5S)-(Boc-amino)-4(S)-[2-(2-methoxyethoxy) -acetyloxy heny1-2 R)ph(-nylmethylhexanoyl.-(L)-Val-fL)-Phe-morpholin-4-ylamide Analogously to Example 4, the corresponding acid chloride is prepared from 240 p1l -184- (2 mmol) of 2-(2-methoxyethoxy)acetic acid (Fluka, Switzerland) with 340 Al of l-chloro-N,N,2-trimethyl-1-propenamine. In the subsequent step a solution of 729 mg (1 mmol) of Boc-PheIIC]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 5 mg of 4-N,N-dimethylaminopyridine in 5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, column chromatography (SiO 2 methylene chloride/methanol: 100/0 to 97/3) yields the pure title compound: TLC Rfgethyl acetate)= 0.33; tRet(I)= 16.9 min; FAB-MS 845.

Example 28: 5(S )-(Boc-amino)-4(S)-(butyloxyacetvloxy)-6-phenyl-2(R)-phenylmethyhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamiide Analogously to Example 4, the corresponding acid chloride is prepared from 265 mg (2 mmol) of 2- (n-butoxy) acetic acid (Janssen, Netherlands) with 340 p1 of 1-chioro- N,N,2-trimethyl- 1-propenamine. In the subsequent step, a solution of 729 mg (1 mmol) of Boc-Phe[jC]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 5 mg of 4-N,N-dimethylaminopyridine in 5 ml of pyridine is added to the acid chloride. After **:working up analogously to Example 17, column chromatography (Si0 2 ethyl acetate) yields the pure title compound: TLC Rf(ethyl acetate)= 0.44; tReL(I)= 18.7 min; FAB-MS 843.

Example 29: 5(S)-(Boc-amino)-4(S)-{2-[2-(2-methoxyethoxy)-ethoxylacetloxy)1-6phenyl-2(R)-phenylmethylhexanioyl-(L)-Val-(L)-Phe-morpholin -4-yiamide Analogously to Example 4, the corresponding acid chloride is prepared from 314 PI (2 mmol) of 2- [2-(2-methoxyethoxy)ethoxy] acetic acid (Fluka, Switzerland) with 340 p1 of 1-chloro-N,N,2-trimethyl-1-propenamine. In the subsequent step, a solution of 729 mg (1 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 5 mg of 4-N,N-dimethylaminopyridine in 5 ml of pyridine is added to the acid chloride. After working up analogou sly to Example 17, column chromatography (Si0 2 methylene chloride/methanol: 100/0 to 97/3) yields the pure title compound: TLC Rfgethyl acetate)= 0.27; tRet(I) 16.7 min; FAB-MS 889.

Example 30: 5(S)-(Boc-amino)-4(S)-(methoxyacetyloxy)-6-phenyl-2(R)-phenylmethvlhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 35, 729 mg (1 mmol) of Boc-Phie[C'-]Phe-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example 2) are converted with 100 R1 1 mmol) of methoxyacetic acid chloride (Fluka, Switzerland) into the title compound, which is purified by column chromatography (SiO 2 ethyl acetate/hexane: TLC Rfgethyl 185acetate)= 0.43; tRet(I)= 16.8 min; FAB-MS 801.

Example 31: 5 (S)-(Boc-arnino)-4(S)-(phenoxyacetyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 35,1450 mg (2 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example 2) are converted with 360 (2.6 mmol) of phenoxyacetyl chloride (Fluka, Switzerland) into the title compound, which is purified by column chromatography (SiO 2 ethyl acetate/hexane: TLC R.(ethyl acetate/hexane: 0.37; tR~t(I)= 18.5 min; FAB-MS 863.

Example 32: 5(S)-(Boc-amino)-4(S)-[(S)-ca-methoxy-ax-phenylacetyloxy)-6-phenyl-2(R)phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, the corresponding acid chloride is prepared from 332.4 mg (2 mmol) of (S)-a-methoxy-ct-phenylacetic acid (Fluka, Switzerland) with 340 g1 of 1- 0chloro-N,N,2-trimethyl-1-propenamine. In the subsequent step, a solution of 729 mg (1 mmol) of Boc-Phe[C]Ptie-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 5 mg of 4-N,N-dimethylaminopyridine in 5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, column chromatography (Si0 2 ethyl acetate) yields the pure title compound: TLC R~(ethyl acetate)= 0.43; tR~t(I)= 18.5 min; FAB-MS 877.

Example 33: 5(S)-(Boc-amino)-4(S)-r(R)-ax-methoxy-a-phenylacetyloxy)]-6-phenl- 2(R)-phenylmethylhexanoyl-(L'j-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, the corresponding acid chloride is prepared from 333 mg (2 mmol) of (S)-Cx-methoxy-a-phenylacetic acid (Fluka, Switzerland) with 340 g1 of 1chloro-N,N,2-trimethyl-1-propenamine. In the subsequent step, a solution of 729 mg (1 mmol) of Boc-Phe[C]Phe-cL)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 5 mg of 4-N,N-dimethyltaminopyridine in 5 ml of pyridine is added to the acid chloride. After working up analogously to Example 17, column chromatography (Si0 2 ethyl acetate) yields the pure title compound: TLC R~(ethyl acetate)= 0.5; tR~t(I)= 18.3 min; FAB-MS 877.

Example 34: 5(S)-(Boc-amino)-4(S)-(valeroyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 35, 729 mg (1 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example 2) are converted with 181 gl (1.5 mmol) of 186valeroyl chloride (Fluka, Switzerland) into the title compound, which is purified by column chromatography (SiO 2 ethyl acetate/hexane: TLC Rf-ethyl acetate/hexane: 411)= 0.33; tRet(I)= 18.9 min; FAB-MS 813.

Example 35: 5(S)-(Boc-amino)-4(S)-(pivaloyloxy)-6-phenyl-2(R)-phenylmethyhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under an argon atmosphere, a solution of 130 p.1 (1.05 mmol) of pivaloyl chloride in 0.4 ml of pyridine is added over a period of 10 minutes to a solution of 510 mg (0.7 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) in 4 ml of pyridine. After the further addition twice of 150 p1 of pivaloyl chloride and 5 mg of 4-N,N-dimethylaininopyridine, no more starting material can be detected by TLC after a total reaction time of 3.75 hours at 50 0 C. The reaction mixture is poured onto approximately 40 ml of saturated aqueous sodium bicarbonate solution and extracted three times with methylene chloride. The combined extracts are washed with brine, dried over sodium *.*sulfate and concentrated. The subsequent column chromatography (SiO 2 methylene chloride/methanol: 100/0 to 98.5/1.5) yields the pure title compound. TLC Rfgmethylene chloride/methanol: 95/5)= 0.6; tRet(II)= 28.3 min; FAB-MS 813.

Example 36: 5(S)-(Boc-amino)-4(S)-(palmitoyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 35, 729 mg (1 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example 2) are converted with 456 pl1(1.5 mmol) of' palmitic acid chloride (Fluka, Switzerland) into the title compound, which is purified by column chromatography (SiO 2 ethyl acetate/hexane: TLC Rfgethyl acetate/hexane: 0.43; tRet(lOO% acetonitrile, isocratic)= 13.8 min; FAB-MS 967.

Example 37: 5(S)-(Boc-amino)-4(S)-(butyroyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 35, 729 mg (1 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phemorpholin-.4-ylamide (Reference Example 2) are converted with 156 PI (1.5 mmol) of butyric acid chloride (Fluka, Switzerland) into the title compound, which is purified by column chromatography (SiO 2 ethyl acetate/hexane: TLC Rf(ethyl acetate)= 0.43; tRet(I)= 18.3 min; FAB-MS 799.

187 Example 38: 5(S)-(Boc-amino)-4(S)-(propai-oyloxy)-6-phenyl-2(R)-phenylmethvlhexanoyl- (L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 35, 729 mng (1 mmol) of Boc-Phe[C7JPhe-(L)-VaI-(L)-Phemorphoiin-4-ylamide (Reference Example 2) are converted with 131 j d (1.5 mmol) of propionyl chloride (Fluka, Switzerland) into the title compound, which is purified by column chromatography (SiO 2 ethyl acetate/hexane: TLC Rfgethyl acetate)= 0.43; tRet(I)= 17.6 min; FAB--MS 785.

Example 39: 5 (S)-(Boc-amino)-4(S)-(benzoyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl- (L)-Val- (L)-Phe-morpholin-4-ylamide Analogously to Example 35, 365 mg (I mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example 2) are converted with 64 gtl (1.1 mmol) of benzoyl chloride (Aldrich, Federal Republic of Germany) into the title compound, which is purified by column chromatography (SiO 2 ethyl acetate). TLC Rfgethyl acetate)= tRet(II)= 27.6 min; FAB-MS 833.

Example 40: 5(S)-(Boc-ariino)-4(S)-(methylpropionyloxy)-6-phenyl-2(R)-phenylmethy- *:hexanc /1-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) is reacted with an excess of isobutyric acid chloride (Fluka; Buchs/Switzerland): tRet()= 8 2 min; FAB-MS 99.

Example 4-1: The following compounds are prepared analogously to one of the above processes: A) 5(S)-(Boc-amino)-4(S)-[3-(ciiethylamino)-propionyloxy]-6-phenyl-2(R)phenylmethylhexanoyl-(L )-Val-(L)-Phe-morphiolin-4-ylamide B) 5(S )-(Boc-amino)-4(S)- [3-(N-Z-N-methylamino)-propionyioxy]-6-phenyl- 2(R)-phenylmethylhexanoyl-(L)-Vat-(L)-Phe-morpholin-4-ylamide C) 5 (S)-(Boc-ami.no)-4(S)-(3-mnethylaminopropionyloxy)-6-phenyl-2(R)phenylmethylhexanoyl-(L)-Vai.(L)-Phie morpholin-4-ylamide D) 5(S )-(Boc-amino)-4(S)-[(dimethylaminoethoxy)-acetyloxy]-6-pheny'a-2(R)- (p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide E) 5(S)-(Boc-amino)-4(S)-[(2-pyridylmethoxy)-acetyloxy] -6-phenyl.-2(R)- (p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide F) 5 (S)-(Boc-amino)-4(S)-(methoxyacetyloxy)-6-phenyl-2(R)-(p-methoxy- 188phenyl methyl) -hexanoyl-()- Val- CH 3 O-Phe)-morpholin-4-ylamide G) 5(S)-(Boc-amino)-4(S)-(pyridine-2-carboxyl)-6-phenyl-2(R)-(p-methoxy.

phenylmethyl)-hexanoyl-(L)-Val-(L)-(p-CH 3 O-Phe)-murpholin-4-ylamide 5 (S )-(Boc-amino)-4(S)-(2-methylthio)acetyloxy-6-phenyl-2(R)-benzylhexanoyl(L) Val- (L)-Phe-morpholin-4-ylamide Analogously to Example 4, a solution of 546 mg (0.75 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and 5 mg of DMAP in 5 ml of pyridine is added to a mixture of 0.174 ml (2 mmol) of 2-methylthioacetic acid (Fluka, Buchs, Switzerland) and 0.34 ml (2.4 mmol) of 1-chloro-N,N,2-trimethyl-1I-propenamine in 15 ml of methylene chloride. After working up and column chromatography (SiO 2 ethyl acetate/hexane: the title compound is isolated: TLC Rf(B)= 0.41; tReL(I)= 17.9 min; FAB-MS 817.

1) 5(S)-(Boc-amino)-4(S)-(benzylthioacetyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl- 5(S)-(Boc-amino)-4(S)-[(L)-(prolyl)oxy]-6-phenyl-2(R)-phenylmethvlhexanoyl-(L)- Val- (L)-Phe-morpholin-4-ylamide 1.12 g (1.166 mmol) of 5(S)-(Boc-amino)-4(S)- [(L)-(N-Z-prolyl)oxy]-6-phenyl-2(R)phenylmethylhexanoyl-(L)..Val-(L)-Phe-morpholin-4-ylamide (Example 41 in 20 ml of ethyl acetate are hydrogenated in the presence of 120 mg of 10 Pd/C. Filtration, 0~concentration of the filtrate by evaporation, and digestion from DIPE yields the title compound: tRetI)=1 3 8 min; FAB-MS (M+H)+=826.

K) 5(S$ (Boc-amino)-4(S)-r(D)-(prolyl)oxy-6-phenyl-2(R)-phenylmethlhexanoyl-(L)- Val-(L)-Phe-n-orpholin-4-ylamide 0% 950 mg (0.989 mmol) of 5(S)-(Boc-amino)-4(S)-[(D)-(N-Z-prolyl)oxy]-6-phenyl-2(R)o phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide (Example 41 M) in 20 ml of ethyl acetate are hydrogenated in the presence of 0.20 g of 10 Pd/C. Filtration, concentration of the filtrate by evaporation, column chromatography (Si0 2 THF/ether 1: 1) and digestion from DIPE yields the title compound: tRP()=l3.5 min; FAB-MS (MN+H)+=8,26.

L) 5(S)-(Boc-amino)-4(S)-r)-(N-Z-proI l)oxy-6-phenyl-2(R)-phenylmethylhexanol- Vl- ()-Phe-morpholin-4-lamide Under a nitrogen atmosphere, 683 mg (2.74 mmol) of Z-(L)-.proline in 5 ml of methylene chloride are reacted at RT with 232 fl (1.644 mmol) of 1-chloro-N,N,2-trimethyl-1- -189propenamine Haveaux, A. Dekoker, M. Rens, A.R. Sidani, J. Toye, L. Ghosez, M.

Murakami, M. Yoshioka, and W. Nagata, Organic Syntheses 59, 26 (1980)]. After 30 min, 2.7 ml of pyridine, 1.00 g (1.37 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phe-morpholin-4ylamide (Reference Example 2) and 3 mg of DMAP are added. Since, according to HPLC, there is still some starting material present after 17 h at RT, a further 1.3 mmol of proline is activated with 0.8 mmol of 1-chloro-N,N,2-trimethyl-1-propenamine and added.

After a further 17 h, the reaction mixture is poured onto sat. NaHCO 3 solution and extracted with 3 portions of methylene chloride. The organic phases are washed with water and brine, dried with Na 2

SO

4 and concentrated by evaporation. Column chromatography (Si0 2 ethyl acetate) yields the title compound: TLC Rf(B)--0.50; tRet(I)= 2 0.0 min; FAB-MS (M+H)*=961.

M) 5(S)-(Boc-amino)-4(S)-V(D)-(N-Z-prolyl)oxyl-6-phenyl-2(R)-phenylmethylhexanoyl- (L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 683 mg (2.74 mmol) of Z-(D)-proline in 5 ml of methylene chloride are reacted at RT with 232 pl1 (1.644 mmol) of 1-chloro-N,N,2-trimethyl-1- V propenamine. After 30 min, 2.7 ml of pyridine, 1.00 g (1.37 mmol) of Boc-Phe[C]Phe- (L)-VaI-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 3 mg of DMAP are added. Since, according to HPLC, there is still some starting material present after 17 h at RT, a further 683 mg of Z-(D)-proline are activated with 232 4l of 1-chloro-N,N,2-trimethyl- 1-propenamine and added. After a further 17 h, working up is carried out S analogously to Example 41L): TLC R(B)=0.47; tRet(I)=1 9 3 min; FAB-MS (M+H)+=960.

There is used as starting material for a number of compounds 5(S)-(Boc-amino)-4(S)- (chloroacetyloxy)-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)-Val-(L)-Phemorpholin-4-ylamide (which can be prepared by reacting chloroacetic acid with 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-(p-fluorophenylmethyl)-hexanoyl-(L)- S* Val-(L)-Phe-morpholin-4-ylamide analogously to Example 4) in which the chlorine atom is converted into a substituted N, S or O atom by nucleophilic substitution, for example in the prmparation of compounds D) with dimethylaminoethanol, and compounds E) with 2-pyridylmethanol.

Example 42: Analogously to one of the processes described in Examples 1 to 41, unless specifically described in the afore-mentioned Examples the compounds of formula I of Reference Examples 1 to 22 and 33 to 56 are converted, by replacing the 4(S)-hydroxy group in the central non-hydrolysable peptide building block, into the corresponding -190- 4(S)-acyloxy compounds in which one of the following radicals stands in place of the 4(S)-hydroxy group in each case: A) 4(S)-(2-furanylcarboxy)-; B) 4(S)-[4-(dimethylamino)-butyryloxy]; C) 4(S)-(N-Z-N-methylaminoacetyloxy); D) 4(S)-(rnethylaminoacetyloxy); E) 4(S)-[N-(imidazol-4-methyl)-N-methylaminoacetyloxy]; F) 4(S)-[3-(l1-triphenylmethylimidazol-4-yl)-propionyloxyl; G) 4(S)-1j3-(4-imidazolyl)-propionyloxy]; H) 4.(S)-(roethoxyacetyloxy); I) 4(S)-((2-picolinoyl); J) 4(S)-(benzyloxyacetyloxy); K) 4(S)-[(S)-a-methoxy-x-pl~enylacetyloxy];.

L) 4(S)-[(R)-cx-methoxy-ax-pheniylacetyloxy]; M) 4(S)-(1-pyrazolylacetyloxy); N) 4(S)-(isoquinoline-3-carbonyloxy); 0) 4(S)-(pyrazinecarbonyloxy); P) -fi(S)-(4-a-chloromethylbenzoyloxy); 4(S)-[4-(4-morpholino)methylbenzoyloxy]; R) 4(S)-(isonicotinoyloxy); S) 4(S)-(nicotinoyloxy); T) 4(S)-(3-methoxypropanoyloxy) U) 4(S)-[(4-chlorophenoxy)methoxyacetyloxy)]; V) 4(S )-[2-(2-methoxyethoxy)acetyloxy)], W) 4(S)-(butyloxyacetyloxy); X) 4(S)-[2-[2-.(2-methoxyethoxy)ethoxy]acetyloxy)]; Y) 4(S)-(methoxyacetyloxy); Z) 4(S)-(phenoxyacetyloxy); AA) 4(S)-[(S)-ax-methoxy-a-phenylacetyloxy); AB) 4(S)-[(R)-ax-methoxy-a-phenylacetyloxy)1; AC) (N,N-dimethylaminoacetyloxy); AD) 4(S)-[N-(pyridine-2-methyl)-N-methylaminoacetyloxy.

Example 43: Analogously to one of the processes described in Examples 1 to 41, unless specifically described in the afore-mentioned. Examples the compounds of formula I of 191 Reference Examples 1 to 22 and 33 to 56 are converted, by replacing the 4(S)-hydroxy group in the 'entral non-hydrolysable p ;ptide building block, into the corresponding 4(S)-acyloxy compounds in which one of the following radicals stands in place of the 4(S)-hydroxy group in each case: A) 4(S)-[3-(dimethylamino)-propionyloxy]; B) 4(S)-[3-(N-Z-N-methylamino)-propionyloxy]; C) 4(S)-(3-methylaminopropionyloxy); D) 4(S)-[(dimethylaminoethoxy)-acetyloxy]; E) 4(S)-[(2-pyridylmethoxy)-acetyloxy]; F) 4(S)-(methoxyacetyloxy); G) 4(S)-(pyridine-2-carboxyl); H) 4(S)-(rnethylthioacetyloxy); 1) 4(S)-(benzylthioacetyloxy); J) 4(S)-((L)-prolyloxy); K) 4(S)-((D)-prolyloxy); 4(S)-((L)-(N-Z-prolyl)oxy); M) 4(S)-(('D)-(N-Z-prolyl)oxy).

Example 44: 5()-(Boc-amino)-4(S)-r3-(N-Z-amino)-propionloxy]-6-phenyl-2(R)phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 612 mg (2.74 mmol) of Z-f3-alanine in 5 ml of methylene chloride are reacted at RT with 232 p1 (1.644 mmol) of 1-chloro-N,N,2-trimethyl-1propenamine. After 40 min, 2.7 ml of pyridine, 1.00 g (1.37 mmol) of Boc-Phe[C]Phe- (L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 2) and 3 mg of DMIAP are added. Since, according to HPLC, there is still some starting material present after 17 h at RT, a further 612 mig of Z-r3-alanine are activated with 232 p1 1-chloro-N,N,2-trimethyl- 1-propenamine and added. After a further 17 h, working up is carried out analogously to Example 41L): TLC Rf(B)=0.38; t~et()=i8.3 min; FAB-MS (iVA+H)+=934.

Example 45: 5(S)-(Boc-amino)-4(S)-(3-amirnopropionyloxy)-6-phenyl-2(R)-phenvlmethylhexanoyl-(L)-Val-(L)-Phe-mnorpholin-4-ylamide Hydrogenation of 1.00 g (1.07 mmol) of 5(S)-(Boc-amino)-4(S)-[3-(N-Z-aminc)propionyloxy]-6-phenyl-2(R)-phenylmnethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide in 20 ml of ethyl acetate in the presence of 0.2 g of 10 Pd/C, followed by filtration, concentration of the filtrate by evaporation and digestion from DIPE, yields the title -192compound: tR,,((l=l 3 .l min; FAB-MS Example 46: 5(S)-(Boc- mino)-4(S)4F(3--dimethylaminopropoxy)-acetyloxy]-6-phenyl- 2(R)-phenylmethylhexa-noyl-(L)-Val-(L)-Phe-morpholin-4-ylamide A solution of 0.124 mmol of 5(S)-(Boc-amino)-4(S)-(iodoacetyloxy)-6-phenyl-2(Rjphenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide in 0.3 ml acetone is added to 13 mg 124 mmol) of 3-dimethylaminopropanol (Fluka; Buchs, Switzerland), the mixture is then washed twice with 0.3 ml of acetone each time and, after the addition of 15.6 mg 187 mnmol) of NaHCO 3 is stirred for 17 h at RT (HPLC: fully reacted). The solvent is carried off in a stream of nitrogen, and the residue is suspended in a small amount of methylene chloride and poured onto a mixture of ice-water and methylene chloride. The organic phase is removed and washed with waiter and brine, and the aqueous phases are extracted twice with methylene chloride. The organic phases are dried with Na 2

SO

4 concentrated by evaporation, and precipitated with DJPE from a concentrated solution in acetone to yield the title compound: tRet(I)=l 3 .5 min; FAB-MS H)+=872.

The starting material is prepared as follows: a) 5 (S )-(Boc-amino)-4(S)-(iodoacetyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)- Val-(L)-Phe-morpholin-4-ylamide 90.5 mg (0.604 mmol) of sodium iodide are added to a solution of 100 mg (0.124 mmol) of 5 (S)-(Boc-amino)-4(S)-(chloroacetyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)- Val- (L)-Phe-morpholin-4-ylamide in 0.3 ml of acetone, and the mixture is stirred for 1.5 h at RT, during the course of which a precipitate separates out. Since HPLC after 1 h *already indicates complete reaction to the title compound, the supernatant solution is pipetted off and immediately used in the above step: tR~t(I)=l 8 2 min.

b) 5(S)-(Boc-amino)-4(S)-(chloroacetyloxy)-6-phenyl-2(R)-phenylmethylhexanoyl-(L)- Val- -Phe-morpholin-4-ylamide Under a nitrogen atmosphere 2.00 g (2.74 mmol) of Boc-Phe[C]Phe-(L)-Val-(L)-Phemorpholin-4-ylamide (Reference Example 2) are introduced into 20 ml of acetonitrile and 12 ml of dioxane, and 1.3 ml of pyridine, a small amount of ONMAP and finally 1.17 g (6.85 mmol) of chloroacetic acid anhydride are added. After having been stirred for 24 h at RT, the mixture is poured onto ice-water and extracted three times with ethyl acetate. The organic phases are washed with 2 portions of sat. NaHICO 3 solution, water and brine, dried with Na 2

SO

4 and concentrated, by evaporation. Column chromatography (Si0 2 mnethylene 193 chloride/ether 1: 1) yields the title compound: TLC 16; min; FAB-MS ==805.

Example 47: 5(S)-(Boc-amino)-4(S)-[2-(2-dimethvlaminoethoxy)-ethoxyacetvloxyl-6phenyl-2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide A solution of 0.285 mmol of 5(S)-(Boc-amino)-4(S)-(iodoacetyloxy)-6-phenyl-2(R)phienylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide in acetone (Example 46a) is added to 37.9 mng (0.285 mmol) of 2-(2-dimethylaminoethoxy)-ethanol (BASF; Ludwigshafen, Germnany), the mixture is then washed twice with 0.7 ml of acetone each time, 36 mg (0.43 mmol) of NaH{C0 3 are added, and the mixture is stirred for 20 h at RT to complete the reaction. The mixture is worked up analogously to Example 46 and the crude product is stirred with DIPE to yield the title compound: tRe(I)=1 3 .5 min; FAB-MS (M+H)+=902.

Example 48: 5(S)-(Boc-amino)-4(S)-[(4-dimethylaminobutoxy)-acetyloxyl-6-phenyl- 2(R)-phenylmethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide A solution of 0.124 mmol of 5(S)-(Boc-amino)-4(S)-(iodoacetyloxy)-6-phenyl-2(R)phenylniethylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide in acetone (Example 46a) is added to 14.5 mg (0.124 mmol) of 4-dimethylamino-1-butanol (BASF; Ludwigshafen, Germany), and the mixture is then washed twice with 0.3 ml of acetone each time and, after the addition of 26 mg 187 mmol) of K 2 C0 3 stirred for 18 h at RT to complete the reaction. Since, according to HPLC, there is still some iodoacetate present, a further 0.25 equivalents of 4-dimethylamino-1-butanol is added. Working up after 17 h analogously to Example 46 yields the title compound: tR,#)=l3.5 min; FAB-MS (M+H)'-886.

Example 49: 5(S)-(Boc-amino)-4(S)-[2-(2-methoxyethoxy)-acetyloxy]-6-phenl2(R)- (p-methoxyphenyl)methylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 0.25 ml of pyridine, 150 mg (0.198 mmol) of Boc- Phe[C](p-CH 3 O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 21 F) 1)) and a small amount of DMAP are added to 75 mg 60 strength; 0.296 mmol) of 2-(2methoxyethoxy)-acetic acid chloride in 1.5 ml of dioxane. After 17 h at RT, the reaction mixture is poured onto sat. NaH-C0 3 solution and extracted three times with methylene chloride, and the organic phases are washed with sat. NaHCO 3 solution, water and brine, dried with Na 2

SO

4 and concentrated by evaporation. Column chromatography (SiO 2 methylene chloride/TH-F 4:1) and stirring with hexane yields the title compound:. TLC RK(B')=O.37; tRt(I)=l 6 7 min; FAB-MS (M+H)'=875.

-194- The starting material is prepared as follows: a) 2-(2-Methoxyethoxy)-acetic acid chloride Under a nitrogen atmi;,sphere, 2.56 ml (29.8 mmol) of oxalyl chloride and 2cixhops of DMF are added to 1.69 mJ) (14.9 mmol) of 2-(2-methoxyethoxy)-acetic acid (Fluka; Buchs/- Switzerland) in 75 ml of methylene chloride. After 17 h at RT, the reaction mixture is carefully concentrated by evaporation in a RE with the exclusion of moisture. A 1 1{.NMR spectrum of the residue exhibits the signals of the title compound in addition to signals of solvent (especially methylere chloride): 'H-NMR (200 MHz, GDCI 3 3.37 (s, MeO), 3.58 and 3.77 (2d, 1=5 HN, CH 2

-CH

2 4.48 That mixture is used above.

Example 50: 5(S)-(Boc-amino)-4(S)-(2-picolinoyloxy)-6-phenyl-2ftR)-(P--methoxyhenyl)methylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Under a nitrogen atmosphere, 48.6 mg (0.395 mmol) of 2-picolinic acid in 0.78 ml of methylene chloride are reacted at 0 0 C with 33.5 g1 (0.237 mmol) of 1.-chloro-N,N,2-trimethyl-1-propenamine. After 30 mm, 0.39 ml of pyridine, 150mg (0.198 mmol) of Boc- Phe[C](p-CH 3 O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide (Reference Example 21 and 0.4 mg of D"A are added thereto. Since, according to HPLC, there is still some Boc-Phe[C](p-CH 3 O)Phe-(L)-Val-(L)-Phe-morpholin-4-ylamide present after 17 h at RT, portions each of 48.6 mg of 2-picolinic acid aic each activated with 33.5 g1 of 1-cliloro- N,N,2-trim-ethyl-1-propenamine and added until, after a reaction time of 16 h in each case, all starting material has reacted. Working up analogously to Example 41L) and column chromatography (Si0 2 methylene chloride/THE 4: 1) yields the title compound: TLC RfB')=0.30; tRe-t(I)=l 6 .5 miri; FAB-MS (M+H)'=865.

Example 51: 5(S)-(Boc-amnino)-4(S)- 12- [2-(2-methoxyethoxy)ethoxyl-acetvloxv 1-6- 0 phenyl-2(R)-(p-methoxyphenyl)mnethylhexanoyl-(L)-Val-(L)-(p-CHgO-Phe)-morpholini- 4-ylamide Under a nitrogen atmosphere, 58 pi1 (0.38 mmol) of 2-[2-(2-methoxyethoxy)ethoxy]-acetic acid (Pluka; Buchs/Switzerland) in 0.7 ml of methylene chloride are reacted at 0 0 C with 32 gl1(0.228 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine. After 30 min, 0.37 ml of pyridine, 150 mg 190 mmol) of Boc-Phe[C](p-CH 3 O)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)morpholin-4-ylamide (Reference Example 21 F) and a small amount of DMAP are added thereto. Since, according to HPLC, there is still some Boc-Phe[C] (p-CH 3 O)Phe- (L)-Val-(L)-(p-C11 7 3 0-Phe)-morpholin-4-ylamide- present after 19 h at RT, a further 58 PI1 -195of 2- [2-(2-methoxyethoxy)ethoxy] -acetic acid is activated with 32 p1l of 1-chloro-N,N,2trimethyl-lI-propenamine and added. Working up after 17 h analogously to Example 41L), column chromatography (Si0 2 methylene chloridefITHF 4:1) and stirring in DIPE yields the title compound: TLC R 1 taet(I)=l6.5 min; FAB-MS Example 52: 5(S)-(Boc-amino)-4(S)-(2-picolinoyloxy)-6-phenyl-2(R)-(p-methoxyphenyl)methylhexanoyl-(L)-VaI-(L)-(P-C O-Phe)-morpholin-4-ylamide Under a nitrogen atmosphere, 46.8 mg (0.380 mmol) of 2-picolinic acid in 0.75 ml of methylene chloride are reacted at 0 0 C with 32 jil (0.228 mmol) of 1-chloro-N,N,2-trimethyl-l-propenamine. After 30 min, 150 mg (0.190 mmol) of Boc-Phe[C](p-CH 3 O)Ph e- -Val- (L)-(p-CH 3 O-?he)-morpholin-4-ylamide (Reference Example 21 F) in 0.38 ml of pyridin6 and 0.4 mg of DMAP are added thereto. Since, according to HPLC, there is still some Boc-Phe[C] p-CH 3 O)Phe-.(L)-Val-(.L)-(p-CH 3 O-Phe)-moxpholin-4-ylamideupresent after 17 h at RT, a further 46.8 mg of 2-picolinic acid is activated with 32 gIt of l-chlor-o-N,N,2-trimethyl-l-propenamine and added. Working up after 18 h analogously to EY r, nple 41IL), column chromatography (SiO 2 methylene chloridefTHF 4: 1) and stirring with hexane yields the title compound: TLC Rf(B')=0.37; tRt(I=l 6 4 min; FAB-MS Example 53: ,5(S)-(Boc-amino)-4(S)-(2-benzyloxy)acetyloxyI-6-phenvl-2(R)-benzvlhexanoyl-(L)-Val-(L)-Phe-norpholin-4-ylamide Analogously to Example 1, 730 mg (1 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6phenyl-2(R)-benizylhexanloyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are reacted with 0.237 ml (1.5 mmol) of benzyloxyacetyl chloride (Fluka, Buchs, Switzerland) and 5 mg of DMAP in 5 ml of pyridine to yield the title compound. Column chromatography (SiO 2 ethyl acetate) yields the title compound: TLC 0.5; tRetM= 19 mm; FAB-MS 877.

Example 54: 5(S)-(Boc-amino)-4(S)-(2-acetyloxy)acetloxv-6-phenl-2(R)-benzylhexano 1-(L)-Val-(L)-Phe-morpholin-4-ylamnide Analogously to Example 1, 730 mg (1 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide are reacted with 0. 166 ml (1.5 mmol) of acetyloxyacetyl chloride (Aldrich, Steinheim, Federal Republic of Germany) and 5 mg of DMAP in 5 ml of pyridine to give the title compounmd. Column chromatography (Si0 2 ethyl acetate) yields the title compound: TLC R 1 0.41; tRet(I) =17.3 min; FAB-MS 8129.

-196- Example 55: 5 (S)-(Boc-amino')-4(S)-r2-(4-tetrahydropyranyloxy)acetyloxy-6-phenyl- 2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, a solution of 365 mg (0.5 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and 5 mg of DMAP in 4 ml of pyridine is added to a mixture of 160 mg (1 mmol) of 4-tetrahydropyranylacetic acid (Chemical Abstracts-Registry No. 85064-61-5) and 0. 17 ml (1.2 mmol) of 1 -chloro-N,N,2-trimethyl- 1-propenamine in 10 ml of methylene chloride. After working up and column chromatography (Si0 2 ethyl acetate/hexane: 4/1) the title compound is isolated: TLC Rf (methylene chloride/methanol: 0.57; tRet(I) 16.9 min; FAB -MS 87 1.

Example 56: 5(S)-(Boc-amino)-4(S)-r2(R)-(4-tetrahydropvranyloxy)l-propionyloxv-6phenyl-2(R)-benzylht xanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, a solution of 219 mg (0.3 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and 5 mg of DMAP in 1.5 ml of pyridine is. added to a mixture of 105 mg (0.6 mmol) of tetrahydropyranyl)-propionic acid (Beilstein E Ill/JV, Vol. 18, p 385 1) and 0. 11 ml (0.72 mmol) of 1-chloro-N,N,2-trimethyl- 1-propenamine in 5 ml of methylene chloride.

After working up and column chromatography (Si0 2 ethyl acetate/hexane: 4/1) the title compound is isolated: TLC Rf(B)= 0.37; tR~t(I)= 17.3 min; FAB-MS 885.

Example 57: 5()-(Boc-amino)-4(S)r2-(2-aminoethoCY)ethoxaceyox)1-6pheny1- 2(R)-benzylhexanoyl-(L)-" 'al-(L)-Phe-morpholin-4-ylamide o Analogouly to Example 45, 0.83 g (0.82 mmol) of 5(S)-(Boc-amino)-4(S)-12-(2-benzyloxycarbonylaminoethoxy)ethoxyacetyloxy)]-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)- Phe-morpholin-4-ylamide (Example 58) in 20 ml of methanol is hydrogenated in the presence, of 0.1 g of 10% Pd/C. Column chromatography (SiO 2 Methylene chloride/methanol: 95/5 to 80/20) yields the title compound: TLC Rf (methylene chloride!methanol: 0.15; tRWt(I 13.1 min; FAI3-MS 874.

Example 58: 5(S)-(Boc-amino)-4(S)-[2-(2-benzyloxycarbonylaminoethoxy)ethoxyacetvloxy)1-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, a solution of 'i.09 g (1.5 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and 10 mg of DMAP in 7.5 ml of pyridine is added to a mixture of 0.9 g (3 mmol) of 2-(2-benzyloxy- -197carbonylamino)-ethoxy)-ethoxyacetic acid and 0.51 ml (3.6 mmol) of 1-chloro-N,N,2trimethyl-l-propenamine in 20 ml of methylene chloride. After working up and column chromatography (SiO 2 methylene chloride to methylene chloride/methanol: 98/2) the title compound is isolated: TLC R 1 0.41; tRet(I)= 17.95 min; FAB-MS 1008.

The starting compounds are prepared as follows: a) 2-f2-(Phthalimidoethoxy)-ethoxy-acetic acid ethyl ester A solution of 10.5 g (50 mmol) of 2-[2-(chloroethoxy)-ethoxy]-acetic acid etiLyl ester (Chemical Abstracts-Registry No. 82227-25-6) in 100 ml of DMF is reacted with 9.25 g mmol) of potassium phthalimide (Fluka, Buchs, Switzerland) and 50 mg of 18-crown-6 ether (1,4,7,10,13,16-hexaoxacyclooctadecane, Fluka, Buchs, Switzerland) and the mixture is stirred for 2.5 h at 100 0 C. The reaction mixture is cooled and then concentrated under reduced pressure. The residue is taken up in ether and washed twice in each case with water and brine. After drying and concentrating, the title compound is obtained by column chromatography (SiO 2 ethyl acetate/hexane: TLC Rf (ethyl acetate/hexane: 0.45; b) 2-r2-(Aminoethoxy)-ethoxyl-acetic acid (see also E.P. 0 410 280 Al) A solution of 9.6 g (29.9 mmol) of 2-[2-(phthalimidoethoxy)-ethoxy]-acetic acid ethyl ester in 195 ml of 20% aqueous HC1 is stirred at reflux for 1.5 h. The mixture is cooled and then concentrated in a rotary evaporator, and the residue obtained is taken up in 45 ml of water. Insoluble material is removed by filtration and the filtrate is extracted three times with ethyl acetate. The combined organic phases are washed with water and brine, dried and concentrated. The white crystalline material obtained is stirred in 110 ml of 6N HC1 for 17.5 h, cooled and concentrated, and the residue is taken up in 20 ml of water. The S aqueous phase is washed three times with ethyl acetate and lyophilised under a high vacuum. TLC Rf (methyl ethyl ketone/acetic acid/water: 3/1/1) 0.45.

c) 2-[2-(Benzyloxycarbonylaminoethoxy)-ethoxy]-acetic acid A suspension of 6.7 g (12.5 mmol) of 2-[2-(aminoethoxy)ethoxy]-acetic acid in 30 ml of THF and 10 ml of water is adjusted to pH 10 with 2N NaOH, and reacted dropwise with 1.95 ml of chloroformic acid benzyl ester (Fluka, Buchs, Switzerland). While the mixture is being stirred for 2.5 h, the pH is maintained between 9 and 9.5 by 2N NaOH, After concentration of the reaction mixture under reduced pressure, the resulting aqueous phase is washed twice with ethyl acetate, adjusted to pH 1.8 with 2N sulfuric acid and extracted 198 3 times with ethyl acetate. The combined organic phases are then washed with water and brine, dried and concentrated under reduced pressure. The title compound so obtained is further used without being further purified. TLC Rf (ethyl acetate/acetic acid: 9/1) 0.39.

Example 59: 5(S )-(Boc-amino)-4(S)-V~methoxycarbonylmethoxy)-acetyloxv]-6-phenyl- 2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, a solution of 219 mg (0.3 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6-phenyl-2(R)-benzyi.hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and 5 mg of DMAP in 1.5 ml of pyridine is added to a mixture of 89 mg (0.6 mmol) of diglycolic acid monomethyl ester (Chem. Ber. 55, 670 (1922) and 0.11 ml (0.72 mmol) of 1-chioro- N,N,2-trimethyl- 1-propenamine in 5 ml of methylene chloride. After working up and.

column chromatography (SiO 2 ethyl acetate/hexane: 4/1) the title compound is isolated.

TLC RK(B)= 0.35; tRt(IV)= 16.84 min; FAB-MS 859.

Example 60: 5(S)-(Boc-amino)-4(S)--[(methoxycarbonvlmethylthio)-acetyloxyl-6-phenyl- 2(R)-benzvlhexanoyl-(T )-Val-(L)-Phe-morpholin-4-ylamide .00000 Analogously to Example 4, a solution of 219 mg (0.3 mmol) of 5(S)-(Boc-amino)-4(S)- :0 hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide and 5 mg 0 of DMAP in 1.5 ml of pyridine is added to a mixture of 98 mg (0.6 mmol) of thiodiglycolic acid monomethyl acetate (Indian J. Chem. 25B, 880 (1986)) and 0. 11 ml (0.72 mmol) of 1-chloro-N,N,2-trimnethyl-1-propenamine in 5 ml of methylene chloride.

Working up and column. chromatography (SiO 2 ethyl acetate/hexane: 4/1) yield the title compound.

*Example 61: 5 (S)-(Boc-amino)-4(S)-[(methoxycarbo~iylm-ethylsulfo)-acetyloxyl-6ph,: .yl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 4, a solution of 219 mg (0.3 mmol) of 5(S)-(Boc-amino)-4(S)hydroxy-6- phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide and 5 mg of DMAP in 1.5 rnl of pyridine is added to a mixture of 117 mg (0.6 mmol) of S,S-dioxothiodiglycolic acid monomethyl ester and 0. 11 ml (0.72 mmol) of 1-chloro-N,N,2trimethyl-l-propenamine in 5 ml of methylene chloride. After working up and column chromatography (SiO 2 ethyl acetate/hexane: 4/1) the title compound is isolated.

The starting compound is prepared as follows: 199 a) S,S-Dioxo-thiodiglycolic acid monomethyl ester Thiodiglycolic acid monomethyl ether (Indian J. Chem. 25B, 880 (1986)) in a methanol/water mixture is oxidised with potassium peroxomonosulfate at approximately 251C to yield the title compound, which is further used.

Example 62: 5 (S)-(Boc-amino)-4(S)-[(pivaloyloxymethioxycarbonylmethoxy)-acetyloxyl- 6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Jodomethyl pivalate (Chem. Abstr. Registry No. 5306~4-79-2) is added to amino)-4(S)-[(carboxymethoxy)-acetyloxy]-6-phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)- Phe-morpholin-4-ylamide. The subsequent column chromatography yields the title compound.

Example 63: 5(S)-(Boc-amino)-4(S)-r(carboxymethoxy)-acetYloxyl-6-phenyl-2(R)benzylhexanoyl-(L)-'Val-(L)-Phe-morpholin-4-ylamide Diglycolic acid anhydride (Fluka, Buchs, Switzerland) is added to a solution of 219 mng (0.3 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-benzylhexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide in pyridine. After working up and column chromatography (SiO 2 ethyl acetate) the title compound is isolated.

Example 64: (S)-(Boc-amino)-4(S)-[(acetoxymethoxycarbonylmethoxy)-acetyloxyl-6phenyl-2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide Analogously to Example 62, 5(S)-(Boc-amino)-4(S)-[(carboxymethoxy)-acetyloxy]-6phenyl 2(R)-benzylhexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide is reacted. with bromomethyl acetate (Aldrich, Steinheim, Federal Republic of Germany). The subsequent column chromatography yields the title compound.

Example Analogously to one of the processes described in Examples 1 to 64, unless explicitly described in the afore-mentioned Examples the compounds of formula I of Reference Examples 57 to 64 are converted, by replacing the 4(S)-hydroxy group in the central nonhydrolysable peptide building block, into the corresponding 4(S)-acyloxy compounds in which one of the following radicals stands in place of the 4(S)-hydroxy group: A) 4(S)-(2-furanylcarboxy)-; B) 4(S)-[4-(dimethylamino)-butyryloxy]; C) 4(S)-(N-Z-N-methylaminoacetyloxy); D) 4(S)-(methylaminoacetyloxy); 200 E) (imidazole-4-methyl)-N--methylaminoacetyloxy]; F) 4(S)-f 1-triphenylmethylimidazol-4-yI)-propionyloxyJ; G) 4(S )-[3-(4-imidazolyl)-propionyloxy]; H) 4(S)-(methioxyacetyloxy); 1) 4(S)-((2-picolinoyl); J) (ben zyloxyacetyloxy); K) 4(S)-f (S)-c-methoxy-a-phenylacetyloxyj; L) [(R)-c-methoxy-ax-phenylacetyloxy]; M) 4(S)-(l1-pyrazolylacetyloxy); N) 4(S)-(isoquinoline-3-carbonyloxy); 0) 4(S)-(pyrazilnecarbonyloxy); P) 4(S)-(4-oa-chloromethylbenzoyloxy,,); Q) 4(S)-[4-(4-morpholino)-methylbenzoyloxy]; R) 4(S)-(isonicotinoyloxy); S) 4(S)-(nicotinoyloxy); T) 4(S)-(3-methoxypropanioyloxy) U) 4(S)-[(4-chlorophenoxy)-methoxyacetyloxy)]; V) 4(S)-[2-(2-me-thoxyethoxy)-acetyloxy)]; W) 4(S)-(butyloxyacetyloxy); X) 4(S)-[2-[2-(2-methoxyetho?,;y)-ethoxy]-acetyloxy)]; Y) 4(S)-(methoxyacetyloxy); Z) 4(S)-(phenoxyacetyloxy); AA) 4(S )-[(S)-ca-methoxy-oa-phenylacetyloxy); AB) [(R)-a-methoxy-a-phenylacetyloxy)]; AC) (N,N-diniethylaminoacetyloxy); AD) 4(S)-[N-(pyridine-2-methyl)-N-methylaminoacetyloxy; AE) [3-(dimethylamino)-propionyloxy]; AF) 4(S)-[3-(N-Z-N-methylamino)-propionyloxy]; AG) 4(S)-(3-rnethylaminopropionyloxy); AH) 4(S)-[(dimethylaminoethoxy)-acetyloxy]; Al) [(2-pyridylmethoxy)-acetyloxy]; AJ) 4(S)-(methoxyacetyloxy); AK) 4(S)-(pyridine-2-carboxyl); AL) 4(S)-(methylthioacetyloxy); AM) 4(S)-(benzylthioacetyloxy); AN) 4(S)-((L)-prolyloxy); -201- AG) 4(S)-((D)-prolyloxy); AP) 4(S)-((L)-(N-Z-prolyl)oxy); AQ) 4(S)-((D)-(N-Z-prolyl)oxy).

Example 66: Analogously to one of the processes described in Examples 1 to 64, unless explicitly described in the afore-mentioned Examples the compounds of formula I of Reference Examples 1 to 22 and 33 to 64 are converted, by replacing the 4(S)-hydroxy, group in the central non-hydrolysable peptide building block, into the corresponding 4(S)-acyloxy compounds in which one of the following radicals stands in place of the 4(S)-hydroxy group: 3-(N-Z-amino)-propionyloxy; 3-aminopropionyloxy; (3 -dimethylaminopropoxy)acetyloxy; 2-(2-dimethylaminoethoxy)-ethoxyacetyloxy; (4-di nethylaminobutoxy)acetyloxy; (2-benzyloxy)acetyloxy; **2-acetyloxy)acetyloxy; .rhdoprnloy-ceyoy 2-(4-tetrahydropyranyloxy)-pret oyloxy; 2(-(-tnetayoyranloxy)-proioylox *2-(2-bezlxroyaminoethoxy)-ethoxyacetyloxy); 2(2enyoxycarbonylaminoy-aetyoxy-toxaeylx) (methoxycarbonylmethoxyhi)-acetyloxy; (methoxycarbonylmethylthifo)-acetyloxy (pivaloyloxymethoxycarbonylmethoxy; (carboxymethoxy)acetyloxy; (acetoxymethoxycarbonylmethoxy)acetyloxy.

Example 67: Gelatin solution A sterile-filtered aqueous solution of one of the compounds of formnula P' mentioned in the preceding Examples I to 43 and 44 to 66 or of formula I from the Reference Examples 42 to 76 that in addition comprises 20 cyclodextrin, and a sterile gelatin solution preserved with phenol, are so mixed under aseptic conditions, with heating, that 1.0 ml of a solution of the following composition is obtained: 202 active ingredient 3 mg gelatin 150.0 mg phenol 4.7 mg dist. water with 20 .yclodextrins 1.0 ml Example 68: Sterile dry substance for injection mg of one of the compounds of formula I' mentioned in the preceding Examples 1 to 43 and 44 to 66, or of formula I from the Reference Examples 42 to 76, are dissolved as active ingredient in 1 ml of an aqueous solution with 20 mg of mannitol and 20% cyclodextrins as solubilisers. The solution is sterile-filtered and introduced under aseptic conditions into a 2 ml ampoule, deep-frozen and lyophilised. Before use, the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of physiological saline. The solution is administered intramuscularly or intravenously. The formulation can also be introduced into double-chamber disposable syringes.

Example 69: Nasal spray 500 mg of finely ground jgm) powder of one of the compounds of formula I' mentioned in the preceding Examples 1 to 43 and 44 to 66, or of formula I from the Reference Examples 42 to 76, are suspended as active ingredient in a mixture of 3.5 ml of Myglyol 812® and 0.08 g of benzyl alcohol. The suspension is introduced into a container fitted with a metering valve. 5.0 g of Freon 12® are introduced under pressure into the container through the valve. The "Freon" is dissolved in the Myglyol/benzyl alcohol mixture by shaking. The spray container contains approximately 100 single doses which can be administered individually.

Example 70: Film-coated tablets The following ingredients are processed to produce 10 000 tablets each comprising 100 mg of active ingredient: active ingredient 1000 g corn starch 680 g colloidal silicic acid 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxymethyl starch 250 g water quantum satis 203- A mixture of one of the compounds of formula I' mentioned in the preceding Examples 1 to 43 and 44 to 66, or of formula I from the Reference Examples 42 to 76, as active ingredient, 50 g of corn starch and colloidal silicic acid is processed with starch paste prepared from 250 g of corn starch and 2.2 kg of demineralised water to form a moist mass which is forced through a sieve of 3 mm mesh size and dried in a fluidised bed drier at 450 for 30 min. The dry granules are pressed through a sieve of 1 mm mesh size, mixed with a pre-sieved mixture (1 mm sieve) of 330 g of corn starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch, and compressed into slightly biconvex tablets.

Example 71: Orally administrable dispersion 1 625 mg of one of the compounds of formula I' mentioned in the preceding Examples 1 to 43 and 44 to 66, or of formula I from the Reference Examples 42 to 76, as active ingredient, and 625 mg of POPC (1-palmitoyl-2-oleoylphosphatidylcholine 1-hexadecanoyl-2-(9-cis-octadecenoyl)-3-sn-phosphatidylcholine) are dissolved in 25 ml of S* ethanol. The solution is diluted with ten times the amount of water. The ethanolic solution is for that purpose added dropwise at room temperature, at a rate of 10 ml/min, to the prescribed amount of water. The ethanol is removed from the mixture by tangential dialysis ("Cross Flow Filtration") against 1750 ml of water (System: Minitan®, 700 cm 2 polyethersulphone membrane with an exclusion limit of 100 kD, supplied by Millipore The mixture is concentrated to 15 mg of active ingredient by ultrafiltration using the same system. After the addition of 1.24 mg/ml of citric acid and 1.24 mg/ml of disodium hydrogen phosphate-2 H 2 0 to adjust the pH to 4.2 and the addition of 1 mg/ml of sorbic acid as antimicrobial preservative, the dispersion is concentrated to 15 mg/ml again and introduced into vials, for example having a capacity of 20 ml. The dispersion S particles have a diameter of from 0.1 2 Jim. They are stable for at least six months at from +2 to 8 0 C and are suitable for oral administration.

Example 72: Orally administrable dispersion 2 The preparation is carried out analogously to Example 71, except that 25 mg of active ingredient and 50 mg of POPC are used to prepare the ethanolic solution.

Example 73: Orally administrable dispersion 3 The preparation is carried out analogously to Example 71, except that 25 mg of active ingredient and 125 mg of POPC are used to prepare the ethanolic solution.

204 Example 74: Orally administrable dispersion 4 The preparation is carried out analogously to Example 71, except that 50 mg of active ingredient and 50 mg of POPC are used to prepare the ethanolic solution.

Example 75: Orally administrable dispersion The preparation is carried out analogously to any one of Examples 71 to 74, except that active ingredient and phosphatidyl choline from soybeans or phosphatidylcholine from egg yolk (70 100 pure) are used inrstead of POPC to prepare the ethanolic solution. If desired, an antioxidant, such as ascorbic acid, is added in a concentration of 5 mg/ml.

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Claims

4-19482/A The Claims defining the invention are as follows: 1. A compound of formula I' H R3 AI 'A N B 1 a wherein T is an acyl radical of formula Z Rz (Z) *O=C wherein R is unsubstituted or substituted hydrocarbyl wherein at least one carbon atom has been replaced by a hetero atom with the proviso that a hetero atom is not bonded directly to the carbonyl to which the radical Rz is bonded, alkyl having two or more carbon atoms, lower alkenyl, lower alkynyl, aryl or unsubstituted or substituted amino, and wherein S. R 1 is hydrogen, lower alkoxycarbonyl, heterocyclylcarbonyl, benzyloxycarbonyl that is unsubstituted or substituted by up to three radicals selected independently of one another from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, heterocyclyloxycarbonyl wherein heterocyclyl is bonded via a carbon atom, one of the mentioned carbonyl radicals wherein the bonding carbonyl group has been replaced by a thiocarbonyl group, heterocyclylsulfonyl, lower alkylsulfonyl or N-(heterocyclyl-lower alkyl)-N-lower alkyl-aminocarbonyl, B 1 is a bond or a bivalent residue of an a-amino acid bonded N-terminally to R 1 and C-terminally to the amino group at the carbon atom carrying R 2 -CH 2 0 206 R 2 and R 3 are each independently of the other phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals selected independently of one another from hydroxy, lower alkoxy, halogen, halo-lower alkyl, sulfo, lower alkylsulfonyl, cyano and nitro, A 1 is a bond between -C=O and A 2 or is a bivalent residue of an a-amino acid bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is a bivalent residue of an a-amino acid bonded N-terminally to A 1 arid C-terminally to the group NR 4 R 5 or AI and A 2 together form a bivalent residue of a dipeptide the central amide bond of which has been reduced and which is bonded N-terminally to the group -C=O and C- terminally to the group NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form unsubstituted or substituted thiomorpholino or morpholino, or a salt of such a compound where salt-forming groups are present. 2. A compound of formula I' according to claim 1, wherein B 1 is a bond and the remaining radicals are as defined, or a salt thereof where salt-forming groups are present. 3. A compound of formula I' according to claim 1, wherein T is an acyl radical of the formula Z shown in claim 1 wherein R is heterocyclyl bonded via a ring carbon atom and selected from pyrrolyl, pyrrolyl, indolyl, indolizinyl, isoindolyl, pyrrolidinyl, hydroxypyrrolidinyl, furyl, tetra- hydrofuryl, thienyl, cyclobepta[b]pyrrolyl, imidazolyl, N-triphenyl-lower alkyl-imid- .azolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, ,y-pyranyl, 4,5-dihydropyranyl, 4H-chromenyl, chromanyl, y-thiopyranyl, pyridazinyl, cinnolyl, phthalazinyl, quinazolinyl, quinoxalinyl, pyrimidinyl, pyrazinyl, phenazinyl, -nenoxazinyl, phenothiazinyl, morpholinyl, thiazinyl and tetra- hydropyranyl, each of which is substituted by up to three radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, hydroxy-lower alkyl, halogen, cyano, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl and halo-lower alkyl, or is unsubstituted, and each of which is bonded via a ring carbon atom; or Rz is lower alkyl which is substituted by at least one radical selected from: lower alkoxy; lower alkoxy substituted by one or two substituents selected from aryl, -207- lower alkoxy, lower alkylthio, ethylthio, lower alkoxy-lower alkoxy, lower alkylthio- lower alkoxy, aryloxy, arylthio, amino, N-lower alkylamino, N,N-di-lower alkylamino, and heterocyclyl as last defined for heterocyclyl Rz bonded via a ring carbon atom; aryloxy; lower alkylthio; lower alkylthio substituted by one or two aryl substituents; arylthio; amino or amino substituted by one or two radicals selected from lower alkyl, heterocyclyl-lower alkyl wherein heterocyclyl is as defined for heterocyclyl RZ bonded via a ring carbon atom, aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl and aryl- lower alkoxycarbonyl; heterocyclyl as defined above for heterocyclyl RZ bonded via a ring carbon atom; heterocyclyl-lower alkyl wherein heterocyclyl is as defined above for hetrocyclyl RZ bonded via a ring carbon atom but may also be bonded via a ring nitrogen atom; lower alkoxycarbonyl; lower alkanoyloxy-lower alkloxycarbonyl; carboxy; phenyl-lower alkoxycarborylamino-lower alkoxy; amino-lower alkoxy; di- lower alkylamino-lower alkoxy; N,N-di-lower alkylamino-lower alkoxy; lower alkoxy- carbonyl-lower alkylsulfo; lower alkanoyloxy; and tetrahydropyranyloxy; and which may-contain as a further substituent aryl, or Rz is aryl, aryl in the said definitions being especially phenyl, naphthyl, or fluorenyl, which is unsub- stituted or substituted by up to three. radicals seleted independently of one another from lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, hydroxy-lower S alkyl, halogen, cyano, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, halo-lower alkyl, piperidinomethyl, piperazin-1-ylmethyl, 4-lower alkyl-piperazin-1-yl-methyl, morpholinomethyl, thiomorpholinomethyl and nitro, which may be present independently Sof one another; R 1 is hydrogen, tert-butoxycarbonyl, isobutyloxycarbonyl, ethoxycarbonyl, pyridine-3- carbonyl, morpholivocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydro-isoquinoline- 0 3-carbonyl, benzyloxycarbonyl substituted by up to thre. radicals selected independently of one another from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or heterocyclyloxycarbonyl wherein heterocycly! is bonded via a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, -carbolinyl, y-pyranyl, furanyl and a fully or partially saturated derivative of those radicals; B, is a bond or a bivalent residue of an a-amino acid bonded N-terminally to R 1 and -208- C-terminally to the amino group at the carbon atom carrying R 2 -CH 2 R 2 and R 3 are each independently of the other phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals selected independently of one another from hydroxy, methoxy, benzyloxy, fluorine, sulfo, lower alkylsulfonyl, trifluoromethyl, cyano, isobutyloxy and n-butyloxy, A, is a bivalent residue of a hydrophobic a-amino acid bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is a bivalent residue of a hydrophobic a-amino acid bonded N-terminally to A, and C-terminally to the radical NR 4 R, or AI and A 2 together form a bivalent residue of a dipeptide consiLting of two hydrophobic a-amino acids, the central amide bond of which has been reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR 4 R5, and R 4 and R 5 together with the bonding nitrogen atom form thiomorpholino, 2,6-dimethyl- morpholino or morpholino, or a compound of formula I wherein R 1 is morpholinosulfonyl or N-(2-pyridylmethyl)- N-methyl-aminocarbonyl and the remaining radicals are as defined; or a pharmaceutically acceptable salt of such a compound where salt-forming groups are present. 4. A compound of formula I' according to claim 1, wherein ST is an acyl radical of the formula Z shown in claim 1 wherein Rz is heterocyclyl bonded via a ring carbon atom and selected from pyrrolyl, pyrrolyl, indolyl, indolizinyl, isoindolyl, pyrrolidinyl, hydroxypyrrolidinyl, furyl, tetra- hydrofuryl, thienyl, cyclohepta[b]pyrrolyl, imidazolyl, N-triphenyl-lower alkyl- imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, piperidyl, 'y-pyranyl, 4,5-dihydropyranyl, 4H-chromenyl, chromanyl, y-thiopyranyl, pyridazinyl, cinnolyl, phthalazinyl, quinazolinyl. quinoxalinyl, pyrimidinyl, pyrazinyl, phenazinyl, phenoxazinyl, phenothiazinyl, morpholinyl and thiazinyl, each of which is substituted by up to three radicals selected independently of one another from lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, triphenyl-lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, hydroxy-lower alkyl, halogen, cyano, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl and halo-lower alkyl, or is unsubstituted, and each of which is bonded via a ring carbon atom; or Rz is lower alkyl which is substituted by at least one radical selected from:
209- lower alkoxy; lower alkoxy substituted by one or two substituents selected from aryl, lower alkoxy, lower alkylthio, ethylthio, lower alkoxy-lower alkoxy, lower alkylthio- lower alkoxy, aryloxy, arylthio, amunino, N-lower alkylamino, N,N-di-lower alkylamino, and heterocyclyl as last defined for heterocyclyl RZ bonded via a ring carbon atom; aryloxy; lower alkylthio; lower alkylthio substituted by one or two aryl substituents; arylthio; amino or amino substituted by one or two radicals selected from lower aickyl, heterocyclyl-lower alkyl wherein heterocyclyl is as defined for heterocyclyl RZ bonded via a ring carbon atom, aryl-lower alkyl, lower alkanoyl, lower alkoxycarbonyl and aryl- lower alkoxycarbonyl; heterocyclyl as defined above for heterocyclyl RZ bonded via a ring carbon atom; and heterocyclyl-lower alkyl wherein heterocyclyl is as defined above for heterocyclyl RZ bonded via a ring carbon atom but may also be bonded via a ring nitrogen atom; and which may carry as a further substituent aryl, or Rz is aryl, aryl in the said definitions being especially phenyl, naphthyl, or fluorenyl, which is unsub- stituted or substituted by up to three radicals selected independently of one another from lower alkyl, lower alkanoyl, hydroxy, lower alkoxy, phenyl-lower alkoxy, hydroxy-lower alkyl, halogen, cyano, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, halo-lower alkyl, piperidinomethyl, piperazin-1-ylmethyl, 4-lower alkyl-piperazin-1-yl-methyl, morpholinomethyl, thiomorpholinomethyl and nitro, which may be present independently S of one another; R, is hydrogen, tert-butoxycarbonyl, isobutyloxycarbonyl, pyridine-3-carbonyl, morpho- linocarbonyl, 3-benzofuranoyl, 1,2,3,4-tetrahydro-isoquinoline-3-carbonyl, benzyloxy- carbonyl substituted by up to three radicals selected independently of one another from fluorine, halo-lower alkyl, lower alkanoyl, sulfo, lower alkylsulfonyl and cyano, or hetero- cyclyloxycarbonyl wherein heterocyclyl is bonded via a carbon atom and is selected from pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, 3-carbolinyl and a fully or partially saturated derivative of those radicals; B, is a bond or a bivalent residue of an a-amino acid bonded N-terminally to R 1 and C-terminally to the amino group at the carbon atom carrying R 2 -CH-, -210- R 2 and R 3 are each independently of the other phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals selected independently of one another from hydroxy, methoxy, benzyloxy, fluorine, sulfo, lower alkylsulfonyl, trifluoromethyl and cyano, AI is a bivalent residue of a hydrophobic a-amino acid bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is a bivalent residue of a hydrophobic a-amino acid bonded N-terminally to A, and C-terminally to the radical NR 4 R 5 or A, and A 2 together form a bivalent residue of a dipeptide consisting of two hydrophobic a-amino acids, the central amide bond of which has been reduced and which is bonded N-terminally to the group -C=O and C-terminally to the group NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form thomorpholino or morpholino, or a compound of formula I wherein R 1 is morpholinosulfonyl or N-(2-pyridylmethyl)- N-methyl-aminocarbonyl and the remaining radicals are as defined; or a pharmaceutically acceptable salt of such a compound where salt-forming groups are present. A compound of formula I' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin-1- or is oquinolin-3-ylcarbonyl, pyrazin- 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, ph'. or naphthyl:.Iower alkoxy-lower alkylcarbonyl, a-lower alkoxy-a-phenyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl- carbonyl, m- .r p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkyl- carbonyl, N-lower alkylamino-lower alkylcarbonyl, N-imidazol(-2-, or N-lower alkylamino-lower alkylcarbonyl, N-(imidazol-4-ylmethyl)-N-methylaminoacetyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, N-phenyl- lower alkoxycarbonyl-N-lower alkylamino-lower alkylcarbonyl, imidazol(-l-, or alkylcarbonyl, N-triphenyl-lower alkylimidazol(-4- or -5-)yl-lower alkyl- carbonyl, pyrazol(-1-, or -5-)yl-lower alkylcarbonyl, such as pyrazol-1-ylacetyl, halo-lower alkylbenzoyl, p-(morpholino- or thiomorpholino-methyl)benzoyl, benzoyl, lower alkanoyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkoxy-lower alkyl- carbonyl, lower alkoxycarbonyl-lower alkylthio-lower alkylcarbonyl, lower alkoxy- I -211- carbonyl-lower alkylsulfo-lower alkylcarbonyl, lower alkanoyloxy-lower alkoxy- carbonyl-lower alkoxy-lower alkylcarbonyl, carboxy-lower alkoxy-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonylamino-lower alkylcarbonyl, amino-lower allylcarbonyl, di-lower alkylamino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl or tetrahydropyranyloxy-la wer alkylcarbonyl; R, is hydrogen, tert-butoxycarbonyl, isobutyloxycarbonyl, pyridine-;-carbonyl, morpho- linocarbonyl, 3-benzofuranoyl or 1,2,3,4-tetrahydro-iocjL inoline-3-carbonyl, ethoxy- carbonyl, 4-tetrahydropyranyloxycarbonyl, tetrahydrofuran-2(R or S)-yloxycarbonyl, morpholinosulfonyl or N-(2-pyridylmethyl)-N-methyl-aminocarbonyl; B 1 is a bond or a bivalent residue of the a-amino acid valine bonded N-terminally to R 1 and C-terminally to the amino group at the carbon atom carrying R 2 -CH 2 R 2 and R 3 are each independently of the other phenyl or cyclohexyl, those radicals being unsubstituted or substituted by from one to three radicals selected independently of one another from hydroxy, methoxy, benzyloxy, fluorine, sulfo, lower alkylsulfonyl, cyano, trifluoromethyl, isobutyloxy and n-butyloxy, A, is a bivalent residue of one of the a-amino acids glycine, valint, isoleucine, leucine and phenylglycine bonded N-terminally to the group -C=O and C.-terminally to A, A 2 is a bivalent residue of one of the a-amino acids glycine, alanine, valine, leucine, iso- leucine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxy-phenylalanine, p-,benzyl- oxyphenylalanine, p-fluorophenylalanine, p-(isobutyloxy)-phenylalanine and p-(n-butyl- oxy)-phenylalanine bonded N-terminally to A, and C-terminally to the group NR 4 R 5 or AI and A 2 together form a bivalent residue of a dipeptide having a reduced central peptide bond that consists of an N-terminal amino acid residue selected from Gly(red), Val(red) and lle(red) and a C-terminal amino acid residue selected from glycine, phenylalanine, cyclohexylalanine, tyrosine, p-methoxy-phenylalanine and p-fluorophenylalanine, and that is bonded N-terminally to the group -C=O and C-terminally to the group NR 4 R 5 as defined above for A 1 and A 2 and R 4 and R 5 together with the bonding nitrogen atom form thiomorpholino, morpholino or 2,6-dimethylmorpholino, or a pharmaceutically acceptable salt thereof where salt-forming groups are present. 6. A compound of formula I' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyi, pyridyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin-1- or isoquinolin-3-ylcarbonyl, pyrazin- 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naphthyl-lower alkoxy-lower 0 -212- a'kylcarbonyl, a-lower alkoxy-a-phenyl-lower alkylcarbonyl, lower alkoxy-lower alcoxy-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl- carbonyl. m- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkyl- carbonyl, N-lower alkylamino-lower alkylcarbonyl, N-imidazol(-2-, or N-lower alkylamino-lower alkylcarbonyl, N-pyridin(-2-, or -4-)ylmethyl-N-lowerl alkylamino-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino- lower alkylcarbonyl, imidazol(- or -5-)yl-lower alkylcarbonyl, N-triphenyl- lower alkylimidazol(-4- or -5-)yl-lower alkylcarbonyl, pyrazol(- or alkylcarbonyl, halo-lower alkylbenzoyl, p-(morpholino- or thiomorpholino-methyl)- benzoyl or benzoyl, R, is hydrogen, tert-butoxycarbonyl, isobutyloxycarbonyl, pyridin-3-ylcarbonyl, morpho- linocarbonyl, 3-benzofuranoyl or. 1 ,2,3,4-tetrahydro-isoquinolin-3-ylcarbonyl, or morpho- linosulfonyl or N-(2-pyridylmethyl)-N-methyl-aminocarbonyl; B I is a bond or a bivalent residue of the a-amino acid valine bonded N-terminally to R 1 and C-terminally to the amino group at the carbon atom carrying RZ-CH 2 R 2 and R 3 are each. independently of the other phenyl or cyclohexyl, those radicals being unsubstituted or substituted by one or two radicals selected independently of one another from hydroxy, methoxy, benzyloxy, fluorine, sulfo, lower alkylsulfonyl, cyano and tri- fluoromethyl, A, is a bivalent residue of one of the a-amino acids glycine, valine and isoleucine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is a bivalent residue of one of the a-amino acids glycine, alanine, valine, leucine, iso- leucine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxy-phenylalanine, p-benzyl- oxyphenylalanine and p-fluorophenylalanine bonded N-terminally to A, and C-terminally to the group NR 4 R 5 or AI and A 2 together form a bivalent residue of a dipeptide having a reduced central peptide bond that consists of an N-terminal amino acid residue selected from Gly(red), Val(red) and Ile(red) and a C-terminal amino acid residue selected from glycine, phenylaanine, cyclohexylalanine, tyrosine, p-methoxy-phenylalanine and p-fluorophenylalanine, and that is bonded N-terminally to the group -C=O and C-terminally to the group NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form thiomorpholino or morpholino, or a pharmaceutically acceptable salt thereof where salt-forming groups are present. 213 7. A compound of formula I' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyI or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or pyridyl-2-vlcarbonyl, isoquinolin-1- or isoquinolin-3-ylcarbonyl, pyrazin- 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naphthyl-lower alkoxy-lower alkylcarbonyl, a-lower alkoxy-a-phenyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alky]- carbonyl, mn- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, NN-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, N,N-di-lower alkylarnino-lower alkyl- carbonyl, N-lower alkylamino-lower alkylcarbonyl, N- idazol(-2-, or N-lower alkylamino-lower al kylcarbonyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino- lower alkylcarbonyl, imidazol(-l-, or -5-)yl-lower alkylcarbonyl, N-triphenyl- lower alkylimidazol(-4- or -5-)yl-lower alkylcarbonyl, pyrazol(-1-, or alkylcarbonyl, pyrazol-1-ylacetyl, halo-lower alkylbenzoyl, p-(morpholino- or thio- morpholino-methyl)benzoyl, benzoyl, lower alkanoyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, lower alkoxyc,.arbonyl-lower alkyl- thio-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylsulfo-lower alkylcarbonyl, lower alkanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, carboxy- lower alkoxy-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonylamino-lower alkyl- carbonyl, amino-lower alkylcarbonyl, di-lower alkylamino-lower alkoxy-lower alkoxy- lower alkylcarbonyl, N-phienyl-lower alkoxycarbonyl-amino-lower alkoxy-lower alkoxy- lower alkylcarbonyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl or tetrahydro- :1 pyranyloxy-lower aklabnl R, is tert-butoxycarbonyl, R 2 is phenyl, cyclohexyl, p-hydroxyphenyl, m- or p-methoxyphenyl, p-benzyloxy- phenyl, m- or p-fluorophenyl, p-trifluoromethylphenyl or m- or p-cyanophenyl, R 3 independently of R 2 has one of the definitions given for R 2 A, is a bivalent residue of one of the a-amino acids glycine, (L)-valine and (L)-isoleucine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is a bivalent residue of one of the a-amino acids glycine, alanine, valine, leucine, iso- leucine, phenylalanine, tyrosine, cyclohexylalani.ne, p-methoxy-phenylalanine, p-benzyl- oxyphenylalaninu and p-fluorophenylalanine bonded N-terminally to A, and C-terminally to the group NR 4 R 5 andR~ and R 5 together with the bonding nitrogen atom form RA/ orpholino; O -214- or a salt thereof where salt-forming groups are present. 8. A compound of formula F' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin-1- or isoquinolin-3-ylcarbonyl, pyrazin- 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naphthyl-lower alkoxy-lower alkylcarbonyl, a-lower alkoxy-a-phenyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, lower alkoxy-1ower alkoxy-lower alkoxy-lower alkyl- carbonyl, m- or p-chloropheny1oxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, NN-di-lower alkylamino-lower alkyl- carbonyl, N-lower alkylamino-lower alkylcarbonyl, N-imidazol(-2-, or N-lower alkylamino-lower alkylcarbonyl, N-pyridin(-2-, cr -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino- lower alkylcarbonyl, imidazol(- or -5-)yl-lower alkylcarbonyl, N-triphenyl- lower alkylimidazol(-4- or -5-)yl-lower alkylcarbonyl, pyrazol(-1-, or alkylcarbonyl, pyrazol-1-ylacetyl, halo-lower alkylbenzoyl, p-(morpholino- or thio- morpholino-methyl)benzoyl or benzoyl, R, is tert-butoxycarbonyl, R 2 is phenyl, cyclohexyl, p-hydroxyphenyl, m- or p-methoxyphenyl, p-benzyloxy- phenyl, m- or p-fluorophenyl, p-trifluoromethylphenyl or m- or p-cyanophenyl, R 3 independently of R 2 has one of the definitions given for R 2 A, is a bivalent residue of one of the a-amino acids glycine, (L)-valine and (L)-isoleucine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is a bivalent residue of one of the a-amino acids glycine, alanine, valine, leucine, iso- leucine, phenylalanine, tyrosine, cyclohexylalanine, p-methoxy-phenylalanine, p-benzyl- oxyphenylalanine and p-fluorophenylalanine bonded N-terminally to A, and C-terminally to the group NR 4 R 5 and R 4 and R 5 together with the bonding nilbogen atom form morpholino; or a salt thereof where salt-forming groups arc: present. 9. A compound of formula I' according to claim 1, wherein T is an acyl radical of the formula Z shown in claim 1 wherein RZ is hydrocarby! wherein at least one carbon atom has boen replaced by a hetero atom with the proviso that a hetero 'tom is not bonded directly to the carbonyl to which the radical Rz is bonded, alkyl having LU -215- two or more carbon atoms, lower alkenyl, lower alkynyl or aryl, and wherein R, is tert- butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is phenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=0 and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. A compound of formula I' according to claim 1, wherein T is an acyl radical of the formula Z shown in claim 1 wherein RZ is hydrocarbyl wherein at least one carbon atom has been replaced by a hetero atom with the proviso that a hetero atom is not bonded directly to the carbonyl to which the radical RZ is bonded, alkyl having two or more carbon atoms, lower alkenyl, lower alkynyl or aryl; R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-methoxyphenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=0 and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. V 11. A compound of formula I' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin-1- or isoquinolin-3-ylcarbonyl, pyrazin- 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naphthyl-lower alkoxy-lower alkylcarbonyl, a-lower alkoxy-a-phenyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl- carbonyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkyl- carbonyl, N-lower alkylamino-lower alkylcarbonyl, N-imidazol(-2-, or N-lower alkylamino-lower alkylcarbonyl, N-pyxridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino- lower alkylcarbonyl, imidazol(- I or -5-)yl-lower alkylcarbonyl, N-triphenyl- lower alkylimidazol(-4- or -5-)yl-lower alkylcarbonyl, pyrazol(-l-, or alkylcarbonyl, pyrazol-1-ylacetyl, halo-lower alkylbenzoyl, p-(morpholino- or thio- morpholino-methyl)benzoyl, benzoyl, lower alkanoyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl- -216- thio-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylsulfo-lower alkylcarbonyl, lower alkanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, carboxy- lower alkoxy-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonylamino-lower ailcyl- carbonyl, amino-lower alkylcarbonyl, di-lower alkylamino-lower alkoxy-lower alkoxy- lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-amino-lower alkoxy-lower dloxy- lower alkylcarbonyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl or tetrahydro- pyranyloxy-lower alkylcarbonyl; R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R3 is phenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R(4 and R5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. 12. A compound of formula I' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin-1- or isoquinolin,-3-ylcarbonyl, pyrazin- yicarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naphthyi-lower alkoxy-lower alkylcarbonyl, a-lower alkoxy-a-phenyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl- carbonyl, m- or p-clhlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N',N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkyl- carbonyl, N-lower alkylarino-lower alkylcarbonyl, N-imidazol(-2, or N-lower alkylaminro-lower alkylcarbnyl, N-pyridin(-2, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino- lower alkylcarbonyl, imidazol(-1-, or -5-)yl-lower aliylcarbonyl, N-triphenyl- lower alkylimidazol(-4- or -5-)yl-lower alkylcarbonyl, pyrazol(-l-, or alkylcarbonyl, pyrazol-l-ylacetyl, halo-lower alkylbenzoyl, p-(morpholino- or thio- morpholino-methyl)benzoyl or benzoyl; R, is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is phenyl; A, is the bivaiient residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. 217 13. A compound of formula F' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furani-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin-1- or isoquinolin-3-ylcarbonyl, pyrazin- 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naphthyl-lower alkoxy-lower alkylcarbonyl, ct-lower alkoxy-a-phenyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl- carbonyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkyl- carbonyl, N-lower alkylamino-lower alkylcarbonyl, N-imidazol(-2-, or N-lower alkylamino-lower alkylcarbonyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino- lower alkylcarbonyl, imidazol(- or -5-)yl-lower alkylcarbonyl, N-n-iphenyl- lower alkylimidazol(-4- or -5-)yl-lower alkylcarbonyl, pyrazol(-1-, or alkylcarbonyl, pyrazol-1-ylacetyl, halo-lower alkylbenzoyl, p-(morpholino- or thio- :m morpholino- 1 1 ethyl) benzoyl, benzoyl, lower alkanoyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl- thio-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylsulfo-lower alkylcarbonyl, lower alkanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, carboxy- lower alkoxy-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonylamino-low w alkyl- carbonyl, amino-lower alkylcarbonyl, di-lower alkylamino-lower alkoxy-lower atkoxy- lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-amino-lower alkoxy-lower alkoxy- lower alkylcarbonyl, amino-lower alcoxy-lower alkoxy-lower alkylcarbonyl or tetrahydro- pyranyloxy-lower alkylcarbonyl; R, is tert-butoxycarbonyl; B3, is a bond; R 2 is phenyl; R 3 is p-methoxyphenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-termninally to A 2 A 2 is the bivalent residue of p-methoxyphenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. 14. A compound of formula F' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin- 1- or isoquinolin-3-ylcarbonyl, pyrazin-' 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naphthyl-lower alkoxy-lower alkylcarbonyl, ax-lower alkoxy-(x-phenyl-lower alkylcarbonyl, lower alkoxy-lower -218- alkoxy-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl- carbonyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkylca: AL~y, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lowver alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkyl- carbonyl, N-lower alkylamino-lIower alkylcarbonyl, N-imidazol(-2-, or N-lower alkylamino-lower alkylcarbonyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkyicarbonyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamnino- lower alkylcarbonyl, imi.daZDl(- or -5-)yl-lower alkylcarbonyl, N-tri- phenyl-lower alkylimidazol or -5-)yl-lower alkylcarbonyl, pyrazol(- or yl-lower alkylcarbonyl, pyrazol- 1-ylacetyl, halo-lower akylbenzoyl, p-(morpholino- or thiomorpholino-methyflbenzoyl, benzoyl, lower alkanoyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkoxy-lower alcylcarbonyl, lower alkoxycarbonyl-lower alkyl- thio-lower alkylcarbonyl, lower alkoxycarbonyl-lower aikylsulfo-lower alkylcarbonyl, lowei- alkanoyloxylower alkoxycarbonyl-lower alkoxy-lower allcyicarbonyl, carboxy- carbonyl, amino-lower alkylcarbonyl, di-lower alkylamino-lowerilkoxy-lower alkoxy- lower alkylcarbonyl, N-phenyl-lower a'jioxycarbonyl-am inc-lower alkoxy-lower alkoxy- low~er alkylcarbonyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl or tetrahydro- pyranyloxy-lower alkylcarbonyl; R, is tert-butoxycarbonyl; B, is a bond; R(2 is phenyl; R(3 is p-fluorophenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -N1R 4 R 5 and R(4 and R(5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. 15. A compound of formula I' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyl, pyfidyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin-1- or isoquinolin-3-ylcarbonyl, pyrazin- 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naphthyl-lower aikoxy-lower alkylcarbonyl, cc-lower alkoxy-cx-pheniyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl- carbonyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkyithio-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkyl- -219- carbonyl, N-lower alkylamino-lower alkylcarbonyl, N-imidazol(-2-, or N-lower alkylamino-lower alkylcarbonyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, N-phenyl-lower alkoxyciprbonyl-N-lower alkylamino- lower alkylcarbonyl, imidazol(-1-, or -5-)yl-lower alkylcarbonyl, N-triphenyl- lower allcylimidazol(-4- or -5-)yI-lower alkylcarbonyl, pyrazol(-1-, or alkylcarbonyl, pyrazol- I1-ylacetyl, halo-lower. alkylbenzoyl, p-(morpholino- or thio- morpholino-methyl)benzoyl, benzoyl, lower alkanoyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl- thio-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylsulfo-lower alkylcarbonyl, lower alkanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, carboxy- lower alkoxy-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyiamino-lower alkyl- carbonyl, amino-lower alkylcarbonyl, di-lower alkylamino-lower alkoxy-lower alkoxy- lower alkylcarbonyl, N-phenyl-lower allcoxycaeonyl-amino-lower alkoxy-lower alkoxy- lower alkylcarbonyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl or tetrahydro- pyranyloxy-lower alkylcarbonyl; R, is tert-butoxycarbonyl; B, is a bond; R 2 is phe nyl; R 3 is p-fluorophenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the :group -C=O and C-terminally to A 2 A 2 is the bivalent residue of p-methoxy- phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino;' or a salt thereof where salt-forming groups are present. 16. A compound of formula F' according to claim 1, wherein T is pyrrolidin-2-ylcarbonyl or -3-ylcarbonyl, furan-3- or furan-2-ylcarbonyl, pyridyl-4-, pyridyl-3- or pyridyl-2-ylcarbonyl, isoquinolin-1- or isoquinolin-3-ylcarbonyl, pyrazin- 2-ylcarbonyl, lower alkoxy-lower alkylcarbonyl, phenyl- or naplithyl-lower alkoxy-lower alkylcarbonyl, lower alkoxy-ct-phenyl-lower alkylcarbonyl, lower alkoxy-lower alkoxy-lower alkylcarbonyi', lower alkoxy-lower alkoxy-lower alkoxy-lower alkyl- carbonyl, m- or p-chlorophenyloxy-lower alkoxy-lower alkylcarbonyl, N,N-di-lower alkylamino-lower alkoxy-lower alkylcarbonyl, 3- or 4-pyridyl-lower alkyloxy-lower alkylcarbonyl, phenyloxy-lower alkylcarbonyl, lower alkylthio-lower alkylcarbonyl, phenyl-lower alkylthio-lower alkylcarbonyl, N,N-di-lower alkylamino-lower ailcyl- carbonyl, N-lower alkylamino-lower alkylcarbonyl, N-imidazol(-2-, or N-lower alkylamino-lower alkylcarbonyl, N-pyridin(-2-, or -4-)ylmethyl-N-lower alkylamino-lower alkylcarbonyl, N-phenyl-lower alkoxycarbonyl-N-lower alkylamino- lower alkylcarbonyl, imidazol(- or -5-)yl-lower alkylcarbonyl, N-triphenyl- lower alkylimidazol(-4- or -5-)yl-lower atkylcarbonyl, pyrazol(-l1-, or 220 alkylcarbonyl, pyrazol-1I-ylacetYl, halo-lower alkylbenzoyl, p-(morpholino- or thio- morpholino-methyi)benzoyl, benzoyl, lower alkanoyloxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkyl- thio-lower alkylcarbonyl, lower alkoxycarbonyl-lower alkylsulfo-lower alkylcarbonyl, lower alkanoyloxy-lower alkoxycarbonyl-lower alkoxy-lower alkylcarbonyl, carboxy- lower alkoxy-lower alkylcarbonyl, N-phenyl-lower alkoxyr'arbonylamino-lower ailcyl- carbonyl, amino-lower alkylcarbonvl, di-lower alkylamino-lower alcoxy-lower aikoxy- lower alkylcarbonyl, N-phenyl-lower alcoxycarbonyl-amino-lower alkoxy-lower alkoxy- lower alkylcarbonyl, amino-lower alkoxy-lower alkoxy-lower alkylcarbonyl or tetrahydro- pyranyloxy-lower alkylcarbonyl; R, is tert-butoxycarbonyl; B, is a bond; RI is phenyl; R 3 is p-methoxyphenylP- A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the -group -NR 4 R 5 and R 4 and R(5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. 17. A compound of formula F' according to claim 1, wherein T is 4(S)-(2-furanylcarboxy);- 4(S)-[4-(dimethyl-amino)-butyryloxy]; methyl-aminoacetyloxy); 4(S)-(methylamino-acetyloxy); 4(S)-[N-(imidazole-4-methyl)-, N-methyl-aminoacetyloxy]; 1-triphenylmethyl-imidazol-4-yl)-propionyloxy]; [3-(4-imidazolyl)-propi, onyloxy]; 4(S)-(methoxy-acetyloxy); 4(S)-(2-picolinoyl); 4(S )-(benzyloxy-acetyloxy); 'ioxy-c-phenyl-acetyloxy]; c-methoxy-c-phenyl-acetyloxyj; -pyrazolylacetyloxy); 4(S)-(isoquinoline- 3-carbonyloxy); 4(S)-(pyrazinecarbonyloxy); 4(S)-(4-a-chloromethyl-benzoyloxy); 4(S)- [4-(4-morpholino)methyt-bernzoyloxy]; 4(S)-(isonicotinoyloxy); 4(S)-(nicotin(,yloxy); 4(S)-(3-methioxypropanoyloxy); 4(S)-[(4-chlorophenoxy)methoxyacetyloxyl; methoxyethoxy)acetyloxy]; 4(S)-(butyloxyacetyloxy); [2-(2-methoxyethoxy)- ethoxy] acetyloxy)]; 4(S)-(methoxyacetyloxy); 4(S)-(phenoxyacetyloxy); ac-methoxy-x-phenylacetyloxy); 4(S)-[(R)-ca-methoxy-ax-phenylacetyloxy]; (N,N-di- methyl-aminoacetyloxy); 4(S)-[N-(pyridine-2-methyl)-N-methyl-aminoacetyloxy]; 4(S)- [3-(dimethyl-amino)-propionyloxy]; 4(S)-[3-(N-Z-N-metihyl-amino)-propionyloxy]; 4(S)- (3-methyl-amino-propionyloxy); 4(S)-[Q-,Imethylaminoethoxy)-acetyloxy]; pyridylmethoxy)-acetyloxy]; 4(S)-(methoxy-acetyloxy); 4(S)-(pyridine-2-carboxy); 4(S)- (methiylthioacetyloxy); 4(S)-(benzylthioacetyloxy); 4(S)-((L)-prolyloxy); prolyloxy); 4(S)-((L)-(N-Z-prolyl)oxy); 4(S)-((D)-(N-Z-prolyl)oxy); 3-(N-Z-amino)- propionyloxy; 3-amino-propionyloxy; (3-dimethylamino-propoxy)- acetyloxy; 2-(2-di- -221- methylamino-ethoxy)-ethoxy-acetyloxy; (4-dimethylamino-butoxy)-acetyloxy; (2-benzyl- oxy)acetyloxy; (2-acetyloxy)acetyloxy; 2-(4-tetrahydropyranyloxy)acetyloxy; tetrahydropyranyloxy)-propionyloxy; 2-(2-amino-ethoxy)ethoxy-acetyloxy); 2-(2- benzyloxycarbonylamino-ethoxy)ethoxy-acetyloxy); (methoxycarbonyl-methoxy)-acetyl- oxy; (methoxycarbonyl-methylthio)-acetyloxy; (methoxycarbonyl-methylsulfo)-acetyloxy) (pivaloyloxymethoxycarbonyl)-methoxy-acetyl; (carboxymethoxy)-acetyloxy; or (acetoxymethoxycarbonyl-methoxy)-acetyloxy; and R, is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is phenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C- terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or in each case a pharmaceutically acceptable salt thereof where salt-forming groups are present. 18. A compound of formula P' according to claim 1, wherein T is 4(S)-(2-fur,-,nylcarboxy); 4(S)-[4-(dimethyl-amino)-butyryloxy]; methyl-aminoacetyloxy); 4(S)-(mothylamino-acetyloxy); 4(S)-[N-(imidazole-4-methyl)- N-methyl-aminoacetyloxyl; 4(S)-113-(l1-triphenylmethyl-imidazol-4-yl)-propionyloxy; a: a 4(S)-[3-(4-imidazolyl)-propionyloxy]; 4(S)-(methoxy-acetyloxy); 4(S)-(2-Picolinoyi); 4(S)-(benzyloxy-acetyloxy); 4(S)-II(S)-ax-methoxy-cx-phenyl-acetyloxy]; ca-methoxy-a-phenyl-acetyloxy]; 1-pyrazolylacetyloxy); 4(S)-(isoquinoline- 3-carbonyloxy); 4(S)-(pyrazinecarbonyloxy); 4(S)-(4-ax-chloromethyl-benzoyioxy); 4(S)- [4-(4-morpholino)methyl-benzoyloxy]; 4(S)-(isonicotinoyloxy); 4(S)-(nicotinoyloxy); 4(S)-(3-methoxypropanoyloxy); 4(S)-[(4-chlorophenoxy)methoxyacetyloxy]; 4(S)- [2-(2-inethoxyethoxy)acetyloxy]; 4(S)-(butyloxyacetyloxy); [2-(2-methoxy- ethoxy)ethoxy]acetyloxy)];, 4(S)-(methoxyacetyloxy); 4(S)-(phenoxyacetyloxy); 4(S)- )-a-methoxy-a-phenylacetyloxy); 4(S)-[(R)-ct-methoxy-a-phenylacetyloxy]; (N,N-di- methyl-aminoacetyloxy); 4(S)-[N-(pyridine-2-methyl)-N-methyl-aminoacetyloxy]; 4(S)- 3-(dimethyl-amino)-propionyloxy]; [3-(N-Z-N-methyl-amino)-propionyloxy]; 4(S)- (3-methyl-amino-propionyloxy); 4(S)-[(dimethylaminoethoxy)-acetyloxyl; 4(S)- [(2-pyridylmethoxy)-acetyloxyl;, 4(S)-(methoxy-acetyloxy); 4(S)-(pyridine-2-carboxy); 4(S )-(methylthioacetyloxy); Ibenzylthioacetyloxy); 4(S)-((L)-prolyloxy); -222- propionyloxy; 3-amino-propionyloxy; (3-dimethylamino-propoxy)-acetyloxy; 2-(2-di- methylamino-ethoxy)-ethoxy-acetyloxy; (4-dimethylamino-butoxy)-acetyloxy; (2-benzyl- oxy)acetyloxy; (2-acetyloxy)acetyloxy; 2-(4-tetrahydropyranyloxy)acetyloxy; tetrahydropyranyloxy)-propionyloxy; 2-(2-amino-ethoxy)ethoxy-acetyloxy); 2-(2-benzyl- oxycarbonylamino-ethoxy)ethoxy-acetyloxy); (methoxycarbonyl-methoxy)-acetyloxy; (methoxycarbonyl-methylthio)-acetyloxy; (methoxycarbonyl-methylsulfo)-acetyloxy; (pivaloyloxymethoxycarbonyl)-methoxy-acetyl; (carboxymethoxy)-acetyloxy; or (acetoxymethoxycarbonyl-methoxy)-acetyloxy; and R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-methoxyphenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=0 and C- terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or in each case a pharmaceutically acceptable salt thereof where salt-forming groups are present. 19. A compound of formula I' according to claim 1, wherein T is methoxyacetyl or pyridin-2-ylcarbonyl; Ri is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is phenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. A compound of formula I' according to claim 1, wherein T is methoxyacetyl or pyridin-2-ylcarbonyl; R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-methoxyphenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of p-mcthoxy-phenylalanine bonded N-terminally to A 1 and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. 21. A compound of formula I' according to claim 1, wherein T is methoxyacetyl or pyridin-2-ylcarbonyl; R 1 is tert-butoxycarbonyl; B 1 is a bond; R2 is -223- phenyl; R 3 is p-fluorophenyl; A, is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with thL oonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. 22. A compound of formula I' according to claim 1, wherein T is methoxyacetyl or pyridin-2-ylcarbonyl; R 1 is tert-butoxycarbonyl; B 1 is a bond; R 2 is phenyl; R 3 is p-fluorophenyl; A 1 is the bivalent residue of (L)-valine bonded N-terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of p-methoxy- phenylalanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R 5 together with the bonding nitrogen atom form morpholino; or a salt thereof where salt-forming groups are present. 23. A compound of formula I' according to claim 1, wherein T is methoxyacetyl or pyridin-2-ylcarbonyl; R 1 is tert-butoxycarbonyl; B, is a bond; R 2 is phenyl; R 3 is p-methoxyphenyl; A 1 is the bivalent residue of (L)-valine bonded N- terminally to the group -C=O and C-terminally to A 2 A 2 is the bivalent residue of phenyl- alanine bonded N-terminally to A, and C-terminally to the group -NR 4 R 5 and R 4 and R together with the bonding nitrogen atom form morpholino; or a salt thereof where salt- forming groups are present. 24. A compound of formula I' according to claim 1 having the name 4(S)-(2-furanylcarboxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamidc. A compound of formula I' according to claim 1 having the name 4(S)-(N,N-dimethyl-aminoacetyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 26. A compound of formula I' according to claim 1 having the name 4(S)-[4-(dimethyl-amino)-butyryloxy]-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamnide, or a pharmaceutically acceptable salt thereof. 27. A compound of formula I' according to claim 1 having the name 4(S)-(N-Z-N-methyl-aminoacetyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl- (L)-Val- -F I 224 (L)-Phe-morpholi n-4-ylamide. 28. A compound of formula F' according to claim 1 having the name 4(S )-(methylamino-acetyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 29. A compound of formula F' according to claim 1 having the name 4(S)-[N-(imidazole-4-methyl)-N-methyl-aminoacetyloxy]-6-phenyl-2(R)-phenylmethyl- hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. A compound of formula I' according to claim 1 having the name [N-(pyridine-2-methyl)-N-methyl-aminoacetyloxy]-6-phenyl-2(R)-phenylmethyl- hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamid,: or a pharmaceutically acceptable salt thereof. 31. A compound of formula P' according to claim 1 having the name oo~o4(S)- 1-triphenylmethyl-irnidazol-4-yl)-propionyloxy]-6-phenyl-2(R)-phenylmethyl- oo hexanoyl-(L)-Val-(L)-Phe-moipholin-4-ylami?,'e. 32. A compound of formula F' according to claim 1 having the name S4(S)- [3-(4-imidazolyl)-propionyloxy]-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 0. 33. A compound of formula 1' according to claim 1 having the name (methoxy-acetyloxy)-6-(p-fluorophenyl)-2(R)-(p-fluorophenyl-methyl)-hexanoyl- -Val -(L)-Phe-morpholin-4-ylamide. 34. A compound of formula F' according to claim 1 having the name 4(S )-(2-picolinoyl)-6-(p-fluorophenyl)-2(R)-(p-fluorophenyl-methyl)-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. A compound of formula F' according to claim 1 having the name (pyridine-2-carboxy)-6-phenyl-2(R)-(p-fluorophenyl-methyl)-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof.
225- 36. A compound of formula P' according to claim 1 having the name 4(S )-[(S)-ax-methioxy-ca-phenyl-acetyloxy]-6-phienyl-2(R)-(p-fluorophenyl-methyl)- hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide. 37. A compound of formula IP according to claim 1 having the name 4(S '-(benzyloxy-acetyloxy)-6-phenyl-2(R)-(p-fluorophenyl-methyI)-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide. 38. A compound of formula F' according to claim 1 having the name [(S)-ac-methoxy-cz-phenyl-acetyloxy] -6-phenyl-2(R)-(p-fluorophenyl-rnethyl)- hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide. 39. A compound of formula I' according to claim 1 having the name 4(S)-[(R)-a&-methoxy-cc-phenyl-acetyloxy]-6-phenyl-2(R)-(p-fluorophenyl-methyl)- hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide. 40. A compound of formula I' according to claim 1 having the name )-(l1-pyrazolylacetyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylaniide, or a pharmaceutically acceptable salt thereof. 4 1. A compound of formula I' according to claim 1 having the name )-(isoquinoline-3-carbonyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 42. A compound of formula I' according to claim 1 having the name 4(S)-(pyrazinecarbonyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylaniide, or a pharmaceutically acceptable salt thereof. 43. A compound of formula I' according to claim 1 having the name 4(S )-(4-a-chloromethyl-benzoyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide. 44. A compound of formula I' according to claim 1 having the name 4(S )-[4-(4-morpholiino)methyl-benzoyloxy-6-phenyl-2(R)-phenylmethyl-hexaloyl- -Val- (L)-Phe-morpholin-4-ylamide, or a pharm aceutically acceptable salt thereof. 226 A compound of formula P' according to claim 1 having the name 4(S )-(isonicotinoyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 46. A compound of formula I' according to claim 1 having the name 4(S)-(nicotinovloxy)-6-phenqyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe-morpholin- 4-ylamide, or a pharmaceutically acceptable salt thereof. 47. A compound of formula I' according to claim 1 having the name 4(S)-(2-picolinoyloxy)-6-phenyl-2(R)-phenylmethyl-h-exanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 48. A compound of formula I' according to claim 1 having the name 4(S)-(3)-methoxypropanoyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide. A compound of formula I' according to claim 1 having the name 4(S)-[(4-chlorophenoxy)meth*Oxyacetyloxy)]-6-phenyl-2(R) -phenylmethyl-hexanoyl- ~:(L)-Val-(L)-Phe-morpholin-4-ylamide. A compound of formula I" according to claim 1 having the name [2-(2-methoxyethoxy)acetyloxy)]-6-phenyl-2(R)-phenylmethiyl-hexanoyl-(L)-Val- ~::(L)-Phe-morpholin-4-ylamide. 1. A compound of formula I' according to claim 1 having the name 4(S)-(butyloxyacetyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide. 52. A compound of formula I' according to claim 1 having the name 4(S)-[2-[2-(2-methoxyethoxy)ethoxy]acetyloxy)]-6-pheny1-2(R)-phenylmethyl-hexanoyl- (L)-Val-(L)-Phe-morpholin-4-ylamide. 53. A compound of formula I' according to claim 1 having the name; 4(S )-(methoxyacetylo~y)-6-phenyl-2(R)-phenylmethyl-hexanov1-(L')-Val-(L)-Phe- morpholin-4-ylamide. 227 54. A compound of formula F' according to claim 1 having the name 4(S )-(phenoxyacetyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide. A compound of formula F' according to claim 1 having the n une 4(S)-[(S)-cx-methoxy-a-phenylacetyloxy)-6-pheny1-2(R)-phenylmethyl-hexanoyl- (L)-Val- (L)-Phe-morpholin-4-ylamide. 56. A compound of formula I' according to claim 1 having the name 4(S)-[(R)-cz-methoxy-a-phenylacetyloxy)]-6-phenyl-2(R)-phenylmethyl-hexanoyl- (L)-Val-(L)-Phe-morpholin-4-ylamide. 57. A compound of formula I' according to claim 1 having the name 4(S)-(valeroyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L1.)-Val-(L)-Phe-morpholin- :lmid: A compound of formula I' according to claim 1 having the name 4(S)-(pivaloyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe-iiio-rpholin- :4-ylamide. 59. A compound of formula I' according to claim 1 having the name 4(S)-(palmitoyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe-morpholin- 4-ylamide. A compound of formnula I' according to claim 1 having the name 4(S)-(butyroyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe-morpholiii- 4-ylamide. 61. A compound of formula I' according to claim 1 having the name 4(S )-(propanoyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe-morpholin- 4-ylamide. 62. A compound of formula P' according to claim 1 having the name 4(S (ben zoyloxy)-6-phenyl-2(R)-pheniylmethyl-hexanoyl-(L)-Val- (L)-Phe-morpholin- 4-ylamide. 228 63. A compound of formula P' according to claim 1 having the name 4(8 )-(methylpropionyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide. 64. A compound of formula I' according to claim 1 having the name [3-(dimethyl-amino)-propionyloxy]-6-phenyl-2(R)-phenylmethyl-hexa--noyl-(L)-Val- (L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt ffierof. A compound of formula I' according to claim 1 having the name [3-(N-Z-N-methyl-amino)-propionyloxy]-6-phenyl-2(R)-phenylmethyl-hexanoyl- (L)-Val-(L)-Phe-morpholin-4-ylamide. 66. A compound of formula I' according to claim 1 having the name 4(S)-(3-methyl-=mino-propionyoxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide, or a pharmuaceutically acceptable salt thereof. 67. A compound of formula I' according to claim 1 having the name 4()[dmtyaiotoy ctlx]6-hnl2R-pfurpnlmty) hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide, or a pharmaceuticaily acceptable salt thereof. 68. A compound of formula I' according to claim 1 having the name o [(2-pyridylmethoxy)-acetyloxy]-6-phenyl-2(R)-(p-fluorophenyl-methyl)-hexanoyl- -Val- (L)-Phe-morpho~in-4-ylamnide, or a pharmaceutically acceptable salt thereof. a 69. A compound of formula I' according to claim 1 having the name 4(8 )-(methoxy-acetyloxy)- 6-phenyl-2(R)-(p-methoxyphenyl-methyl)-hexanoyl-(L)-Val- (L)-(p-CH 3 0-Phe)-morphc~lin-4-ylamide. A compound of formula I' according to claim 1 having the name 4(8 )-(pyridine-2-carboxy)-6-phenyl-2(R)-(p-methoxyphenyl-methyl)-hexanoyl-(L)-Val- (p-CH 3 O-Phe)-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 7 1. A compound of formula P' according to claim 1 having the name 4(S)-(methylthioacetyloxy)-6-phenyl-2(R)-phenylmethyl-hexanioyl-(L)-Val-(L)-Phe- morpholin-4-ylamide. 229 72. A compound of formula F' according to claim 1 having the name 4(S )-(benzylthioacetyloxy)-6-phenyl-2(R)-phenylmethyl-liexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide. 73. A compound of formula F' according to claim 1 having the name 4(S)-((L)-prolyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe-morpholin- 4-ylamide, or a pharmaceutically acceptable salt thereof. 74. A compound of formula P' according to claim 1 having the name 4(S)-((D)-rrolyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl.fL)-Val-(L)-Phe-morpholin- 4-ylamide, or a pharmaceutically acceptable salt thereof. A compound of formula F' according to claim i having the name 4(S )-((L)-(N-Z-prolyl)oxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide. 76. A compound of formula P' according to claim 1 having the name 4(S )-((D)-(N-Z-prolyl)oxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide. 77. A compound of formnula F' according to claim 1 having the name rj(s)-(Boc-amino)- 4(S)-[13-(N-Z-amino)-propionyloxy]-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide. 78. A compound of formula F' according to claim 1 having the name (3-amino-propionyloxy)-6-phenyl-2(R)-phenylmethyl-hexanoyl-(L)-Val-(L)-Phe- morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 79. A compound of formula P' according to claim 1 having the name (3-dimethylamino-propoxy)-acetyloxyI-6-pheny1-2(R)-phenylmethyl-hexaloyl- (L)-Val-(L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. A compound of formula P' according to claim 1 having the name [2-(2-dimethylamino-ethoxy)!,ethoxy-acetyloxy-6-phenyl-2(R)-phelylmethylh hiexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt 230 thereof. 8 1. A compound of formula F' according to claim 1 having the name [(4-dimethylamino-butoxy)-acetyloxy]-6-plhenyl-2(R)-phenylmethyl-hexanoyl- Val- (L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 82. A compound of formula I' according to claim 1 having the name [2-(2-methoxy-ethoxy)-acetyloxy]-6-phenyl-2(R)-(p-methoxy-phenyl)methyl- hexanoyl-(L)-Val -(L)-Phe-morpholin-4-ylamide. 83. A compound of formula I' according to claim 1 having the name 4(S)-(2-picolinoyloxy)-6-phenyl-2(R)-(p-methoxy-phenyl)methyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide. 84. A compound of formula F' according to claim 1 having the name [2-(2-methoxy-ethoxy)ethoxy]-ace tyloxy)}-6-phenyl-2(R)-(p-methoxy-phenyl)- methyl-hexanoyl-(L)-Val-(L)-(p-CH 3 O-Phe;)-morpholin-4-ylamide. A compound of formula I' according to claim 1 having the name 4(S)-(2-picolinoyloxy)-6-phenyl-2(R)-(p-methoxy-phenyl)methyl-hexanoyl-(L)-Val-(L)- (p-CH 3 O-Phe)-morpholin-4-ylamide. 86. A compound of formula P' according to claim 1 having the name 4(S )-(2-benzyloxy)acetyloxy-6-phenyl-2(R)-benzyl-hexanoyl-(L)-Val-(L..)-Phe- morpholin-4-ylamide. 87. A compound of formula F' according to claim 1 having the name (2-acetyloxy)acetyloxy-6-phenyl-2(R)-benzyl-hexaoyl-(L)-Val-(L)-Phe-morpholil- 4-ylamide. 88. A compound of formula P' according to claim 1 having the name [2-(4-tetrahydropyranyloxy )acetyloxy]-6-phenyl-2(R)-benzyl-hexanoyl-(L)-Val- (L)-Phe-morpholi n-4-ylamnide. 89. A compound of formula P' according to claim 1 having the name [2(R)-(4-tetrahydropyranyloxy)]-propionyloxy-6-phenyl-2(R)-beizyl-hexanoyl- 231 Val-(L)-Phe-morpholin-4-ylamide. A compound of formula F' according to claim 1 having the name [2-(2-amino-ethoxy)ethoxy-acetyloxy)]-6-phenyl-2(R)-benzyl-hexanioyl-(L)-Val- (L)-Phe-morpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 9 1. A compound of formula F' according to claim 1 having the name [2-(2-benzyloxycarbonylamino-ethoxy)ethoxy-acetyioxy]-6-phenyl-2(R)-benzyl- hexanoyl-(L)-Val-(L)-Phe-morpholin-4-ylamide. 92. A compound of formula F' according to claim 1 having the name [(methoxycarbonyl-methoxy)-acetyloxy]-6-phenyl-2(R)-benzyl-hexanoyl-(L)-Va- (L)-Phe-rnorpholin-4-ylamide. 93. A compound of formula F' according to claim 1 having the name [(methoxycarbonyl-methylthio)-acetyloxy] -6-phenyl-2(R)-benzyl-hexanoyl-(L)-Val- (L)-Phe-morpholin-4-ylamide. 94. A compound of formula I' according to claim 1 having the name 4(S)-[(methoxycarbonyl-methylsulfo)-acetyloxy-6-phenyl-2(R)-benzyl-hexanoyl-' Val- (L)-Phe-morpholin-4-ylamide. A compound of formula F' according to claim 1 having the name f(pivaloyloxymethoxycarbonyl-methoxy)-acetyloxyl-6-phenyl-2(R)-benzyl- hex anoyl- (L)-Val-(L)-Phe-morpholin-4-ylamide. 96. A compound of formula F' according to claim 1 having the name [(carboxymethoxy)-acetyloxyl-6-phenyl-2(R)-benzyl-hexanl-yl-(L)-Val-(L)-Phe- rnorpholin-4-ylamide, or a pharmaceutically acceptable salt thereof. 97. A compound of formula F' according to claim 1 having the name (S)-(Boc-amino)- [(acetoxymethoxycarbonyl-methoxy)-acetyloxy] -6-phenyl-2(R)-benzyl-hexanoyl- Val- (L)-Phe-morpholin-4-ylamide. 98. A compound of formula F' or a pharmaceutically acceptable salt thereof according to any one of claims 1, 50 and 52 for use in a method for the diagnostic or therapeutic 232 treatment of the human or animal body. 99. The use of a compound of formula I' according to any one of claims 1, 50 and 52, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical composi- tion for the treatment of AIDS. 100. A pharmaceutical composition comprising a compound of formula I' according to any one of claims 1, 50 and 52, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, together with a pharmaceutically acceptable carrier. 101. The use of one of the compounds of formula I' mentioned in claims 1, 50 or 52, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, in the treatment of retroviral diseases. S102. The use of one of the compounds of formula I' mentioned in claims 1, 50 or 52, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, in the treatment of AIDS. 103. A method of treating warm-blooded animals suffering from retroviral diseases, wherein a compound of formula I' according to any one of claims 1, 50 or 52, or a pharmaceutically acceptable silt thereof, is administered in a dose effective in the treatment of retroviral diseases to a warm-blooded animal requiring such treatment. 104. A method of treating warm-blooded animals suffering from AIDS, wherein a 0. compound of formula I' according to any one of claims 1, 50 or 52, or a pharmaceutically acceptable salt thereof, is administered in a dose effective in the treatment of AIDS to a warm-blooded animal requiring such treatment. 105. A pharmaceutical composition suitable for administration to a warm-blooded animal for the treatment or prevention of a retroviral disease responsive to the inhibition of retro- viral aspartate proteases, comprising an antiretrovirally effective amount of a compound of formula I' according to any one of claims 1, 50 and 52, or a salt thereof 'here salt- forming groups are present, and a pharmaceutically acceptable carrier. 106. A process for the preparation of a compound of formula I' according to claim 1, -233- wherein a) for the preparation of a compound of formula 1- R .A R A 2 R wherein R 1 has the meanings given for R 1 in compounds of formula I' with the exception of hydrogen, the hydroxy group present at the carbon atom adjacent to the carbon atom carrying the radical R 2 -CH 2 is in free or protected form and the remaining radicals are as defined for compounds of formula an acid of formula r o D D D n RI'-OH or a reactive acid derivative thereof, wherein R 1 has the meanings given for R 1 in compounds of formula I' with the exception of hydrogen, is condensed with an amino compound c 'formula H N. H-B 1 (III'), oc o or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula free functional groups in the starting materials of formulae II and III', with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or b) for the preparation of a compound of formula 234 H R i N. BN /R4 wherein B 1 may be the same residues as B] in compounds of formula I' but may not be a bond, the hydroxy group present at the carbon atom adjacent to the carbon atom carrying the radical R 2 -CH 2 is in free or protected form and the remaining radicals are as defined for compounds of formula a carboxylic acid of formula R 1 -BI'-OH (IV), or a reactive acid derivative thereof, wherein R 1 is as defined for compounds of formula I' and B 1 is as last defined, is condensed with an amino compound of formula Co CC. N R4 N.f or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula free functional groups in the starting materials of formulae IV and with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or c) a carboxylic acid of formula R 1 \N B 1 or a reactive derivative thereof, wherein the radicals are as defined for compounds of -235- formula is condensed with an amino compound of formula Al N, R4 A, 4 (VII), 2 or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula free functional groups in the starting materials of formulae VI' and VII, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or d) for the preparation of a compound of formula e o o H \N B 1 R I wherein A 1 and A 2 are as defined for A 1 and A 2 in compounds of formula but A 1 is not a bond and the peptide bond between and A 2 is not in reduced form, the hydroxy group present at the carbon atom adjacent to the carbon atom carrying the radical R 2 -CH 2 is in free or protected form and the remaining radicals are as defined for compounds of formula a carboxylic acid of formula R3 H O o BR2 R2 (VIII'), -I -236- or a reactive derivative thereof, wherein the radicals are as last defined, is condensed with an amino compound of formula H N R4 (IX), or with a reactive derivative thereof, wherein the radicals are as last defined, free functional groups in the starting materials of formulae VIII' and IX, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or e) a carboxylic acid of formula D \N B 1 A, AOH or a reactive derivative thereof, wherein the radicals are as defined for compounds of formula is condensed with an amino compound of formula R4 H R 5 (XI), or with a reactive derivative thereof, wherein the radicals are as defined for compounds of formula free functional groups in the starting materials of formulae X' and XI, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are. removed, or -237- f) in a compound of formula I' wherein the substituents are as defined above with the proviso that in the compound of formula I' in question at least one functional group is protected by protecting groups, the protecting groups are removed, or g) a compound of formula I R, N B 1 A N.R A wherein the radicals are as defined for compounds of formula is reacted with a carboxylic acid of formula XXV e e r r r oe o ~o T-OH (XXV), wherein T is as defined for compounds of formula or with a reactive acid derivative thereof, free functional groups in the starting materials of formulae XXV and I, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, or h) for the preparation of a compound of formula I' wherein T is a radical of formula Z wherein Rz is lower alkyl substituted by etherified or esterified hydroxy or mercapto, by unsubstituted or substituted amino or by heterocyclyi bonded via nitrogen, and the remaining radicals are as defined for compounds of formula a compound of formula W, (C mH 2 m) H 0N RI, N B1 N R4 "A' 2 R (XXVI) wherein W 1 is a leaving group, -(CmH 2 is a lower alkylene radical (m is from 1 to 7) -238- and the remaining radicals are as defined for compounds of formula is reacted with a compound of formula L-H (XXVII), wherein L is etherified or esterified hydroxy or mercapto, unsubstituted or substituted amino, or heterocyclyl bonded via nitrogen, or with a reactive derivative thereof, free functional groups in the starting materials of formulae XXVI and XXVII, with the exception of those participating in the reaction, being if necessary in protected form, and, if desired, any protecting groups present are removed, and/or, if desired, a compound of formula I' obtainable in accordance with any one of the above processes a) to h) having at least one salt-forming group is converted into its salt S and/or an obtainable salt is converted into the free compound or into a different salt and/or isomeric mixtures of compounds of formula I' which may be obtainable are separated and/or a compound of formula I' according to the invention is converted into a different Scompound of formula I' according to the invention. 107. A compound having the name Boc-Phe[C](o-CN)Phe-(L)-Val-(L)-Phe-morpholin- 4-ylamide. 108. A compound having the name Boc-Phe[C](m-CN)Phe-(L)-Val-(L)-Phe-morpho- S: lin-4-ylamide. 109. A compound having the name Boc-Phe[C](p-BzlO)Phe-(L)-Val-(L)-Phe-morpho- lin-4-ylamide. o 110. A compound having the name Boc-Phe[C](p-BzlO)Phe-(L)-Val-(L)-(p-BzlOPhe)- morpholin-4-ylamide. 111. A compound having the name Boc-(p-BzlO)Phe[C]Phe-(L)-Val-(L)-Phe-morpho- lin-4-ylamide. 112. A compound having the name Boc-(p-BzlO)Phe[C]Phe-(L)-Val-(L)-(p-BzlOPhe)- morpholin-4-ylamide. -239- 113. A compound having the name Boc-(p-BzlO)Phe[C](p-BzlQ)Phe-(L)-Val-(L)-Phe- morpholin-4-ylamide. 114. A compound having the name Boc-(p-Bz1O)Phe[G](p-Bz1O)Phe-(L)-Va-(L)- (p-BzIOPhe)-morpholin-4-ylamide. 115. A compound having the name Boc-Phe[C](o-F)Phe-(L)-Val-(L)-Phe-morpho- lin-4-ylamide. 116. A compound having the name Boc-Phe[C](o-F)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)- morpholin-4-ylamide. 117. A compound having the name Boc-Phe[C](m-F)Phe-(L)-Va1-(L14Phe-morpho- lin-4-ylamide. 118. A compound having the name Boc-Phe[C](m-F)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)- morpholin-4-ylamide. 119. A compound having the name Boc-Phe[C]Phe-(L)- Val-(L)-Leu-morpholin-4-ylamide. 120. A compound having the name Boc-Phe[C]Phe-(L)-VaI- (L)-Ala-morpholin-4-ylamide. 121. A compound having the name Boc-(p-CH 3 O)Phe[C](p-BziO)Phe-(L)-Val-(L)-Phe- morpholin-4-ylamide. 122. A compound having the name Boc-(p-GH 3 O)Phe[C](p-Bz1O)Phe-(L)-Val-(L)- (p-CH 3 O-Phe)-morpholin-4-ylamide. 123. A compound having the name Boc-(p-CH 3 O)Phe[C](p-Bz1O)Phe-(L)-Va1-(L.}Tyr- morpholin-4-ylamide. 124. A compound having the name Boc-(p-CH 3 O)Phe- -C](3-CH 3 O)Phe-(L)-Va-(L)-Phe-morpholin-4-ylamide. 1 RA41 0> 240 125. A compound having the name Boc-(p-CH 3 O)Phe[C](2-CH 3 O)Phe-(L)-Val-(L)-Phe- morpholin-4-ylamide. 126. A compound having the name Boc-Phe[C](3-CH 3 O)- Phe-(L)-Val-(L)-Phe-morpholin-4-ylarnide. 127. A compound having the name Boc-Phe[G](2-CH 3 O)- Phe-(L)-VaI-(L)-Phie-r'-orpholin-4-ylamide. 128. A compound having the name Boc-Phe[C](3-CH 3 O)- Phe-(L)-Va1-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide. 129. A compound having the name Boc-Phe[C](2-CH 3 O)- Phe-(L)-Val-(L)-(p .1- 3 0-Phe)-morpholin-4-ylamide. 130. A compound having the name Boc-Phe[CI@p-BzlO)Phe-(L)-Val-(L)-(p-CH 3 O-Phe)- morpholin-4-ylamide. 13 1. A compound having the name Boc-(p-CH 3 O)Phe[C]- Phe-(L)-VaI-(L)-Phe-morpholin-4-ylamide. 132. A compound having the name Boc-(p-CH 3 O)Phe[C](p-CH 3 O)Phe-(L)-V7a1-(L)-Phe- morpholin-4-ylamide. 133. A compound having the name Boc-(p-CH 3 Q)Phe[C]- Tyr-(L)-Val-(L)-Phe-morpholin-4-ylamide. 134. A compound having the name Boc-(p-CFI 3 O)Phe[C]- Phe-(L)-Val-(L)-(p-CH 3 O-Phe)-morpholin-4-ylamide. 135. A compound having the name Boc-(p-CH 3 Q)Phe[C)- Phe-(L)-Val-(L)-Tyr-morpholin,-4-ylamide. 136. A compound having the name Boc-(p-CH 3 O)Phe[C](p-CH 3 O)Phe-(L)-Val-(L)- 4 ~p-CH-Phe)-morphoin-4-ylamide. Ri4 0 P:\WPDOCS\GRS\499420.AMD 26/2/97 -241 137. A compound having the name Boc-(p-CH30)Phe[C](p-CH 3 0)Phe-(L)-Val-(L)- Tyr-morpholin-4-ylamide. 138. A compound having the name Boc-(p-CH30)Phe[C]-Tyr-(L)-Val-(L)-(p-CH 3 0- Phe)-morpholin-4-ylamide. 139. A compound having the name morpholin-4-ylamide. 140. A compound having the name morpholin-4-ylamide. 141. A compound having the name 4 morpholin-4-ylamide. 142. A pharmaceutical composition comprising a compound of formula I according to claim 140 or 141, or a pharmaceutically acceptable salt of such a compound having at least one salt-forming group, together with a pharmaceutically acceptable carrier. S: 20 143. A method of treating warm-blooded animals suffering from retroviral diseases, wherein a compound of formula I according to claim 140 or 141, or a pharmaceutically acceptable salt thereof, is administered in a does effective in the treatment of retroviral diseases to a warm-blooded animal requiring such treatment. a. 144. A method of treating warm-blooded animals suffering from AIDS, wherein a compound of formula I according to claim 140 or 141, or a pharmaceutically acceptable salt thereof where salt-forming groups are present, is administered in a dose effective in the treatment of AIDS to a warm-blooded animal requiring such treatment. l 5 ^r g P':\WPlDOCS\;RS\499420.AMD -26/2/97 242 145. A pharmaceutical composition suitable for administration to a warm-blooded animal for the treatment or prevention of a retroviral disease responsive to the inhibition of retroviral aspartate proteases, comprising an antiretrovirally effective amount of a compound of formula I according to claim 140 or 141, or a salt thereof where salt-forming groups are present, and a pharmaceutically acceptable carrier. DATED this 27th day of February, 1997. CIBA-GEIGY AG By Its Patent Attorneys D 15 DAVIES COLLISON CAVE qa..* o0 *9 9 0: 1~ IIWI 4-1.9 82/A Abstract Acvloxvhexanoic Acid Derivatives 0* C. C Compounds of formula I' T N T R4 1 o R, wherein T is an acyl radical of formula Z R z O O0---C C wherein Rz is unsubstituted or substituted hydrocarbyl wherein at least one carbon atom has been replaced by a hetero atom with the proviso that a hetero atom is not bonded directly to the carbonyl to which the radical Rz is bonded, alkyl having two or more carbon atoms, lower alkenyl, lower alkynyl, aryl or unsubstituted or substituted amino, and wherein the radicals R 1 B R 2 R 3 A 1 A 2 and NR 4 R 5 are as defined in the description, and precursors thereof, are described. The compounds have pharmaceutical activity, for example in the treatment of AIDS.