AU622014B2 - Renin-inhibiting dipeptides, a process for their preparation, agents containing them and their use - Google Patents

Description

F Form CftWZOrf'WALT-HaF AUSTRAUiA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Ciass Int. Class Application N~,sber: Lodged: Cornomplete Specification Lodged: a 0 Accepted: 00000 &00 00 0 0 o 000 00 00 0 0 0 0 0 00 0' C 0000 P~ublished: Priority: Related Art o 1) 00 00Q Name of Applicant: "1.,00 01) 0 ocoo Address of Applicant 0000 Actual Inventor 00 0 o 0C0 o 0 0 Address for Service HOECHST AKTI ENGESELLSCHAFT D-6230 Frankfurt arn Main 80, Federal Republi~C of Germany.

ADALBERT WAGNER, T-ANSJORG URBACH, DIETER RUPPERT, WOLFGANG LINZ and BERNWARD SCHOLKENS WATERMARK PATENT Tf2 'DEMARK ATTORNEYS.

LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA Complete Specification for the Invention entitled: REN2IN-I NHTBITING DIPEPTIDES, A PROCESS FOR THEIR PREPARATION, AGENTS CONTAINING THEN AND THEIR USE.

The following stat~nt is a full description of this Invention, Including the best method of performing It known to -us HOECHST AKTIENGESELLSCHAFT HOE 89/F 129 Dr.!MY/gm Description Renin-inhibiting dipeptides, a process f or their preparation, agents containing them and their use Di- and tripeptid'a derivatives and their use as renin inhibitors are known from EP-A-152,255, EP-A-15-5,809, EP-A-163,237, EP-A-1'721346, '.P-A-172,347, EP-A-1791352 EP-A-255,082.

Novel pentide derivatives have now been found which highly effectively inhibit the enzyme renin in vitro and in vivo.

00 00 0 0 0 a cO The invention relates to compounds of the formula I 0 0 000 0

OHR

Rl- A- B-HN- CH- CH- CH- R 00000 in which 00015 R1 denotes a radical of the formula II 0o where W stands for -SO 2 -or-IC- 0400 and R' denotes hydrogen, IC3.-Cl)-alkyl which is op'lionally monounsaturated or diunsaturated and which is optionally substituted by up to 3 identical or different radicals from the series comprising o 0d hydroxyl, (Cl-C 7 -alkoxy, (C 1

-C

7 -alkanoyloxy, carboxyl, (Cl-C 7 )-aJlkoxycarbonyl, halogen, amino, (Cl-

C

7 -alkylamino, di- (C 1

-C

7 -alkylamino, (C 1

,-C

5 -alkoxycarbonylamino, (C 7

-C

15 -aralkoxycarbonylamino and 9-fluorenylmethyloxycarbonylamino,

(C

3

-C

8 -CYC owhich is optionally substituted by one or two identical or, different radicals from the series comprising Cl, Br, 1, hydroxyl, (C.-C 7 )-alkoxy,

(C

1

-C

7 -alkyl, (C 1

-C

7 -alkoxycarbonyl, amino, anilino, optionally substituted by up to 2 halogens and trifluoromethyl, (C6-C 14 -aryl- -alkyl, where

.I

-2 0 0 000000 0 0 00 0 0 0 00 000 i0 00 1 0 o 1 6 00 oo 4 0 000* 000000 o0000 0 00a 0o 0 0000 O000 the aryl moiety .s optionally substituted b~y one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cl-CA)-alkoxy, (Cl-CA)-alkyl, (C 1

-C

7 -alkoxycarbonyl, amino, (Cl-C 7 alkylamino, di- (Cl-C 7 -alkyl amino, carboxyl, carboxymethoxy, aminu- (Cl-C 7 )-alkyl, (Cl-C 7 -alkylamino- (C 1

C

7 )-alkyl, di- 1 -C7) -alkyl amino- (CI-C 7 -alkyl, (Cl-

C

7 )-alkoxyciarbonylmethoxy, carbamoyl, sulfamoyl, (Ci-

C

7 )-alkoxysulfonyl, sulfo and guanidinomethyl, or stands for the radical of a 5- or 6-inenbered monocyclic or 9- or lO-membered bicyclic heterocycle having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom in addition as ring members, which is optionally disubztituted or trisubstituted by one or more radicals from the series comprising F, Cl, Br, hydroxyl, (C 1

-C

7 alkoxy-, (Cl-CA)-alkyl, (C, 2 -alkoxyc arbonyl, amino or trifluoromethyl, R4~ denotes a radical of the formula III A denotes a radical linked to R 1 at the N terminus and to B at the C terminus of an amino acid from the series comprising phen3"lalanine, histidine, tyrosine, tryptophan, methilonine, leucine, isoleucine, asparagine, aspartic acid, ,p-2-thienylalanine, p- 3-thienylalanine, p-2-fu-,anylalanine, p-3-furanylalanine, lysine, ornithine, valine, alanine, 2,4diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2pyridylalanine, 3-pyridylalanine, 4 -pyridylalanine, cyclohexylalanine, cyclohexylglycinelim-rmethylhistidine, 0-methyltyrosine, O-benzyltyrosine, 0-tert. buty-Ityrosine, phenylglycine, 1-naphthylalanine, 2naphthylal.anine, 4-nitrophenylalanine, norvaline, pi- 2 -benz-o1%b) thienylalanine, fi-3-benzo thienylalanine, 2-f "luorophenylalanine, 3-f luorophenylalanine, 4-flIuorophenylalanine, norlencine, cysteine, Smethylcysteine, 1,2,3, 4-tetrahydroisoayinoline-3carboxylic acid, homophenylalanine, DOPA, 0 0 4

A

~4 -3- O-diraethyldopa, 2-aniino-4- (2-thienyl )butyric acid, 2-amino-4-( 3-thienyl)butyric acid, 3-(2-thienyl) serine, (Z )-dehydrophenylalanine and -dehydrophenylalanine, B denotes a radical of an amino acid, as def ined under

A,

RI denotes hydrogen, (Cl-Cl 0 -alkyl, (C 4

-C

7 -cycloalkyl,

(C

4

-C

7 -cycloalkyl- (C 1

-C

4 -alkyl, (C6-C 14 -aryl or (C 8 R3 denotes hydrogen, (Cl-C 10 -alkyl (C6-C 1 4 -aryl or

C

14 -aryl- (Cl-C 4 -alkyl, X can either be absent or denotes 0 or S, n can be 2, 3 or 4 and R 7 denotes hydroxyl or amino or stands f or the radical 15 of a 5-membered heterocycle having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom, which is optionally substituted by one or more radicals from the series comprising F, Cl,, Br, hydroxyl, (Cl-C 7 -alkoxy, (Cl-C 7 -alkyl (C 2

-C

8 20 alkoxycarbonyl, amino or trifluoroniethyl, where oxazoline, is excluded, and their physiologically tolerable salts.

0 0 0'r .00 0 0 00 0 0 00 0) 00 D 0

Z)

0 0)0 0000 0 0 00000 00 00 00 0 0 0 25 0 OD The carbon atoms substituted by R 2 hydroxyl and R 3 can in each case have the R, S or RS configuration.

Alkyl can be straight-chain or branched. The same applies to radicals derived therefrom,, such as, for example, alkoxy, alkylthior alkylamino, dialkylamino, alkanoyl and aralkyl.

Cycloalkyl is also understood as meaning alkyl- U 5UDL)S!.vUteu r~ cyclohexyl or

(C

8

-C,

4 -Aryl i yl or f luoreny radicals derii oxy, aroyl, ar 2, 3-dimethylcyclopentyl.

s, for example, phenyl, naphthyl, biphenylphenyl is preferred. The same applies to Ted therefrom, such as, for example, arylalkyl and aralkyloxy. Aralkyl is understood U r I;4.

4 as meaning an unsubstituted or substituted (C 6 -C4) -aryl radical linked to (Ci-C) -alkyl, such as, for example, benzyl, a- and p-naphthylmethyl, halobenzyl and alkoxybenzyl, but where aralkyl need not be limited to the compounds mentioned.

0 00aoI 10 0 r 0 0 0 C 0 0 00 00 00 40 0 0

O

Soo2 a C 20

I

I ct 10'Q A radical of a 5- or 6-membered monocyclic or 9- or membered bicyclic heterocycle having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members and standing for R a is understood as meaning heterocycles such as are defined, for example, in Katritzky and Lagowski, Chemie der Heterocyclen [Heterocyclic Chemistry], Berlin, Heidelberg 1968, pages 3-5, Monocyclic heterocycles are, for example, thiophene, furan, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-triazole, thiazole, tetrazole, isothiazole, oxazole and isoxazole and the completely or partially hydrogenated heterocycles derived therefrom. Bicyclic heterocycles are, for example, benzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline and cinnoline and the completely or partially hydrogenated heterocycles derived therefrom.

A radical of a 5-membered heterocycle having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom standing for R 7 is understood as meaning, in particular, thiophene, furan, pyrrole, imidazole, pyrazole, 1,2,4-triazole, thiazole, tetrazole, isothiazole, oxazole, isoxazole and completely or partially hydrogenated cycles derived therefrcm, where oxazoline is excluded.

The amino acids A anrd B in formula I are linked to one another by an amide bond, and they are natural or unnatural a-amino acids of the L, D or D,L configuration, preferably the L configuration.

Salts of compounds of the formula I are understood as meaning, in particular, pharmaceutically utilizable or I non-toxic salts.

Such Lalts are formed, for example, by compounds of the formula I which contain acidic groups, for example carboxyl, with alkali metals or alkaline earth metals, such as Na, K, Mg and Ca, and with physiologically tolerable organic amines, such as, for example, tr~iethylamine and tri- (2-hydroxyethvll) amine.

Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, form, salts with inorganic acids, such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid and with organic carboxylic or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acici, fumaric acid, tartaric acid and p-toluenesulfonic acid.

R1 preferably denotes -alkanoyl, such as t 9 6 9n-decanoyl, formyl, acetyl, pivaloyl, isovaleryl or isobutyryl; substituted (C-~-alkanoyl, such as 2hydroxypropior~yJ., 2 -hydroxy- 3 -nethylbutyryl or optionally protocted amino- (C 2

-C

1 1 -alkanoyl such as 4-aminobutyryl, 5-aminopentanoyl, 6-aminohe.xanoyl, 4-N-tert butoxycarbonylaminobutyryl, 5-N-tert butoxycarbonyla.minopentanoyl or 6-N-tert. -butoxycarbonylaminohexanoyl or di- (Cl-C 7 -alkylainino- (C 2

-C

11 alkanoyl, such as dimethylaminoacetyl; (C 4 -Cq) cycloaJlkylcarbonyl, such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl; (C6-C 10 -aryl- (C 2

-C

11 -alkanoyl, such as phenylacetyl, phenylpropanoyl or phenylbutanoyl, 2- 6-dichioroanilino) -phenylacet-yl, 2- (N-benzyl-2 ,6dichioroanilino) -phenylacetyl; benzoy. optionally subst.Atuted by halogen, (Cl-C 7 -alkyl, (Cl-C 7 -alkoxy or (C-C 7 )-alkoxycarbonyl, such as 4-chlorobenzoyl,

L

4-methylbenzoyl, 2-methoxycarbonylbenzoyl or 4methoxybenzoyl, pyrrolyl-2-carbonyl, pyridyl-3carbonyl, benzylsulfonyl; (C 2 -Cll) -alicoxycarbonyl, k141 such as methoxycarboil ethoxycarbonyl or tert butoxycarbonyl; (C 2

-C

11 -alkoxycarbonyl substituted by halogen, such as 2,2,2-trichioroethoxycarbonyl 1, l-dimethyl-2, 2, 2-trichioroethoxycarboniyl; or

C

14 )-aryl-(C 2

-C

7 )-alkoxycarbonyl, such as benzyloxycarbonyl or 9-fluorenylmethylcarbonyl.

R

2 is preferably isobutyl, benzyl or cyclohexylmethyl.

R

3 is preferably hydrogen, isopropyl or isobutyl.

Preferred amino acids A and B independently of one 000000l1 another are phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, 00 aspartic acid, p-2-thienylalanine, p-3-thienylalanine, A- 0 Q Q2-fury'Lalanine, lysine, ornithine, 2,4-diaminobutyric 0 1 acid, arginine, norvaline, 4-chiorophenylalanine, methioa 0 15 nine sulfone, methionine sulf oxide, 2-pyridylalanine, 3pyridylalanine, 4-pyridylalanine, cyclohexylalanine, cyciohexylglycine, im-methyihistidine, O-methyltyrosine, O-benzyltyrosine, 0-tert. -butyltyrosine, phenyiglycine,A 0000 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylala-.

00 20 nine, norleucine, valine, alanine, 1,2,3,4.-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, 2-amino- 00- 00 0 4-(2-thienyl)butyric acid, (Z)-dehydrophenylalanine or -dehydrophenylalanine.

0000% Sis referbly absent.

0 5 n preferably denotes 2 or 3, preferably 2.

R

7 preferably stands for the radical of a heterocycle having one or two heteroatoms, which is optionally substituted by (CI-CA)-alkyl.

R 7 particularly pretferably stands for 2-.imidazolyl, 2-Nmethylimidazolyl, 2-N-ethylimidazolyl, 2-N-n-propylimidazoJlyl and 2-N-isopropylimidazolyl.

The invention furthermore relates to a process for the preparation of compounds of the formula I which comprises coupling a fragment Jhaving a terminal carboxyl group or its reactive derivative to a corresponding fragment pA -7having a f ree amino group, if appropriate removing (a) protective group(s) temporarily7 introduced for the protection of further functional groups and optionally converting the compound thus obtained into its physiologically tolera-ble salt.

Fragments of a compound oi the formula I having a termrinal carboxyl group have the formulae IVa-IVc below: R'-OH (IVa) 000000 a R'-A-OH (IVb) 000 000 ~s0 00 0 0. 10 R--A-B-OH (IVc) 00 0 00 a 0 0 a000~ Fragments of a compound of the formula I having a ter- 0"0 minal amino group have the formulae Va-Vc below: ~00 0 2 3H~

H

2 4 (Va) 0 0R H 00 R HV 12 f3 0 15 H N- CH- CH-eCM R 4

VC

I Methods which are sultable for the preparation of an amide bond are described, for example, in Houben-Wyl, xf.thoden der organischen Chemie (Methods of organic Chemistry], Volume 15/2; Bodanszky et al., Peptide synthesis, 2nd ed. (WLJ~ay Sons, New York 1976) or Gross, Mejenhofer, T?,e Peptides. Analysis, synthesis, biology (Academic Press, New York 1979). The following methods are preferably used.- tht: active ester miethod using N-hydroxylsuccinimide as the ester component, coupling with a carbodilmide such as dicyclohexylcarbodiimide or with propanephosphonic anhydride and the mixed anhydride method using pivaloyl chloride.

8 -8- The preparation of the optically active amines used as a starting ompound, of the formula Vc R2 R3 I I 4 (Vc)

H

2

N-CH-CH-CH-R

OH

wherein R 2

R

3 and R 4 are as defined above, is carried out starting from optically active a-amino acids, their asymmetric center being retained. For this purpose, an N- ,.BOQ protected amino acid aldehyde is prepared in a known Smanner and converted into a corresponding heteroarylalkyl 1 building block after an aldol addition. After removal of 1 "o 10 the N-protective group, aminoalcohols of the formula Vc Q 0OO OO are obtained. Mixtures of diastereomers relative to the 0 Cn OH-carrying center are obtained, which are separated in a manner known per se, for example by fractional crystallization or by chromatography. Checking of the diastereomeric purity is carried out by means of HPLC, and the checking of the enantiomeric purity can be carried.

o000 out in a known manner by converting into Mosher oo 0 derivatives Mosher et al., J. Org. Chem. 34, 2543 0U Q (1969)).

The preparation of N-protected amino acid aldehydes ia op0 0 carried out according to B. Castro et al. (Synchesis 0oo o 1983, 676).

The aldol-analogous addition to N-protected amino acid aldehydes (preferably N-tert.-butoxycarbonyl and benzyloxycarbonyl protective groups) is carried oL in a solvent inert to bases, such as ether, THF, toluene, DMF, DMSO or dimethoxyethana.

Bases which ca be used for the deprotonation of the heteroarylalkyl component are alkali metal alcoholates, such as potassium o-tert.-butylate or sodium methylate, alkali metal hydrides, such as sodium hydride or potassium hydride, organometallic bases, such as n-butyl-

Y

.4 B~ a t a a0 a~ a a a0 a 0 Oti a3 a aoa -a aqa aso a at aao 'a a a a 1

C

lithium, s-butyllithium, methyllithium or phenyllithium, sodium amide and alkali metal salts of organic nitrogen bases, such as lithium diisopropylamide.

The substituted 4-amino-3-hydroxybutyric acids are known from the literature and are prepared according to D.H. Rich et al., J. Org. Chem. 43, 3624 (1978).

The preliminary and subsequent operations necessary for the preparation of compounds of the formula I such as introduction and removal of protective groups are known from the literature and are described, for example, in T.W. Greene, "Protective Groups in Organic Synthesis".

Salts of compounds of the formula I containing saltforming groups are prepared in a manner known per se by reacting, for example, a compound of the formula I containing a basic group with a stoichiometric amount of a suitable acid. Mixtures of stereoisomers, in particular mixtures of diastereomers which are obtained using racemic amino acids A or B can be separated by fractional crystallization or by chromatography in a manner known per se.

The compounds of the formula I according to the invention exhibit enzyme-inhibitng properties; in particular, they inhibit the action of the natural enzyme renin. Renin is a proteolytic enzyme of the aspartyl pr;tease class which, as a result of various stimuli (volume depletion, sodium deficiency, p-receptor stimulation), is secreted into the blood circulation by the juxtlaglomerular cells of the kidney. There, it cleaves the decapeptide angiotensin 1 from the angiotensinogen secreted from the liver. This angiotensin 1 is converted by the "angiotensin converting enzyme" (ACE) into angiotensin 2.

Angiotensin 2 plays an essential role in blood pressure regulation, since it directly increases the blood pressure by vascular contraction. It additionally stimulates the secretion of aldosterone from the adrenal gland and increases the extracellular fluid volume in this manner 10 via the inhibition of sodium excretion, which in turn contributes to an increase in blood pressure. Inhibitors of the enzymatic activity of renin cause a reduced formation of angiotensin 1 which results in a reduced formation of angiotensin 2. The lowering of the concentration of this active peptide hormone is the direct cause of the hypotensive action of renia inhibitors.

The activity of renin inhibitors can be checked by in vitro tests. The reduction in the formation of angioten- 310 sin 1 in various sytems (human plasma, porcine renin) is °o 0 measured in this connection. For this purpose, for coooo0 example, human plasma which contains both renin and 0 0 0o° angiotensinogen is incubated at 37 C with the compound to a o n0 oa oo be tested. The concentration of the angiotensin 1 formed 0 "15 during the incubation is then measured using a radio- 0 001 Qoo o immunoassay. The compounds of the general formula I described in the present invention show inhibitory effects at concentrations of about 10-5 to 10 1 mol/1 in 0 the in vitro tests used.

0 0 0000 oo 20 Renin inhibitors cause a lowering of blood pressure in o0 salt-depleted animals. Since human renin differs fzr. ,he 0"00 renin of other species, primates (marmosets, rhesus monkeys) are used to test renin inhibitors in vivo.

1 s Primate renin and human renin are substantially homoloo °25 gous in their sequence. An endogenous effusion of renin o0 is initiated by i.v. injection of furosemide. The test Scompounds are then administered by continuous infusion and their effect on blood pressure and heart rate is measured. The compounds of the present invention are effective here in a dose range from about 0.1-5 mg/kg i.v. The compounds of the general formula I described in the present invention can be used as antihypertensives and also for the treatment of cardiac insufficiency, The invention therefore also relates to the use of compounds of the formula I as pharmaceuticals and to pharmaceutical preparations which contain this compound.

11 Use in primates is preferred, in particular in humans.

Pharmaceutical preparations contain an effective amount of the active compound of the formula I together with an inorganic or organic pharmaceutically utiliz le excipient. Administration can take place ir ranasally, intravenously, subcutaneously or perorally. The dose of the active compound depends on the warm-blooded species, body weight, age and the manner of administration.

The pharmaceutical preparations of the present invention 4,o 10 are prepared in a dissolving, mixing, granulating or tablet coating process known per se.

O° For a form for oral administration, the active compounds 0 are mixed with the additives customary therefor such as r 4 5excipients, stabilizers or inert diluents and brought into a suitable form for administration, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily sola-.

oooo tions by customary methods. Inert excipients which can be o 0 used are, for example, gum arabic, magnesia, magnsium 00 a carbonate, potassium phosphate, lactose, glucose, ae magnesium stearyl fumarate or starch, in particular corn starch. Preparation can be carried out both as dry or movt granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower i 25 oil and cod liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable salts are brought into solution, suspensions or alsions, if desired with the substances Custo.ary therefor such as solubilizers, emulsifiers or other auxiliaries. Possible solvents, for example, are: water, physiological saline solutions or alcohols, for example ethanol, propanediol or glycerol, and in additioil also sugar solutions such as glucose or mannitol solutions, or even a mixture of the various solvents mentiod.

Ac

ACHPA

0444aa44 a a 4 11~e

BCC

TLC

DCC

DNP

DMF

DMSO

EA

Etoc

FAB

H

HOBt Iva

M

MeOll

MS

20 MTE R.pT Thi

THF

25 Z -12 List of the abbreviations used: Acetyl 3S, 4 S -4 -Amino- 3-hydroxy-5 -cyc lohexylpentanoic acid tert Butoxycarbonyl Thin layer chromatography Dicyc lohexylcarbodiiinide 2, 4-Dinitrophenyl Dimethyl farmamide Dimethyl o;ulf oxide Ethyl acetate EthoxKycarbonyl Fast atom bombardment Hexane l-Hydroxybenzotriazole Isovaleryl Molecular pea~k 1" ethano 1 Mass spectrum Methyl tert.-butyl ether Room temperature Melting point fi-2 -Thienylalanine Tetrahydro furan Benzyloxycarbonyl 44.4 0 4 4440 4040 4 44 44 444 4444 44 4~ C The other abbreviation~s used for amino acida correspond to the three-letter =ode customary in peptidei chemistry as is described, for example, in Europ. J. Biochem. 138, 9-37 (1984) i If not expressly stated otherwise,. the amino acids are always in the L-configuration.

The examples below serve to ill,ustrate the present invention, without limiting it thereto.

1, 13 Example 1 Iva-Phe-His-1 ()ii -cyclohexylmethyl-2 -hydroxi 2imidazolyl) -pentylamide mg of Iva--Phe-Fiis-(S)-cyclohexylmethyl-2(S)-hydroxy- 5-(2-N-benzyloxymethyl-imidazolyl)-pentylamide are dissolved in 15 ml of ethanol. After addition of 35 mg of strength palladium on active carbon and 1.5 ml of glacial acetic acid, the mixture is hydrogenated at room temperature and normal prcsisure for 20 h. After filtering, it is concentrated. After addition of 20 ml of saturated NaHCO 3 solution, the mixture is extracted 3 000 a1 tires using EA. After drying the EA phases with Na 2 S0 4 0 they are concentrated, the title compound being obtained 0 Gas a faintly yellow iubstance.

O 0 .015 Rf (EA/MeOH 2/1) 0.1, MS(FAB) 634 (M+1) a) Iva- Phe-His-l S -cyclohexylmethyl-2 (S)-hydroxy-5-(2 N-benzyloxymethyl-imidazolyl) -pentylamide.

0000 0 0 0000 0000 0 0 0 00 a 20 000a 0a00 0I 00 064 a O t tC~ 00 200 mg of Iva-Phe-His(DNP) )-cyclohexylmethyl-2 hydroxy 2-N-J nzyloxymethyl-imidazolyl) antylami.de are stirred at room temperature for 3 h in 5 ml of acetonitrile containing 0.5 ml of thiophenol. The mixture is concentrated in vacuo and digested 3 times using diisopropyl ether. After chromatography on silica gel .eluent EA/methanol 10:1) and concentration of the product-containing fractions, a colorless powder is obtained.

Rf (EA/MeOH 10/1) 0.2 MS(FAB) 754 (M+I) b) Iva-Phe-His (DNP) -cyclohexylmethyl-2 -hydroxy- 5-(2-N-benzyloxymethylimidazolyl)-pentylamide.

44 jil of pivaloyl Chloride are added it -5 0 C to 192 mg of Iva-Phe-His(DNP)-OH1, 30 p of pyridine and 50 ul of N-ethylpiperidine in 10 ml of CH 2 Cl. The mixtuv:e Is stirred at +5 to +10 0 C for 30 min, cooled to -10"C 14nd 1(S)-cyclohexylmethyl-2(S)-hydroxy-5- (2-N-bqnzyloxy- 14 methyl-imidazolyl)-pentylamine in 5 ml of CK 2 Clz is added dropwise. The mixture is stirred for 16 h without cooling, concentrated in vacuo and taken up in, 100 ml of EA.

The solution is extracted 3 times using aqueous KCO 3 solution, once using H 2 0, dried over Na 2

SO

4 and concentrated in vacuo. After chromatography on silica gel (eluent EA/methanol 10:1), the title compound is obtained as a faintly yellowish powder.

R, (EA/methanol 10/1) 0.4 MS(FAB) 920 (M+1) c) 1(S)-Cyclohexylmethyl-2 )-hydroxy-5-[2-N-benzyloxy- 0 o o methyl-imidazolyl]-pentylamine.

000 )00 0 a3 o0 500 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[3- 0o (2-N"benzyloxymethyl-iiidazolyl)-propyl ]-oxazolidine are 0" dissolved in 15 ml of dioxane. 10 ml of 12% strength HC1 o ,0°15 in dioxane are added with slight cooling After 3 h at room temperature, the mixture is concentrated in vacuo, and the residue is taken up in H20, adjusted to 0 pH 9-10 using saturated aqueous Na 2

CO

3 solution and oooo extracted 3 times using EA. The title compound, which can 0ooo0 0"o 20 be used without further purification in the next coupling steps, is obtained after drying with Na2SO 4 and concen- POO trating in vacuo.

d) 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-[3-(2-No n benzyloxymethyl-imidazolyl) -propyl -oxazolidinI 00 0 0 00 550 mg of 2-methyl-N-benzyloxymethyl-imidazole are dissolved in 5 ml of dry THF. 1.9 ml of 1.5 M n-butyllithium in hexane are added at -60" under an argon atmosphere. After 15 min, 500 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5- 2-bromoethyl)-oxazolidine in 5 ml of THF are added. After 1 h at -60 0 C, 10 ml of saturated NaHCO 3 solution are added. After warming to room temperature, the mixture is extracted 3 times using EA, and the extracts are dried using Na 2

SO

4 and concentrated.

The title compound is obtained by chromatography on silica gel (eluent EA).

Rf (EA) 3 XS(FM 2~(X+1) e) 2-Methy.,l-N-benzyloxymethyl-imidazole g of 2-irethylimidazole are added in portions to 16.8 g of potassium hydroxide in 200 ml of dry acetone. After 51 5 min, 8.5 ml of benzyloxymethyl chloride are added dropwise at room temperature. After 15 min, the mixture is concentrated and adjusted to pH 1 using 2 N HCl. It is then extracted 3 times using EA, and the organic phases are discarded. The aqueous phase is adjusted to pH 9-10 o0ooO10 using KOH and extracted 3 times using EA. The combined EA 0000 0 ooe phases are dried using Na 2

SQ'

4 and concentrated. Chromato- 00 Q 000 bgoooc'title compound.

o (EA/MeOH 10/1) 0.4 00 0 f) 3-Boc-4 (S)-cyclohexylmethyl-2 ,2-dimethyl-5-(2-brcnuoethyl) -oxazolidine 0000 1.6 ml of diethyl azodicax'boxylate are added dropwise at oo0 a20 0 C under argon to 690 mg of 3-Boc-4(S)-cyclohexylmothyl-2, 2-dimethyl-5- (2-hydroxyethyl) -oxazolidine, 2.6 g 0020 of triphenylphosphine and 1.6 g of pyridinium hydrobromide in 15 ml of CHCl 2 After 16 h at.R.T., H 2 0 is 00 00added and the mixture is diluted with 100 ml of CH 2 Cl 2 0 C o The organic phase is washed twice with saturated NaHCO 3 00 0 0 d10solution and once with saturated NaCl solution. ThIe organic phase dried using Na2SO4 is concentrated, the residue is taken up in a little EA and filtered to separate off PPh 3 Purification on silica gel yields the title compound (eluent: H/EA 15:1).

Rf (H/EA 15/1) MS 404 (M) 3-Boc-4 (S )-cyclohexylmethyl-2, 2-dimethyl-5- (2-hydroxyethyl) -oxazolidine g of Boc-ACHPA-QEt (preparation according to J. Med.

Chem. 28~ [1985], 1779), 500 mg of p-toluenesulfonic acid

U

4 4 16 and 7.2 ml of dimethoxypropane are heated at 80 0 C in 160 ml of toluene under argon for 2 h. The mixture is then concentrated. The residue is added dropwise at 0 0

C

to a suspension of 2 g of LiAlH 4 in 200 ml of THF. After 2.5 h at 0 0 C, 100 ml of 5% strength NaHSO 4 solution are added and the mixture is extracted 3 times using EA, The combined orga.c phases are washed once using saturated NaiCO 3 solution. After drying with Na 2

SO

4 the solution is concentrated and chromatographed (eluent: HIEA 2:1).

Rf (H/EA 4:1) 0.1; MS=342 (M+1) Examples 2-10 are prepared analogously to Example 1.

Example 2 Iva-Phe-His-1(S)-cyclohexylmethyl-2(S)-hydroxy-5-(2-Nmethyl-imidazolyl)-pentylamide 'R (EA/MeOH 3/1) 0.1 MS(FAB) 48 (M+l) Example 3 Iva-Phe-His-1(S)-cyclohexylmethyl-2(5)-hydroxy-5-(2-Nethyl. -imirazolyl) -pertyamide R. (CH 2 Cl 2 /NH0H 4 OH/eOH. 10/0.1/1) 0.35 MS(FAB) 662 (M+1)

I.-

a 20 Example 4 Iva-Phe-His-1(S)-cyclohexylmethyl-2(S)-hydroxy-5-(2-N-npropyl-imidazolyl)-pentylamide Rg (EA/MeOH 3/1) 0.1 MS(FAB) 676 (M+1) 'C ,xample Iva-Phe-His-1(S)-cyclohexylmethyl-2 ()-hydroxy-5-(2-Nisopropyl-imidazolyl)-pentylamide R. (EA/MeOH 3/1) 0.1 MS(VAB) 676 (M+l) The preparation of 2-methyl-N-alkyl-imidazoles is described in the following as exemplified by 2-methyl-N-npropyl imidazole: 171 2 -Methyl-N-n-propyl-imidazole g of 2-methylimidazole are heated t'o boiling for 2 h in 40 ml of n-propyl bromide. The mixture is then poured into 150 ml of 5% strength NaHS0 4 solution, extracted 3 times using EA, dried using Na 2

SO

4 and concentrated. The residue is taken up in ether and insoluble starting material is removed by filtration. In 'this manner, the title compound is obtained as a colorless oil.

R. (EA/MeOH 10/1) =0.2 0 0 0 Q Example 6 000000 Iva-Phe-Nva-1 -cyclohexylmethyl-2 -hydroxy-5--(2- 0 000 imidazolyl)-pentyamid~e 0000 Rf (EA/MeOH 5/1) 0,1 14S(FAB) =596 (M+1) 00 000 0Example 7 Iva-Phe-Nva- -cyclohexylmethyl-2 (5)-hydroxy-5-(2-N,methyl-inidazolyl) -pentylamide 0000 RfE (CH 2 Cl 2 /Me0H/NH~rOH 20/1/0.1) 0.15 MS(FAB) 610 0000 0000 00 0 Example 8 00C Iva-Phe-Nva- -cyclohexylmethyl-2 (S)-hydroxy-5-(2-N- 0000 20 ethyl-imidazolyl )-pentylamide Rf (CH 2 Cl 2 /MeOH/NI 4 OH 20/1/0.1) 0.15 MS(FAB) 624 (M+1) 0 0 4 0 1Example 9 0,Iva-Phe-Nva-1 -cyclohexylmethyl-2 -hydroxy-5- 2-N.-npropyl-imidazolyl )-pentylamide Rf (EA/MeOH 10/1) 0.3 MS(FAB) =638 (M+1) Example Ival-Phe-Nva- 1 -cyclohexylmethyl-2 -hydroxy-5- (2-NisopropyJ,-imidazolyl) -pentylamide Rf (EA/MeOH 10/1) 0.3 MS(FAB) 638 (M+l)

Claims (6)

1. A compound of the formula I ROR R 3 (I R -B-INCH-CHCH-R 4 iwhich R 1 denotes a radical of the formvla II where W stands for -0-CO-1 -SO 2 or -NH-CO- and RB denotes hydrogen, (Cl-C 1 0 )-alkyl which is 0 a optionally mcalounsaturated or diunsaturated and 00 0 C' which is optionally substituted by up to 3 00 00identical or different radicals from the series 0 0 4 0 a 0 04comprising hydroxyl, (C,-C 7 -alkoxy, (Cl-C 7 00 t 00>0 a alkanoyloxy, carboxyl, (Cl-C 7 -alkoxycarbonyl halogen, amino, (Cl-C 7 -alkylamino, di- (Cl-C 7 alkylamino, (Cl-C 5 alkoxyc arbonyl amino, (C7-C 15 0000 aralkoxyc arbonyl amino and 9-f luorenylmethyloxy- 00 carbonylamino, (C 3 -cycloalkyl, -cyclo- 0 0 0alkyl-(Cl-C,)-alkyl, (C 6 -C 14 )-aryl which is option- 0004 ally substituted by one or two identical or C.000different radicals from the series comprising V, Cl, Br, I, hydroxyl, (Cl-C 7 )-alkoxy, (Cl-C 7 )-alkyl, 000 (Cl-C 7 )-alkoxycarbonyl, amino, anilino, optionally 0 0 B0 0 0 00 methyl, (C 6 -C 1 4 )-aryl-(C-C)-alkyl, where the aryl moiety is optionally substituted by one or twc, identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cl-C 7 )-alkoxy, (Cl-C 7 )-alkyl, (Cl-C 7 )-alkoxycarbonyl, amino, C 7 )-alkylamino, di- (Cl-C 7 -alkylamino, carboxyl, carboxymethoxy, amino- (Cl-C 7 -alkyl, (Cl-C 7 alkylamino- (C 1 -C 7 -alkyl, di- (Cl-C7) -alkylamino- (r'-C 7 -alkyl, (Cl-C 7 -alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (Cl-C 7 -alkoxysulf onyl, sulfo and guanidinomethyl, or stands for the radical of a 5- or 6-meinbered monocyclic or 9- or -19 lO-membered bicyclic hetarocycle having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom in addition as ring membeezs, which is optionally disubstituted or trisubstituted by one or more radicals from the series comprising F, Cl, Br, hydroxyl, (Cl-C 7 -alkoxy, (Cl-C 7 )-alkyl, -alkoxycarbonyl amino or trif luoromethyl, R 4 denotes a radical of the formula III A denotes a radical linked to R 1 at the N terminus and to B at the C terminus of an amino acid from 0 the seaies comprising phenylalanine, histidine, a 0 0tyrosine, tryptophan, methionine, leucine, 0isoleucine, asparagine, aspartic acid, p-2- coo 00 thienylalanine, p-3-thienylalanine, p-2-furantyl- alanine, ,p-3-furanylalanine, lysine, otnithine, valine, alanine, 2,4-diaxninobutyric acid, arginine, 4 -chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine,

3-Dyridylalanine, 4-pyridylalanine, cyclohexyl- 0000 alanine, cyclohexylglycine, im-methyihistidine, 00 methyltyros ine O-benzyltyrosime, 0--tert. 0 6 d -1butyltyrosine, phenylglycine, l-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, nor- valine, fl-2-bertzo (b)thienylalanine, p-3-ben- zo thienylalanine, 2-f luorophenylalanine, 3- fluorophenylalanine, 4-f luorophenylalanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4- tetrahydroisoquinoline-3-carbolc~ acid, homo- phenylalaninai, DOPA, 0-dimetchyldopa, .1-amino-4- (2-thienyl )butyric aeld, 2-amino-4- (3-thir~j) butyric acid, 3- (2-thienyl) serine, (Z )-dehydro- phenylalanine 'and -dehydrophenylpan~ine, B denotes a radical of an amino acid, as defino-A under A, R 2 denotes hydrogen, (Cl-C 1 )-alkyll ('C 4 -C 7 )-CYClO- alkyl, (C 4 -C 7 -cycloalkyl- (Cl-C 4 -alkyl, (C 6 -C14)- aryl. or (C 6 -C 1 4 -aryl- (Cl-CO-alkyl, R 3 denotes ,yrgn (C 1 -C 10 -alkyl, (CO-CI) -aryl or X cani either be abaant or denotes 0 or S, n can be 2, 3 or 4 and R 7 denotes hydxoxyl or amino or stands for the radical of a 5-membered heterocycle having at least 1 carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom, which is optionally substituted by one or more radicals from the series comprising F, Cl, Br, hydroxyl, (C 1 -C 7 alkoxy, (Cl-C 7 -alkyl (C 2 -C 8 -alkoxycarbonyl, amino or trif luoromethyl, where oxazoline is excluded, and ,;'eir phys io logic ally tolerable 000000 a 0 salts. 00 0 000 2. The compound as claimed in claim 1, wherein 0 0 R' denotes (C 2 -C)-alkanoyl, such as n-decanoyl, a 00 000 0 formyl, acetyl, pivaloyl, isovaleryl or iso- butyryl; substituted (C 2 -C 11 -alkanoyl, such as 2- hydroxyprol~j±onyl, 2-hydroxy-3-methylbutyryl or 0 0000 optionally protected amino- (C 2 -C 11 -alkanoyl such 00CO as 4-aminobutyryl, 5-aminopentanoyl, 6-amino- 00 0 hexanoyl, 4-N-tert -Iutoxycarbonylaminobutyzyl,

00005-N-tert butoxycarbonylaminopentanoyl or 6-N- 00 %000tert butoxycarbonylaminohexanoyl or di- (Cl-C 7 alkylamino- (C 2 -Cll) -alkanoyl, such as dimethyl- 00,04"aminoacetyl; (C 4 -Cq) -cycloalk-ylcarbonyl, such as 0 o0 cyclopropylcarbonyl, cycJlobutylcarbony., cyclo- 0 pentylcarbonyl or cyclohexylcarbonyl; (C 8 -C 1 O)- aryl-(C 2 -Cil)-alkanoyl, such as phenylacetyl, phenyipropanoyl or phenylbutanoyl, 2- 6-di- chloroanilino) -phenylacetyl, 2- (N-benzyl-2 ,6- dichloroanilino) -phenylacetyl; benzoyl optionally substituted by halogen, (C,-C 7 )-alkyl, (C,-C 7 alkoxy or (C 1 -C 7 -alkoxycarbonyll such as 4- chlorobenzoyl, 4-methylbenzoyl, 2-methoxy- carbonylbenzoyl or 4-methoxybenzoyl, pyrrolyi-2- carbonyl., pyridyl-3-carbonyt, benzylsulfonyl; (C 2 c 1 1 )-alkoxyoarbony1, such as methoxycarbonyli ethoxycarboy or tert.-butoxycarbinyl; (C 2 -C 1 j)- -21- alkoxycarbonyl substituted by halogen,, such as 2,2, 2-trichioroethoxycarbonyl or 1, 1-dimethyl- 2,2, 2-trichioroetl-hoxycarbonyl; or (C 6 -C 14 -aryl- (C 2 -C 7 )-a~lcoycarbonyl, such as benzyloxycarbonyl or 9-fluorenylmethylcarbonyl. 3. The compound as claimed in claim 1 and/or 2, wherein Rdenotes isobutyl, benzyl or cyc-lohexylmethyl. 4. The compound as claimed in one or more of claims 1 to 3, wherein R 3 denotes hydrog isopropyl or iso- 0 CI 0 1 (3 tsbutyl. 0 3 The compound as claimed in one or more of claims 1 t4,wherein A and B independently of one another 0. denote phenylalanine, histidine, tyrosine, trypto- phan, methionine, leucine, isoleucine, asparagine, aspartic acLft p-2-thianylalanine, p-3-thienylala- nine, p-2-furylalanine# lysine, ornithine, 2,4- 1)a o'diaminobutyric acid, arginine, norvaline, 4-chioro- phenylalanine, methionine sulfone, methionine sulf oxide, 2-pyridylalanlne, 3-pyridylalanine, 4- 000cipy'zi4dylalanine, cyclohexylalanine, cyclohexylqly- 1000cine, im-niethylbistidine, O-methyiltyrosine, 0- benzyltyrosinet 0-tert butyltyrosine, phenyigly- bd cine, 1-naphthylalanine, 2-naphthylalanine, 4- nitrophenylalanine, norleucine, valine, alanine, 1,2,3, 4 -tetrahydroisoquiinoline-3-carboxylic acid, homophenyl~alanine, 2-aminio-4'-( 2-thienyl )butyr.ic ai, (Z -4--hydrophenylalanine or -dehydropheny.- alanine.

6. The compound as cl.aimed in one or more of claims 1. to 5, wherein N stands for the radical of a membered heterocyo~le having ona or two heteroatoms, which is optionally substituted by (C)-C 7 )-alkyle

7. A process for the preparation of, a compound of the formula 1. azz claimned in one of claims 1 to 6, 22 wherein a fragment having a terminal carboxyl group or its reactive derivative is coupled to a cor- responding fragment having a free amino group, (a) temporarily introduced protective group(s) optional- ly introduced for the protection of further functional groups is/are removed and the compound thus obtained is optionally converted into its physiologically tolerable salt.

8. The use of a compound as claimed in one of claims 1 to 6 as a pharmaceutical. OOQOQQ 000444 0 o 9, The use of a compound as claimed in one of claims 1 Go o °o to 6 as a pharmaceutical in the treatment of high 4oo"P blood pressure and cardiac insufficiency. 0 0 A pharmaceutical agent containing a compound as claimed in one of claims 1 to 6. "0 DATED THIS 19th day of April, 1990 d 44 HOECHST AKTIENGESELLSCHAFT *4 ,ATERMARK PATENT TRADEMARK ATTORNEYS, C 2nd Floor, The Atrium, 290 Burwood Road, ScHAWTHORN. VICTORIA 3122. 1 ATHR