AU708306B2

AU708306B2 - Esters and amides as PLA2 inhibitors

Info

Publication number: AU708306B2
Application number: AU64696/96A
Authority: AU
Inventors: Naoki Fukami; Keiji Hemmi; Keisuke Imai; Seiji Yoshimura
Original assignee: Fujisawa Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd
Priority date: 1995-07-24
Filing date: 1996-07-18
Publication date: 1999-07-29
Anticipated expiration: 2016-07-18
Also published as: AU6469696A

Description

WO 97/03951 PCT/JP96/01995 -1-

DESCRIPTION

ESTERS AND AMIDES AS PLA2 INHIBITORS TECHNICAL

FIELD

The present invention relates to a novel fatty acid derivative and a pharmaceutically acceptable salt thereof which are useful as a medicament.

BACKGROUND

ART

A phospholipase

A

2 inhibitor having the structure of that of the present invention has not been known.

DISCLOSURE OF INVENTION The present invention relates to novel fatty acid derivative and a pharmaceutically acceptable salt thereof, which are phospholipase

A

2 inhibitors and are useful for the prevention and/or the treatment of pancreatitis, hepatitis, chronic renal failure, etc; shock endotoxin shock, gram-negative septic shock, etc), arthritis rheumatoid arthritis, osteoarthritis, etc), respiratory disease (e.g.

bronchial asthma, bronchitis, adult respiratory distress syndrome, etc), heart disease myocardial ischemia, etc), allergic disease, thrombosis, arteriosclerosis, pain, autoimmune disease, dermal disease atopic dermatitis, psoriasis, contact dermatitis, etc), inflammatory bowel disease Crohn's disease, ulcerative colitis, etc), ophthalmic disease allergic ophthalmic disease, inflammatory ophthalmic disease, etc), nasal diseases (e.g.

allergic rhinitis, etc), gout, trauma induced inflammation spinal cord injury, etc), liver diseases (e.g.

cirrhosis, hepatitis, etc), or the like; to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for using the same therapeutically in human being and animals for the prevention WO 97/03951 PCT/JP96/01995 2 and/or treatment of the aforesaid diseases.

The object fatty acid derivative can be represented by the following formula

R

2

R

1 -NH 0

X

R3 'R 4 wherein

R

1 is acyl group,

R

2 is acyl(lower)alkyl,

R

3 is hydrogen, aryl(lower)alkyl which may have one or more suitable substituent(s), aryl(higher)alkyl which may have one or more suitable substituent(s), heterocyclic(lower)alkyl which may have one or more suitable substituent(s), higher alkoxy(lower)alkyl, lower alkyl, or higher alkyl,

R

4 is acyl(lower)alkyl, and

R

I

X is -NH- or -N- [wherein

R

5 is lower alkyl, [cyclo(lower)alkyl] (lower)alkyl, aryl(lower)alkyl, or heterocyclic(lower)alkyl],

R

with proviso that X is (wherein

R

5 is as defined above), when R 3 is lower alkyl or higher alkyl.

WO 97/03951 PCT/JP96/01995 3 It is to be noted the object compound may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.

It is further to be noted isomerization or rearrangement of the object compound may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.

It is also to be noted that the solvating form of the compound hydrate, etc) and any form of the crystal of the compound are included within the scope of the present invention.

The object compound or a salt thereof can be prepared according to the following reaction schemes.

R

2

R

1 -NH

COOH

X-H

R3, R 4

(III)

or a salt thereof

(II)

or a reactive derivative at the carboxy group or a salt thereof 1j WO 97/03951 PCT/JP96/01995 -4 R2

X

(I)

or a salt thereof 4 R1-OH

(IV)

or a reactive derivative at the amino group or a salt thereof

(V)

or a reactive derivative or a salt thereof WO 97/03951 PCT/JP96/01995 5 Rl-NH-

O

X

R R4

(I)

or a salt thereof PZLQca

R

1

-NH'

R3- R4 (Ia) or a salt thereof elimination 2 reaction of carboxy protective

R

1 -NH 0 group

X

R3,'R 4 (Ib) or a salt thereof wherein

R

1

R

2

R

3

R

4 and X are each as defined above, Ra is protected carboxy(lower)alkyl, R2 Rb is carboxy(lower)alkyl.

The starting compound (IV) or a salt thereof can be prepared according to the following reaction scheme.

WO 97/03951 PCT/JP96/01995 6 Process A R2 R l-NH 0 x R3

R

4 elimination reaction of acyl group

H

2

N

R3' R 4

(I)

or a salt thereof

(IV)

or a salt thereof wherein

R

1

R

2

R

3

R

4 and X are each as defined above.

Among the starting compounds, there are some novel compounds. They can be prepared according to the methods as described in Preparations in the present specification or the conventional manners in this field of the art.

Suitable pharmaceutically acceptable salts of the object compound are conventional ones and include a metal salt such as an alkali metal salt sodium salt, potassium salt, etc) and an alkaline earth metal salt calcium salt, magnesium salt, etc), an ammonium salt, an organic base salt trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'dibenzylethylenediamine salt, etc), an organic acid salt acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc), an inorganic acid salt (e.g.

hydrochloride, hydrobromide, hydriodide, sulfate, phosphate, WO 97/03951 PCT/JP96/01995 7 etc), a salt with an amino acid arginine, aspartic acid, glutamic acid, etc), and the like.

In the above and following descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention includes within the scope thereof are explained in detail as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s) unless otherwise indicated.

The term "higher" is intended to mean 7 to 20 carbon atoms unless otherwise indicated.

Suitable example of "lower alkyl" and "lower alkyl" moiety in the terms used in the present specification may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or the like.

Suitable "lower alkenyl" and "lower alkenyl" moiety in the terms used in the present specification may include vinyl, l-(or 2 -)propenyl, l-(or 2- or 3-)butenyl, l-(or 2- or 3- or 4 -)pentenyl, l-(or 2- or 3- or 4- or methylvinyl, ethylvinyl, l-(or 2- or 3-)methyl-l-(or propenyl, l-(or 2- or 3 -)ethyl-1-(or 2 -)propenyl, l-(or 2- or 3- or 4 -)methyl-l-(or 2- or 3-)butenyl or the like, in which the preferred one may be (C 2

-C

4 )alkenyl.

Suitable "higher alkyl" and "higher alkyl" moiety in the terms used in the present specification may include straight or branched one such as heptyl, 2 -methylheptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, 11-methyldodecyl, 1 2 -methyltridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl or the like, in WO 97/03951 PCT/JP96/01995 8 which the preferred one may be (C7-C 16 )alkyl, and the more preferred one may be heptyl, octyl, nonyl, decyl, or tridecyl.

Suitable "halogen" may include fluorine, chlorine, bromine, iodine, in which more preferable one may be chlorine.

Suitable "aryl" and "aryl" moiety in the terms used in the present specification may include phenyl, naphthyl and the like.

Suitable "acyl group" and "acyl" moiety in the terms used in the present specification may be aliphatic acyl, aromatic acyl, heterocyclic acyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and the like.

S b Suitable example of the "acyl group" thus explained may be lower alkanoyl formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, hexanoyl, pivaloyl, etc] which may have one or more (preferably 1 to 3) suitable substituent(s) such as halogen fluoro, chloro, bromo, iodo); hydroxy; lower alkoxy methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc); amino; protected amino, preferably, acylamino such as lower alkoxycarbonylamino (e.g.

methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, t-butoxycarbonylamino, pentyloxycarbonylamino, hexyloxycarbonylamino, etc); or the like; di(lower)alkylamino dimethylamino, N-methylethylamino, diethylamino, N-propylbutylamino, dipentylamino, dihexylamino, etc); lower alkoxyimino methoxyimino, ethoxyimino, propoxyimino, butoxyimino, t-butoxyimino, WO 97/03951 PCT/JP96/01995 -9pentyloxyimino, hexyloxyimnino, etc); ar(lower)alkoxYimino such as phenyl(J.ower)alkoxyimino benzyloxyimino, phenethyloxyimjno, benznydryloxyimino, etc); or the like; higher alkanoyl heptanoy., octanoyl, nonanoyl, decanoy., undecanoyl, lauroyl, tridecanoyl, myristoyl, pentadecanoyl, palmitoyl, l 4 -methylpentadecanoyl, 10, l 2 -dimethyltetradecanoyl, heptadecanoyl, stearoyl, fonadecanoyl, icosanoyl, etc] which may have one or more (preferably 1 to 3) suitable substituent(s) as exemplified for those of "lower alkanoyl"; lower alkenoyl acryloyl, crotonoyl, isocrotonoyl, methacryloyl, 3 -pentenoyl, 2 1 4 -pentadienoyl, 2 4 -hexadienoyl, etc] which may have one or more (preferably 1 to 3) suitable substituent(s) as exemplified for those of "lower alkanoyl"; higher alkenoy. 4 -heptenoyl, 3 -octenoyl, 3, G-decadienoyl, 3, 7 ,ll-trimethyl-2, 6, l-dodecatrienoyl, 4 ,lO-heptaciecadienoyl, etc] which may have one or more (preferably 1 to 3) suitable substituent(s) as exemplified for those of "lower alkanoyl"; protected carboxy, in which the preferred one may be esterified carboxy such as lower alkoxycarbonyl [e.g.

me thoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, Pentyloxycarbonyl, hexyloxycarbonyl, etc], halo (lower) alkoxycarbonyl (chloromethoxy) carbonyl, 2 2 ,2-trichloroethoxy)carbonyi, (2,2,2trifluoroethoxy) carbonyl, 2 -chloropropoxy) carbonyl, (l-fluoro-4-bromobutoxy) carbonyl, 4 -chloropentyloxy) carbonyl, (6-chlorohexyloxy)carbolyi etc], higher alkoxycarbonyl heptyloxycarbonyl, octyloxycarbonl 2 -ethylhexyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, 3, 7 -dizethyloctyloxycarbony 1 undecyloxycarbonl dodecyloxycarbonyi, tridecyloxycarbonyl, tetradecyloxycarbonl pentadecyloxycarbonyl, 3 WO 97/03951 PCT/JP96/O1 995 10 ethyldodecyloxycarbonyl, hexadecyloxycarbonyl, heptadecyloxycarbonyl, octadecyloxycarbonyl, nonadecyloxycarbonyl, iCoSyloxycarbonyl, etc], aryloxycarbonyl [ie phenoxycarbonyl, naphthyloxycarbonyl, etc], aryl(lower)alkoxycarbonyl which may have one or more (preferably 1 to 3) suitable substituent(s) such as PhenYl(lower)alkoxycarbonyl which may have nitro or lower alkoxy lie benzyloxycarbonyl, phenethyloxycarbonyl, P-flitrobenzyloxycarbonyl, P-methoxybenzyloxycarbonyl, etc], or the like; carboxy; lower alkylsulfonyl methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, pentylsulfonyl, butylsulfonyl, etc]; arylsulfony. phenylsulfonyl, l-(or naphthylsulfonyl, etc] which may have one or more (preferably 1 to 3) suitable substituent(s) such as lower alkyl, di(lower)alkylamino, lower alkylamino methylamino, ethylamino, propylamino, butylamino, t-butylamino, pentylamino, hexylamino, etc), or the like; aryl(lower)alkylsulfonyl such as phenyl (lower) alkylsulfonyl benzylsulfonyl, Phenethylsulfonyl, benzhydrylsulfonyl, etc], or the like; (10) aryl(lower)alkanoyl such as phenyl(lower)alkanoyl or naphthyl.(lower) alkanoyl benzoyl, naphthoyl (e.g.

1-naphthoyl, 2-naphthoyl, etc), 2 -phenylacetyl, 2 -phenylpropionyl, 4- (l-naphthyl) butyryl, 3 -phenylvaleryl, 2 5 -diphenylhexanoyl, etc], each of which may have one or more (preferably 1 to 3) suitable substituent(s) such as lower alkoxy, aryl phenyl, naphthyl, anthryl, etc), carboxy(lower) alkyl carboxymethyl, 2 -carboxyethyl, l-carboxypropyl, 4 -carboxybutyl, 3 -carboxypentyl, G-carboxyhexyl, etc), protected carboxy(lower)alkyl (e.g.

methoxycarbonylmethyl, 2 -methoxycarbonylethyl, WO 97/03951 PCT/JP96O1 995 2 -(t-butoxycarbonyl)ethyl, etc) which may be substituted by aryl phenyl, naphthyl, etc), protected carboxy(lower)alkenyl 2 -methoxycarbonylvinyl, etc), amidated carboxy(lower)alkyl 2 -carbamoylethyl, etc), aryl(lower)alkyl benzyl, phenethyl, etc) which may have one or more suitable substituent(s), or the like; (11) aryl (lower)alkenoyl 3 -phenylacryloyl, 2 -phenylacryloyl, 2 -naphthylacryloyl, 3 -phenylcrotonoyl, 4 -phenylisocrotofloyl, 2 -benzylacryloyl, 5-phenyl-3-pentenoyl, 3 -naphthyj-2, 4 -pentadienoyl, 2 -phenya-5-hexenoyl, 6-phenyl- 2, 4 -hexadienoyl, etc); (12) heterocyclic(lower)alkanl which may have one or more (preferably 1 to 3) suitable Substituent(s) such as lower alkyl, aryl(lower)alkyl which may have one or more suitable substituent benzyl, l-naphthylmethyl, 4 -methyJlbenzyl, 2-chlorobenzyl, 3 -chlorobenzyi, 4 -chlorobenzyl, etc), heterocyclic(lower)alkyl (e.g.

2 -pyr-idylmethyl, etc) which may have one or more suitable substituent(s), or the like; (13) heterocyclicsulfonl; (14) amidated carboxy such as carbamoyl, N-heterocyclic..carbamoyi which may have one or more (preferably 1 to 3) suitable substituent(s) such as lower alkyl, halogen, or the like, N-lower aly--eeoylccraol N-lower alkylcarbamoyl N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-butylcarbamoyl, N-t-butylcarbamoyl, N-pentylcarbamoyl, N-hexylcarbamoyl, etc) which may have one or more (preferably 1 to 3) suitable substituent(s) such as heterocyclic group, hydroxy, or the li ke, N-rllwraklabmy such as N- (mono- or di- or tri-)phenyl (lower) alkylcarbamoyl N-benzylcarbamoyl, N-phenethylcarbamoyl, N-benzhydrylcarbamoyl, N-tritylcarbamoyl, etc), or the like; or the like.

WO 97/03951 PCT/JP96/01995 12 Suitable "heterocyclic" moiety in the terms used in the present specification may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group such as unsaturated 3 to 8 -membered (more preferably 5 to 7membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, azepinyl 1H-azepinyl, etc), pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl 4 H-1,2,4-triazolyl, 1H-1,2,3-triazolyl 2 H-1, 2 ,3-triazolyl, etc), tetrazolyl 1Hi-tetrazolyl, 2H-tetrazolyl, etc), etc; saturated 3 to 8-membered (more preferably 5 to 7membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, perhydroazepinyl perhydro-1Hazepinyl, etc), pyrrolidinyl, imidazolidinyl, piperidyl, Piperazinyl, etc; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, quinoxalinyl, imidazopyridyl [e.g.

etc], tetrahydroimidazopyridyl [e.g.

4,5,6, 7 -tetrahydro[4,5-c]pyridyl, etc], etc; saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, 7 -azabicyclo[2.2.1heptyl, 3 -azabicyclo[3.2.2]nonanyl, etc; unsaturated 3 to 8 -membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, Isoxazolyl, oxadiazolyl 1,2, 4 -oxadiazolyl, 1,3,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, etc), etc; saturated 3 to 8 -membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl, sydnonyl, etc; unsaturated condensed heterocyclic group containing 1 to 35auae odne eeocci ru otiig1t WO 97/03951 PCT/JP96/01995 13 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc; unsaturated 3 to 8-membered (more preferably 5 or 6- S membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl 1,2,3-thiadiazolyl, 1,2,4thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc) dihydrothiazinyl, etc; saturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, etc; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc; saturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), and saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing 1 to 2 oxygen atom(s), for example, furyl, etc; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzofuranyl (e.g.

benzo[b]furanyl, etc), etc; unsaturated 3 to 8-membered (more preferably 5 or 6membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc; unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, benzoxathiinyl, etc; or the like.

WO 97/03951 PCT/JP96/01995 14 Suitable "aryl(lower)alkyl" may include mono-(or di- or tri-)phenyl(lower)alkyl benzyl, phenethyl, 2 -phenylpropyl, 2, 4 -diphenylbutyl, 1,3,5-triphenylpentyl, 6 -phenylhexyl, etc), mono-(or di- or tri-)naphthyl(lower)alkyl 2 -naphthylmethyl, 2 1 -naphthyl)ethyl, 2-(2naphthyl)ethyl, etc), and the like.

This "aryl(lower)alkyl" may have one or more (preferably 1 to 3) suitable substituent(s) selected from the group consisting of lower alkyl methyl, ethyl, butyl, etc), higher alkyl pentyl, etc), lower alkoxy methoxy, ethoxy, propoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, etc), aryl phenyl, naphthyl, etc), halogen fluoro, chloro, bromo, iodo), and the like.

Suitable "aryl(higher)alkyl" may include mono-(or di- or tri-)phenyl(higher)alkyl 7 -phenylheptyl, 6-phenylheptyl, 4,6-diphenylheptyl, 3,5, 7 -triphenylheptyl, 8 -phenyloctyl, etc), mono-(or di- or tri-)naphthyl(higher)alkyl 7-( 2 -naphthyl)heptyl, 8-(l-naphthyl)octyl, etc), and the like.

Each of the "aryl(higher)alkyl" and "heterocyclic(lower)alkyl" may have one or more (preferably 1 to 3) suitable substituent(s) as exemplified for those of "aryl(lower)alkyl" above.

Suitable "higher alkoxy" moiety in the terms used in the present specification may include straight or branched one such as heptyloxy, 2 -methylheptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, 11-methyldodecyloxy, 1 2 -methyltridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy or the like, in which the preferred one may be (C7-C 16 )alkoxy and the more preferred one may be nonyloxy, or decyloxy.

Suitable "cyclo(lower)alkyl" moiety in the terms used in the present specification may include the ones having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, or WO 97/03951 PCT/JP96/0I 995 cyclohexyl.

In aforesaid "acyl group", the preferred one may be lower alkoxycarbonyl, in which the more preferred one may be (Cl-C 4 )alkoxycarbonyl, and the most preferred one may be t-butoxycarbonyl; aryl(lower)alkanoyl which may have one or more suitable substituent(s), in which the more preferred one may be phenyl (lower) alkanoyl or naphthyl (lower) alkanoyl, each of which may have 1 to 3 suitable substituent(s) selected from the group consisting of carboxy(lower)alkyl (e.g.

carboxymethyl, 2 -carboxyethyl, l-carboxypropyl, 4 -carboxybutyl, 3-carboxypentyl, 6 -carboxyhexyl, etc), protected carboxy (lower) alkyl methoxycarbonylmethyl, 2 -methoxycarbonylethyl, 2- (t-butoxycarbonyl) ethyl, etc) which may be substituted by aryl phenyl, naphthyl, etc), protected carboxy(lower) alkenyl 2 -methoxycarbonylvinyl, etc), amidated carboxy(lower)alkyl 2 -carbamoylethyl, etc), and aryl(lower)alkyl benzyl, phenethyl, etc), the much more preferred one may be phenyl(oj-C 4 )alkanoyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of carboxymethyl, 2 -carboxyethyl, methoxycarbonylmethyj, benzyloxycarbonylmethyl, 2 -methoxycarbonylethyl, 2- (t-butoxycarbonyl) ethyl, 2 -methoxycarbonylvinyl, 2 -carbamoylethyl, benzyl, and phenethyl, or naphthy1(Cl-C 4 )alkanoyl which may have benzyl, the most preferred one may be benzoyl, 2- (carboxymethyl)benzoyl, 2- 2 -carboxyethyl)benzoyl, 2- (methoxycarbonylmethyl) benzoyl, benzyloxycarbonylmethyl) benzoyl, 2- 2 -methoxycarbonylethyl) benzoyl, 2- (t-butoxycarbonyl) ethyllbenzoyl, 2- 2 -methoxycarbonylvinyl) benzoyl, 2- 2 -carbamoylethyl)benzoyl, 2 -benzylbenzoyl, 3 -benzylbenzoyl, 2 -phenethylbenzoyl, 2-naphthoyl, or WO 97/03951 PCT/JP96/01 995 -16 3 -benzylnaphthalen-2ylcarbo 0 fl or heterocyclic(iower)alkanoyl hc a av n rmr suitable substituent(s), in which the more preferred one may be etr-ycic'lweralknoyl, wherein heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), which may have 1. to 3 lower alkylaryl (lower)alkyl, haloaryl (lower)alkyl, or heterocyclic (lower) alkyl, wherein heterocyclic moiety is unsaturated 3 to B-membered heteromonocyciic group containing 1 to 4 nitrogen atom(s), the 'more preferred one may be quinolyl (Ci-C 4 )alkanoyl, isoguinolyl (Cl-C 4 )alkanoyl, or indolyl (Cl-C 4 )alkanoyl which may have (Cl-C4)alkylphenyl (C I- 04) alkyl, haiophenyl

(C

1

-C

4 alkyl, or pyridyl(Cl-C 4 )alkyl, the much more preferred one may be quinolylcarbonyl, isoquinolylcarbonyl, or indolylcarbonyl which may have benzyl, 1-naphthylmethyl, 4 -methylbenzyl, 2 -chlorobenzy., 3 -chlorobenzyl, 4 -chlorobenzyl or 2 -pyridylmethyi, the most preferred one may be 2 -(or 3 -)quinolylcarbonyl, l-(or 3 -)isoquinolylcarbonyl, l-benzylindol-2- (or ylcarbonyl, 1- (l-naphthylmethyl) indol-3-ylcarbonyl, 1- 4 -methylbenzyl) indol-2- (or ylcarbonyl, 1-[ 2 -(or 3- or 4 -)chlorobenzljidol3ylab o 1- 2 -pyridylmethyl) indol-3-ylcarbonyl.

The preferred "acyl" moiety in the term facyl (lower) alkyl" may be carboxy; protected carboxy, in which the more preferred one may be lower alkoxycarbonyl or aryl(lower)alkoxycarbonyl, the much more preferred one may be (Cl-C 4 )alkoxycarbonyl or phenyl(C 1 -c 4 )alkoxycarbonyl, and the most preferred one may be methoxycarbonyl or benzyloxycarbonyl; or amidated carboxy, in which the more preferred one may be carbamoyl.

WO 97/03951 PCT/JP96/01995 17 The preferred "substituent" in the terms "aryl(lower)alkyl which may have one or more suitable substituent(s)", "aryl(higher)alkyl which may have one or more suitable substituent(s)" and "heterocyclic(lower)alkyl which may have one or more suitable substituent(s)" may include lower alkyl as exemplified above, preferably (Cl-C 4 )alkyl, more preferably methyl, ethyl or butyl; higher alkyl as exemplified above, preferably

(C

7

-C

16 )alkyl, more preferably heptyl; aryl as exemplified above, preferably phenyl; or the like.

In the following, some of the preferred embodiments of the fatty acid derivative of the present invention are shown.

the derivative wherein

R

1 is protected carboxy; aryl(lower)alkanoyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkoxy, aryl, carboxy(lower)alkyl, protected carboxy(lower)alkyl which may be substituted by aryl, protected carboxy(lower)alkenyl, amidated carboxy(lower)alkyl, and aryl(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; heterocyclic(lower)alkanoyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, aryl(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen, and heterocyclic(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group WO 97/03951 PCT/JP96/01995 18 consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen;

R

2 is carboxy(lower)alkyl or protected carboxy(lower)alkyl,

R

3 is hydrogen; aryl(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; aryl(higher)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; heterocyclic(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, higher alkyl, lower alkoxy, aryl and halogen; higher alkoxy(lower)alkyl; lower alkyl; or higher alkyl, 4 is carbamoyl(lower)alkyl, and

R

X is -NH- or -N- [wherein

R

5 is lower alkyl, [cyclo(lower)alkyl]- (lower)alkyl, aryl(lower)alkyl, or heterocyclic(lower)alkyl],

R

with proviso that X is (wherein R5 is as defined above), when R 3 is lower alkyl or higher alkyl.

the derivative wherein

R

1 is esterified carboxy (preferably lower alkoxycarbonyl); WO 97/03951 PCT/JP96/01995 19 phenyl(lower)alkanoyl or naphthyl(lower)alkanoyl, each of which may have 1 to 3 suitable substituent(s) selected from the group consisting of carboxy(lower)alkyl, esterified carboxy(lower)alkyl (preferably lower alkoxycarbonyl(lower)alkyl) which may be substituted by phenyl, esterified carboxy(lower)alkenyl (preferably lower alkoxycarbonyl(lower)alkenyl), carbamoyl(lower)alkyl and phenyl(lower)alkyl; or heterocyclic(lower)alkanoyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of pyridyl(lower)alkyl, naphthyl(lower)alkyl and phenyl(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl and halogen, in which the heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s),

R

2 is carboxy(lower)alkyl or esterified carboxy(lower)alkyl (preferably methoxycarbonyl(lower)alkyl or benzyloxycarbonyl(lower)alkyl), R is hydrogen; phenyl(lower)alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting of lower alkyl, higher alkyl and phenyl; or naphthyl(lower)alkyl which may be substituted by lower alkyl,

R

4 is carbamoyl(lower)alkyl, and X is the derivative wherein

R

1, R 2

R

3 and R 4 are each as defined above in and WO 97/03951 PCT/JP96/01995 20

R

I

X is -NH- or -N- [wherein

R

5 is lower alkyl, phenyl(lower)alkyl, or pyridyl(lower)alkyl].

the derivative wherein R R 2

R

4 and X are each as defined above in and R is phenyl(higher)alkyl.

the derivative wherein

R

1

R

2

R

3 and R 4 are each as defined above in and

R

X is -NH- or -N- [wherein

R

5 is as defined above in the derivative wherein R1, R 2

R

4 and X are each as defined above in and is heterocyclic(lower)alkyl, in which the heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s).

the derivative wherein R, R 2

R

3 and R 4 are each as defined above in and

R

X is -NH- or -N- [wherein

R

5 is as defined above in the derivative wherein

R

1

R

2

R

4 and X are each as defined above in and R is higher alkoxy(lower)alkyl.

WO 97/03951 PCT/JP96/01995 21 the derivative wherein

R

1

R

2

R

3 and R 4 are each as defined above in and

R

is -NH- or -N- [wherein

R

5 is as defined above in the derivative wherein

R

1

R

2 and R 4 are each as defined above in and

R

3 is lower alkyl, and

R

X is -N- [wherein

R

5 is as defined above in (11) the derivative wherein

R

1

R

2 and R 4 are each as defined above in and R is higher alkyl, and

R

X s -N- [wherein

R

5 is as defined above in (12) the derivative wherein

R

1 is (C1-C 4 )alkoxycarbonyl; phenyl(Cl-C 4 )alkanoyl or naphthyl(C1-C4)alkanoyl, each of which may have carboxy(C 1

-C

4 alkyl,

(C

1

-C

4 )alkoxycarbonyl(C1-C 4 )alkyl which may be substituted by phenyl, (C1-C 4 )alkoxycarbonyl- (C2-C4)alkenyl, carbamoyl(C 1

-C

4 )alkyl or phenyl(C1-C4)alkyl; heterocyclic(C 1

-C

4 )alkanoyl which may have pyridyl(C 1

-C

4 )alkyl, naphthyl(C1-C4)alkyl or phenyl(C 1

-C

4 )alkyl which may have 1 to 3 suitable substituent(s) selected from the group consisting WO 97/03951 PCT/JP96/01995 22 Of (Cl-C 4 )alky1 and ch2.oro, in which the heterocyclic moiety is indolyl, qruinolyl or isoquinolyl, Ris carboxy(C 1

-C

4 )alkyl, methoxycarbonyl (01-04) alkyl, or benzyloxy(c 1 .0 4 )alkyl,

R

3 is hydrogen; phenyl.(01-04) alky. which may have (01-04) alkyl, (C7-C 16 )alkyl or phenyl; or 4 naphthyl 0 4 )alkyl which may have (C- 4 )alkyl, R is carbamoyl(0 1 0C 4 )alkyl, and X is (13) the derivative wherein

R

1

R

2

R

3 and R 4 are each as defined above in and

R

X is -NH- or-N [wherein

R

5 is (C 1

-C

5 )alkyl, phenyl(C 1 -c 4 )alkyl, or pyridyl (01-04) alkyll.

(14) the derivative wherein

R

1

R

2

R

4 and X are each as defined above in and

R

3 is pheny1(C 7

-C

16 )alkyl.

(15) the derivative wherein R R R 3 and R are each as defined above in and

R

X is -NH- or -N- [wherein

R

5 is as defined above in (13)]j.

(16) the derivative wherein

R

1

R

2

R

4 and X are each as defined above in and

R

3 is benzofuranyl(C 1 c 4 )alkyl.

WO 97/03951 PCT/JP96/01995 23 (17) the derivative wherein

R

1

R

2

R

3 and R 4 are each as defined above in and

R

X is or -N- [wherein

R

5 is as defined above in (18) the derivative wherein R, R 2

R

4 and X are each as defined above in and R is (C7-C6)alkoxy(Cl-C4)alkyl.

(19) the derivative wherein

R

1

R

2

R

3 and R are each as defined above in and

R

I

X is -NH- or -N- [wherein

R

5 is as defined above in the derivative wherein

R

1

R

2

R

4 and X are each as defined above in and R is (C3-C 6 )alkyl.

(21) the derivative wherein RI, R 2

R

3 and R 4 are each as defined above in and

R

5 X is -N- [wherein

R

5 is as defined above in (22) the derivative wherein RI, R 2

R

4 and X are each as defined above in and R is (C7-C1 6 )alkyl.

(23) the derivative wherein

R

1

R

2

R

3 and R 4 are each as defined above in and WO 97/03951 PCT/JP96/01995 24

R

X is -N- [wherein

R

5 is as defined above in The processes for preparing the object compound of the present invention are explained in detail in the following.

Process 1 The compound or a salt thereof can be prepared by reacting the compound (II) or a reactive derivative at the carboxy group or a salt thereof with the compound (III) or a salt thereof.

Suitable salts of the compounds (II) and (III) can be referred to the ones as exemplified for the compound

(I)

Suitable reactive derivative at the carboxy group of the compound (II) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.

Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid methanesulfonic acid, etc], aliphatic carboxylic acid acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2 -ethylbutyric acid, trichloroacetic acid, etc] or aromatic carboxylic acid benzoic acid, etc]; a symmetrical acid anhydride; an activated amide with imidazole, 4 -substituted imidazole, dimethylpyrazole triazole, tetrazole or l-hydroxy-lH-benzotriazole; or an activated ester cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl

[(CH

3 2 N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2 4 -dinitrophenyl WO 97/03951 PCT/JP96/01995 25 ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8 -quinolyl thioester, etc] or an ester with a N-hydroxy compound N,N-dimethylhydroxylamine, l-hydroxy-2-(1H)pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc], and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (II) to be used.

R

In the case that the group X is in the compound (III), the compound (III) can be used in the form of its reactive derivative at the amino group.

Suitable said reactive derivative at the amino group may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (III) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene, and the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, etc], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

In this reaction, when the compound (II) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing WO 97/03951 PCT/JP96/01995 26 agent such as N,N'-dicyclohexylcarbodiimide; l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; benzotriazole-l-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, or the like.

The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine triethylamine, etc), pyridine, di(lower)alkylaminopyridine N,N-dimethylaminopyridine, etc), N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Process 2 The compound or a salt thereof can be prepared by reacting the compound (IV) or a reactive derivative at the amino group or a salt thereof with the compound or a reactive derivative or a salt thereof.

Suitable salts of the compounds (IV) and can be referred to the ones as exemplified for the compound

(I)

The reaction of this process can be carried out according to a similar manner to that of Process 1, and so the reaction condition can be referred to the explanation therein.

Process 3 The compound (Ib) or a salt thereof can be prepared by subjecting a compound (Ia) or a salt thereof to elimination reaction of carboxy protective group.

This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base may include an inorganic base and an WO 97/03951 PCT/JP96/01995 27 organic base such as an alkali metal sodium, potassium etcj, an alkaline earth metal magnesium, calcium, etc], the hydroxide or carbonate or bicarbonate thereof, trialkylamine trimethylamine, triethylamine, etc], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7ene, or the like.

Suitable acid may include an organic acid formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc] and an inorganic acid [e.g hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc].

The elimination using Lewis acid such as trihaloacetic acid trichloroacetic acid, trifluoroacetic acid, etc], aluminium halide aluminium chloride, etc] or the like is Preferably carried out in the presence of cation trapping agents anisole, phenol, etc].

The reaction is usually carried out in a solvent such as water, an alcohol methanol, ethanol, etc], nitromethane, methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are a combination of metal tin, zinc, iron, etc] or metallic compound chromium chloride, chromium acetate, etc] and an organic or inorganic acid formic acid, acetic acid, propionic acid, trifluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc].

WO 97/03951 PCT/JP96/01995 28 Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc], palladium catalysts e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, etc], nickel catalysts reduced nickel, nickel oxide, Raney nickel, etc], cobalt catalysts reduced cobalt, Raney cobalt, etc], iron catalysts reduced iron, Raney iron, etc], copper catalysts reduced copper, Raney copper, Ullman copper, etc] and the like.

The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, dioxane, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above-mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent.

Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc, or a mixture thereof.

The reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.

It is to be noted the compound or a salt thereof can be prepared by the methods other than aforesaid Processes 1 for examples, by the other methods disclosed in Examle in this specification.

Biolo1ai ai Proerty of he m ,nd In order to show the utility of the object compound the biological test data on phospholipase

A

2 assay of the WO 97/03951 PCT/JP96/01995 29 representative compound of the compound is shown in the following.

Test on the inhibitory effect against phospholipase

A

2

(PLA

2 Test Method

PLA

2 activity was assayed with a fluorescent phospholipid analogue [l-palmitoyl-2-(10-pyrenyldecanoyl)sn-glycero-3-monomethylphosphatidic acid PA-monomethyl ester)] as a substrate, according to Radvanyi et al. (1989) with several modifications. Briefly, the reaction medium was prepared by sequential additon of 1160 Ps of 50 mM Tris-HCl (pH 7.4) buffer containing 100 mM NaCl and 1 mM EDTA, 10 p1 of 120 pM 10-pyrene PA-monomethyl ester in ethanol, 10 p1 of drug sample in methanol and 10 pl of 1.2 pg/ml human recombinant

PLA

2 group II enzyme. The enzymatic reaction was then initiated with 10 p1 of 0.84 M CaCI 2 Following incubation at room temperature for 10 minutes, the reaction was terminated by addition of 25 pl of 1 M EDTA and p1 of 10 mg/ml P-cyclodextrin. Fluorescence measurements were carried out with a JASCO Corporation FP-777 spectrofluorometer. Excitation and emission wavelengths were 345 nm and 380 nm, respectively. All data are the average of at least duplicate determinations corrected for the spontaneous fluorescence of the reaction medium. Data were expressed as percent inhibition.

Reference F. Radvanyi, L. Jordan, F. Russo-Marie and C. Bon: A sensitive and continuous fluorometric assay for phospholipase

A

2 using pyrene-labeled phospholipids in the presence of serum albumin. [Anal. Biochem. 177 pages 103-109 (1989)] WO 97/03951 PCT/JP96/01995 30 [II] Test Compound 3 carboxypentanoyl]oxy-4-(2-naphthyl)butanamide (the compound of Example 24) [III] Test Result Percent inhibition dose inhibition 1 x 10-6 100 The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object compound or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous, intramuscular and intra-articular) administrations or insufflation.

The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use. And, if necessary, in addition, auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.

The object compound or a pharmaceutically acceptable salt thereof is/are included in the pharmaceutical composition in an amount sufficient to produce the desired WO 97/03951 PCT/JP96/01995 31 effect upon the process or condition of the diseases.

The pharmaceutical composition of the present invention can be manufactured by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavailability of a drug can be applied to the pharmaceutical composition of the present invention.

For applying the composition to a human being or an animal, it is preferable to apply it by intravenous (including i.v. infusion), intramuscular, pulmonary, or oral administration, or insufflation including aerosols from metered dose inhalator, nebulizer or dry powder inhalator.

While the dosage of therapeutically effective amount of the object compound varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.001-100 mg of the object compound per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.001-100 mg of the object compound per kg weight of a human being or an animal, in the case of oral administration, a daily dose of 0.001-200 mg of the object compound per kg weight of a human being or an animal is generally given for the prevention and/or the treatment of aforesaid diseases in a human being or an animal.

The following preparations and examples are given only for the purpose of illustrating the present invention in more detail.

WO 97/03951 PCT/JP96/01995 32 Preparation 1 2-(6-Ethylnaphthalen-2-yl)acetic acid (1.88 g) was dissolved in thionyl chloride (9.6 ml) and the mixture was stirred at room temperature for 1 hour and then the mixture was concentrated in vacuo. The residue was dissolved in methylene chloride (20 ml) and the solution was added dropwise to a stirring solution of Meldrum's acid (1.26 g) and pyridine (1.56 ml) in methylene chloride (20 ml) at room temperature. After being stirred overnight at the same temperature, the mixture was washed with 1N hydrochloric acid and the organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol ml) and refluxed for 2 hours and the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with lN hydrochloric acid, water, aqueous sodium bicarbonate and brine, successively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate hexane 1:9, as an eluent) to give methyl 4 -(6-ethyl-2-naphthyl)-3oxobutanoate (0.61 g).

NMR (CDC1 3 5) 7.74 (2H, dd, J=8.0, 7.5Hz), 7.64 (1H, 7.60 (1H, 7.36 (1H, d, J=8.0Hz), 7.28 (1H, d, J=8.0Hz), 3.96 (2H, 3.70 (3H, 3.46 (2H, 2.80 (2H, q, J=7.5Hz), 1.30 (3H, t, ESI-MS 271 [M+H] Preparation 2 Methyl 4-(2-naphthyl)-3-oxobutanoate was obtained according to a similar manner to that of Preparation 1.

NMR (CDC1 3 6) 7.82 (3H, 7.70 (1H, 7.48 (2H, 7.32 (1H, 4.00 (2H, 3.70 (3H, 3.48 (2H, s) WO 97/03951 PCT/JP96/01995 33 Preparation 3 Methyl 4-( 6 -ethyl-2-naphthyl)-3-oxobutanoate (0.60 g), D-camphorsulfonic acid (4.1 mg) and [Ru 2 Cl2((S)-BINAP)2]NEt3 (di[(S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]dichlorodirhutenium triethylamine complex) (4.5 mg) in methanol (6 ml) was hydrogenated at 65°C under hydrogen atmosphere under 10 atmosphere for 5 hours. After cooling at room temperature, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography (ethyl acetate hexane 1:4, as an eluent) to give methyl (3S)-4-(6-ethyl-2-naphthyl)-3-hydroxybutanoate (0.55 g).

NMR (CDC1 3 6) 7.72 (2H, dd, J=8.0, 6.0Hz), 7.64 (1H, 7.60 (1H, 7.32 (2H, t, J=7.5Hz), 4.36 (1H, br 3.70 (3H, 2.96 (2H, ABX), 2.80 (2H, q, J=7.5Hz), 2.52 (2H, ABX), 1.30 (3H, t, ESI-MS 273 [M+H] The following compounds (Preparations 4 and 5) were obtained according to a similar manner to that of Preparation 3.

Preparation 4 Methyl (3R)-3-hydroxy-4-(2-naphthyl)butanoate NMR (CDC1 3 5) 7.74-7.84 (3H, 7.66 (1H, s), 7.4-7.5 (2H, 7.34 (1H, d, J=8.0Hz), 4.36 (1H, 3.70 (3H, 2.98 (2H, ABX), 2.87 (1H, d, 2.52 (2H, ABX) ESI-MS 245 [M+H] Preparation Methyl 3 S)-3-hydroxy-4-(2-naphthyl)butanoate NMR (CDC1 3 5) 7.74-7.84 (3H, 7.66 (1H, s), 7.4-7.5 (2H, 7.34 (1H, d, J=8.0Hz), 4.36 (1H, 3.70 (3H, 2.98 (2H, ABX), 2.87 (1H, d, J=5.0Hz), 2.52 (2H, ABX) WO 97/03951 PCT/JP96/01995 34 ESI-MS 245 [M+H] Preparation 6 To a solution of methyl 3 R)-3-hydroxy-4-(2naphthyl)butanoate (3.02 g) and methanesulfonyl chloride (2.12 g) in methylene chloride (60 ml) was added triethylamine (2.5 g) at 0°C. After being stirred at room temperature for 1.5 hours, the mixture was diluted with ethyl ether and the mixture was washed with 0.5N hydrochloric acid, water, aqueous sodium bicarbonate and brine, successively.

The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in DMF ml) and sodium azide (2.02 g) was added to this solution.

After being stirred at 60°C for 1 hour, the mixture was diluted with ethyl ether and the mixture was washed with water and brine. The organic layer was dried with magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol (100 ml) and hydrogenated at room temperature under hydrogen atmosphere under atmospheric pressure for 6 hours. The catalyst was filtered off and the solvent was removed under reduced pressure. The residue was dissolved in 4N hydrogen chloride in ethyl acetate (50 ml) at room temperature. After being stirred at the same temperature for minutes, the mixture was concentrated in vacuo and the residue was triturated with ethyl ether to give methyl (3S)- 3 -amino-4-( 2 -naphthyl)butanoate hydrochloride (0.44 g) NMR (CDC1 3

-CD

3 0D, 6) 7.74-7.84 (3H, 7.72 (1H, 7.42-7.52 (2H, 7.34 (1H, d, J=8.0Hz), 3.90 (1H, 3.46 (1H, dd, J=15.0, 5.0Hz), 3.12 (1H, dd, J=15.0, 10.OHz), 2.80 (2H, ABX) Preparation 7 Methyl (3S)-4-(6-ethyl-2-naphthyl)- 3 -hydroxybutanoate (0.54 g) was dissolved in 15N ammonia in methanol (5 ml) at room temperature and the mixture was allowed to stand for six WO 97/03951 PCT/JP96/01995 days. The solvent was evaporated in vacuo and the residue was triturated with isopropyl ether to give 3 SV-4-(6-ethyl.

2 -naphthyl) 3 -hydroxybutanamide (0.49 g).

NNR (DMSO-d 6 6) 7.76 (2H, dd, J=8.0, 4.0Hz), 7.64 (2H, 7.34 (2H, d, J=8.0Kz), 7.28 (1H, br s), 6.80 (1H, br 4.86 (1H, d, J=4.0Hz), 4.14 (1H, in), 2.80 (21H, d, J=7.5Hz), 2.74 (2H, q, 2.16 (2H, d, J=7.5Hz), 1.26 (3H, t, The following compounds (Preparations 8 and 9) were obtained according to a similar manner to that of PreagratioQn 7.

Pre3-Laatipf 8 3 S)-3-Aino-.4-( 2 -naphthyljbutanamide NMR (CDC1 3 :7.8 (4H, mn), 7.64 (1H, 7.44 (3K, in), 7.30 (1K, d, J=10.0Kz), 3.5 (1K, in), 3.00 (1K, dd, J=12.0, 7 .5Hz), 2.76 (1H, dd, J=12.0, 10.0Hz), 2.48 (1H, dd, J=15.0, 5.0Hz), 2.25 (1H, dd, J=15.0, 10.0Hz) ESI-MS :229

LM+H]

Pearation 9 (3S)- 3 -Hydroxy-4- 2 -naphthyl) butanainide NM-R (DMSO-d 6 6) :7.78-7.90 (3H, in), 7.70 (1K, s), 7.34-7.52 (3K, in), 7.30 (1H, br 6.82 (1H, br 4.90 (1K, d, 4.14 (1H, in), 2.74-2.90 (2H, mn), 2.15 (2H, d, J=5. OHz) Preparatio A mixture of 2 -acetyl-6-.ethylnaphthalene (9.09 g) and inorpholine (6 ml) and sulfur (2.2 g) was heated at 12000 for one hour and then refluxed for ten hours. The mixture was cooled to room temperature and diluted with ethyl acetate.

The mixture was washed with 1N hydrochloric acid, aqueous WO 97/03951 PCT/JP96/01995 36 sodium bicarbonate and brine, successively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate hexane 1:1, as an eluent) to give 6-ethyl-2-naphthylacetothiomorpholide. The thiomorpholide thus obtained was dissolved in acetic acid ml), concentrated sulfuric acid (3 ml) and water (4.5 ml) and the mixture was refluxed for five hours. The mixture was cooled to room temperature and poured into ethyl acetate and the mixture was washed with water and brine, successively.

The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to give 2-(6-ethylnaphthalen-2-yl)acetic acid (1.90 g).

NMR

(CDC

3 6) 7.74 (2H, t, J=7.5Hz), 7.70 (1H, s), 7.60 (1H, 7.36 (2H, t, J=7.

5H 3.80 (2H, s), 2.80 (2H, q, J=7.5Hz), 1.30 (3H, t, ESI-MS 213

[M-H]

Preparation 11 To an ice-cooled suspension of sodium hydride (60% in oil dispersion, 6.75 g) in tetrahydrofuran (50 ml) was added (10.1 g) in tetrahydrofuran (50 ml).

After stirring for 30 minutes, l-bromononane (31.1 g) in tetrahydrofuran (100 ml) was added. This mixture was refluxed overnight, poured into saturated aqueous ammonium chloride (300 ml), and extracted with diethyl ether (300 ml) The organic phase was separated, washed with water (300 ml) and brine (200 ml), dried over magnesium sulfate, and evaporated to dryness. The residue was chromatographed on a silica gel (1000 cc), eluting with ethyl acetate in n-hexane to give 4 -pentenyl nonyl ether (17.2 g).

NMR (CDC1 3 5) 5.83 (1H, 4.92-5.07 (2H, m), 3.35-3.45 (4H, 2.12 (2H, 1.48-1.73 (4H, m), 1.17-1.39 (12H, 0.87 (3H, t, J=7Hz) WO 97/03951 PCT/JP96/01995 37 Preparation 12 A solution of 4 -pentenyl nonyl ether (7.0 g) in a mixture of methanol (150 ml) and dichloromethane (50 ml) was cooled to -78°C. Ozone was passed through this solution keeping temperature below -60*C until the color turned to be light blue. Then, methylsulfide (12.1 ml) was added dropwise, and this solution was warmed to room temperature over 3 hours. The resulting solution was concentrated and partitioned between diethyl ether (150 ml) and water (100 ml). The ethereal solution was dried over magnesium sulfate and evaporated to dryness to give a crude product of 1,1dimethoxy-4-nonyloxybutane (7.76 g).

NMR (CDC1 3 6) 4.38 (1H, t, J=5Hz), 3.42 (2H, t, J=6Hz), 3.38 (2H, t, J=6Hz), 3.32 (6H, 1.37- 1.73 (6H, 1.17-1.41 (12H, 0.88 (3H, t, J=7Hz) Preparation 13 To an ice-cooled solution of l,l-dimethoxy-4nonyloxybutane (3.00 g) in acetone (150 ml) was added 2N Jones' reagent drop by drop. After stirring for 1 hour at 4°C, isopropyl alcohol was added until the orange color disappeared. This solution was neutralized with 1N aqueous sodium hydroxide, concentrated in vacuo, acidified with IN hydrochloric acid, saturated with ammonium chloride, and extracted with ethyl acetate (50 ml). The organic phase was washed with brine, dried over magnesium sulfate, and evaporated to dryness to give 4 -nonyloxybutyric acid (2.68 g).

NMR (CDC1 3 6) 3.35-3.52 (4H, 2.48 (2H, t, J=7Hz), 1.90 (2H, 1.47-1.66 (2H, 1.16-1.41 (12H, 0.88 (3H, t, J=7Hz) Preoaration 14 To a solution of 4 -nonyloxybutyric acid (2.66 g) and a WO 97/03951 PCT/JP96/01995 38 drop of dimethylformamide in dichloromethane (50 ml) was added oxalyl chloride (1.11 ml). This solution was stirred for 1 hour and concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 ml), and added to a solution of Meldrum's acid (1.66 g) and pyridine (1.87 ml) in dichloromethane (25 ml) at 4°C. This solution was stirred at room temperature overnight. The resulting mixture was washed with 10% hydrochloric acid (50 ml x 3) and water, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in methanol, and refluxed for 3 hours.

Then., the mixture was evaporated in dryness, and chromatographed on a silica gel (150 cc) eluting with ethyl acetate in n-hexane to give methyl 6-nonyloxy-3oxohexanoate (0.96 g).

NMR (CDC13, 5) 3.74 (3H, 3.47 (2H, 3.41 (2H, t, J=6Hz), 3.36 (2H, t, J=6Hz), 2.63 (2H, t, J=7Hz), 1.86 (2H, 1.47-1.61 (2H, 1.18-1.40 (12H, 0.88 (3H, t, J=7Hz) Preparation Methyl (3S)-3-hydroxy-6-nonyloxyhexanoate was obtained according to a similar manner to that of Preparation 3.

NMR (CDC13, 5) 4.04 (1H, 3.71 (3H, 3.49 (1H, d, J=3Hz), 3.45 (2H, t, J=6Hz), 3.41 (2H, t, J=7Hz), 2.41-2.53 (2H, 1.46-1.80 (6H, 1.17- 1.38 (12H, 0.88 (3H, t, J=7Hz) Preparation 16 (3S)- 3 -Hydroxy-6-nonyloxyhexanamide was obtained according to a similar manner to that of Preparation 7.

NMR (CDC1 3 5) 6.37 (1H, br 5.33 (1H, br s), 4.39 (1H, d, J=2Hz), 3.99 (1H, 3.40-3.53 (4H, 2.30-2.44 (2H, 1.49-1.82 (6H, 1.18-1.41 (12H, 0.87 (3H, t, J=7Hz) WO 97/03951 PCT/JP96/01995 39 Preparation 17 To an ice-cooled solution of methyl (3R)-3hydroxyhexadecanoate (5.35 g) and triethylamine (5.21 ml) in dichloromethane (50 ml) was added methanesulfonyl chloride (2.17 ml). After stirring in an ice-water bath for minutes, this solution was poured into a mixture of ethyl acetate (150 ml) and IN hydrochloric acid (150 ml). The organic phase was separated and washed with IN hydrochloric acid (100 ml), saturated aqueous sodium bicarbonate (100 ml), and brine (100 ml). Dryness over magnesium sulfate and evaporation gave methyl (3R)- 3 -methanesulfonyloxyhexadecanoate (6.77 g).

NMR (CDCL 3 6) 5.04 (1H, 3.72 (3H, 3.02 (3H, 2.78 (1H, dd, J=16, 8Hz), 2.65 (1H, dd, J=16, 5Hz), 1.77 (2H, 1.15-1.55 (22H, 0.88 (3H, t, J=7Hz) Precaration 18 A solution of methyl (3R)-3methanesulfonyloxyhexadecanoate (6.77 g) and sodium azide (2.33 g) in dimethylformamide (60 ml) was heated to 60°C for minutes. This solution was poured into a mixture of ethyl acetate (300 ml) and water (500 ml). The organic phase was separated and washed with water (500 ml) and brine (300 ml).

The resulting solution was dried over magnesium sulfate and evaporated to dryness to give methyl (3S)-3azidohexadecanoate and some by-products. This crude product g) was used in the next step without any further purification.

Preparation 19 Methyl 3 S)-3-azidohexadecanoate (5.0 g) in methanol ml) was hydrogenated over 100 palladium on carbon (0.50 g) under atmospheric pressure of hydrogen for 4 hours at room temperature. Then, the catalyst was filtered off with celite WO 97/03951 PCT/JP96/01995 40 and the filtrate was concentrated under reduced pressure.

The residue was dissolved with 4N hydrogen chloride in ethyl acetate (20 ml), evaporated, and triturated with diisopropyl ether (20 ml) to give methyl (3S)-3-aminohexadecanoate hydrochloride (930 mg).

NMR (CDCl 3 5) 3.75 (3H, 3.60 (1H, 2.74-2.93 (2H, 1.57-1.98 (4H, 1.14-1.51 (20H, m), 0.87 (3H, t, J=7Hz) Preparation To a suspension of methyl (3S)-3-aminohexadecanoate hydrochloride (890 mg) in water (1.8 ml) was added formalin (0.67 ml) and cyclopentadiene (1.14 ml) successively. The mixture was sonicated for 15 minutes, and stirred for hours. The resulting mixture was washed with n-hexane, made basic with saturated sodium bicarbonate, and extracted with chloroform The combined organic phase was dried over magnesium sulfate, and concentrated under reduced pressure.

To the residue in dichloromethane (12 ml) and trifluoroacetic acid (12 ml) was added triethylsilane (1.32 ml). This mixture was stirred overnight, and evaporated. This residue was dissolved in ethyl acetate (30 ml), washed with saturated aqueous sodium bicarbonate (20 ml), and dried over magnesium sulfate. After evaporation, the residue was purified on a silica gel (20 cc) to give methyl (3S)-3- (methylamino)hexadecanoate (686 mg) NMR (CDC1 3 5) 3.69 (3H, 2.98 (1H, 2.89 (1H, br 2.50 (2H, 2.45 (3H, 1.18-1.63 (24H, 0.87 (3H, t, J=7Hz) Preparation 21 Methyl 4-(3-benzo[bjfuranyl)-3-oxobutanoate was obtained according to a similar manner to that of Preparation 1.

NMR (CDC13, 6) 7.64 (1H, 7.43-7.57 (2H, m), 7.21-7.36 (2H, 3.92 (2H, 3.71 (3H, s), WO 97/03951 PCT/JP96/01995 41 3.52 (2H, s) Preparation 22 Methyl 3 -benzo[b]furanyl)-3 -hydroxybutanoate was obtained according to a similar manner to that of re 3.

NMR (CDC1 3 6) 7.58 (1H, d, J=7Hz), 7.52 (1H, s), 7.47 (IH, d, J=7Hz), 7.19-7.34 (2H, 4.39 (1H, 3.68 (3H, 2.80-3.08 (3H, 2.42-2.65 (2H, m) Preparation 23 To an ice-cooled solution of methyl benzo[b]furanyl)-3-hydroxybutanoate (250 mg) in methanol (2 ml) was added N aqueous sodium hydroxide (1.1 ml). This solution was stirred at room temperature overnight. Then it was diluted with water (20 ml), washed with diethyl ether ml), acidified with 1N hydrochloric acid (1.4 ml), extracted with ethyl acetate (10 ml x and dried over magnesium sulfate. After evaporation, the residue was dissolved in dimethylformamide (2 ml). To this solution, HOBt (1hydroxybenzotriazole) (136 mg), WSCD-HCl [l-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride] (193 mg) was added successively. After 30 minutes, 28% ammonium hydroxide (91 pl) was added, and the mixture was stirred overnight.

Then, the resulting mixture was diluted with 1 N hydrochloric acid (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was washed with IN hydrochloric acid (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine.

Dried over magnesium sulfate, evaporated to dryness, and chromatographed on a silica gel (20 cc) to give benzo[b]furanyl)-3-hydroxybutanamide (110 mg).

NMR (DMSO-d 6 5) 7.76 7.65 (1H, d, J=7Hz), 7.53 1 H, d, J=8Hz), 7.19-7.40 (3H, 6.82 (1H, br 4.94 (I1, d, J=6Hz), 4.17 (1H, 2.79 (1H, WO 97/03951 PCT/JP96/01995 42 dd, J=15, 5Hz), 2.70 (1H, dd, J=15, 7Hz), 2.11 (2H, d, J=7Hz) Preparation 24 To a suspension of methyl triphenylphosphoranylideneacetate (2.45 g) in tetrahydrofuran (20 ml) was added 2-carboxybenzaldehyde (1.0 g) at 4"C. The resulting clear solution was stirred at room temperature for 30 minutes, and concentrated under reduced pressure. The residue was diluted with chloroform (20 ml) and extracted with saturated aqueous sodium bicarbonate (20 ml x The combined aqueous phase was washed with diethyl ether (20 ml), acidified with lN hydrochloric acid (pH and extracted with ethyl acetate ml x The combined organic phase was washed with water (20 ml), brine (20 ml), dried over magnesiu sulfate, and evaporated to dryness. The residue was triturated with diisopropyl ether to give methyl 2 -carboxycinnamate (350 mg) NMR (CDC1 3 8.55 (1H, d, J=16Hz), 8.12 (1H, d, J=8Hz), 7.56-7.67 (2H, 7.49 (1H, 6.34 (1H, d, J=16Hz), 3.83 (3H, s) Preparation t-Butyl 2-carboxycinnamate was obtained according to a similar manner to that of Preparation 24.

NMR (CDC1 3 6) 8.47 (1H, d, J=16Hz), 8.10 (1H, d, J=8Hz), 7.54-7.67 (2H, 7.47 (1H, 6.27 (1H, d, J=16Hz), 1.55 (9H, s) Preparation 26 A solution of methyl 2-carboxycinnamate (100 mg), palladium(II) acetate (5 mg) and potassium formate (108 mg) in dimethylformamide (1 ml) was stirred at 600C under nitrogen flow. The mixture was diluted with saturated aqueous ammonium chloride (20 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with water WO 97/03951 PCT/JP96/01995 43 ml) and brine (20 ml), dried over magnesium sulfate, and evaporated to dryness. The residue was triturated with diisopropyl ether to give methyl 3-(2carboxyphenyl)propionate (82 mg).

NMR (CDC1 3 6) 8.06 (1H, 7.49 (1H, 7.33 (3H, 3.34 (2H, t, J=8Hz), 2.72 (2H, t, J=8Hz) Preparation 27 t-Butyl 3 2 -carboxyphenyl)propionate was obtained according to a similar manner to that of Preparation 26.

NMR (CDC1 3 6) 8.04 (1H, d, J=7Hz), 7.47 (1H, t, J=7Hz), 7.27 (2H, 3.29 (2H, t, J=7Hz), 2.53 (2H, t, J=7Hz), 1.42 (9H, s) Preparation 28 3-( 2 -Carboxyphenyl)propionamide was obtained according to a similar manner to that of Preparation 7.

NMR (DMSO-d 6 5) 7.77 (1H, d, J=8Hz), 7.45 (1H, dd, J=7, 6Hz), 7.17-7.38 (3H, 6.74 (1H, br 3.11 (2H, t, J=8Hz), 2.37 (2H, t, J=8Hz) Precaration 29 In a three-necked flask, under nitrogen flow, was placed magnesium turnings (1.26 In this flask, was added a solution of l-bromohexane (8.59 g) in tetrahydrofuran (100 ml) dropwise. When the addition was completed, the whole was stirred for 30 minutes. The resulting mixture was added to an ice-cooled mixture of 4 -bromobenzyl bromide (10.0 g) in tetrahydrofuran (100 ml) and 0.1M dilithium tetrachlorocuprate in tetrahydrofuran (10 ml). This mixture was stirred at 4°C for 1.5 hours and at room temperature overnight. Then, it was poured into a mixture of ice and IN hydrochloric acid (300 ml), and extracted with diethyl ether (300 ml). The etheral solution was washed with water (300 ml), saturated aqueous sodium bicarbonate (150 ml), and WO 97/03951 PCT/JP96/01995 44 brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified on a silica gel (200 cc) eluting with n-hexane to give l-bromo-4heptylbenzene (7.61 g).

NMR (CDC1 3 5) 7.38 (2H, d, J=8Hz), 7.04 (2H, d, J=8Hz), 2.55 (2H, dd, J=7, 8Hz), 1.48-1.67 (2H, m), 1.17-1.38 (8H, 0.88 (3H, t, J=7Hz) Preparatin l-Allyl-4-heptylbenzene was obtained according to a similar manner to that of Preparation 29.

NMR (CDC 3 5) 7.12 (2H, d, J=8Hz), 7.08 (2H, d, J=8Hz), 5.97 (1H, 5.02-5.13 (2H, 3.36 (2H, d, J=7Hz), 2.58 (2H, t, J=8Hz), 1.60 (2H, m), 1.19-1.40 (8H, 0.88 (3H, t, J=7Hz) Preparation 31 To a mixture of 1-allyl-4-heptylbenzene (2.4 acetone ml) and water (40 ml) was added sodium metaperiodate (11.9 g) and potassium permanganate (70 mg). This mixture was stirred at room temperature overnight. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting aqueous solution was extracted with ethyl acetate (60 ml), and the organic phase was washed with water (60 ml) and brine (30 ml). This solution was dried over magnesium sulfate, and evaporated to dryness. The residue was purified on a silica gel (40 cc) eluting with methanol in chloroform to give l-allyl-4-heptylbenzene (1.82 g) and 2-(4-heptylphenyl)acetic acid (300 mg).

NMR (CDC1 3 5) 7.11-7.23 (4H, 3.62 (2H, 2.57 (2H, dd, J=8, 7Hz), 1.59 (2H, 1.18-1.42 (8H, 0.87 (3H, t, J=7Hz) Preparation 32 Methyl 4 -heptylphenyl)-3 -hydroxybutanoate was WO 97/0395 1 PCT/JP96/OI 995 obtained according to a similar manner to that of Pre~araion 3.

NMYR (ODdl 3 6) 7.12 (4H, 4.25 (1H, mn), 3.69 (3H, 2.70-2.88 (3H, in), 2.39-2.61 (4H, mn), 1.59 (2H, in), 1.20-1.39 (8H, mn), 0.87 (3H, t, J=7Hz) PearptL- io n 33 Methyl 4- 4 -heptylphenyl)- 3 -oxobutanoate was obtained according to a similar manner to that of EPaato NMR (ODdl 3 6) :7.15 (2H, di, J=8Hz), 7.10 (2H, cd, J=8Hz), 3.78 (2H, .3.70 (3H, 3.45 (2H, s), 2.58 (2H, in), 1.59 (2H, in), 1.20-1.40 (8H, mn), 0.88 Pre~arat ion 34 (3S) 4 -Heptylphenyl)- 3 -hydroxybutanamide was obtained according to a similar manner to that of eLaration 7.

NMVR (ODC1 3 6) :7.12 (4H, 5.88 (1H, br 5.41 (1K, br 4.23 (1H, mn), 3.24 (1H, d, J=3Hz), 2.84 (1H, dci, J=14, 7Hz), 2.76 (1K, dci, J=14, 7Hz), 2.57 (2H, dd, J=8, 7Hz), 2.44 (1H, dci, J=15, 3Hz), 2.33 (1K, dci, J=15, 8Hz), 1.51-1.67 (2H, mn), 1.18-1.40 (8H, in), 0.88 (3H, t, J=7Hz) Exainole 1 (2S) -S-BenzYioxycarbonyl- 2 -(tert-butoxycarbonylanino) pentanoic acid dicyclohexylamonium salt (1.00 g) was suspended with ethyl acetate and the mixture was washed with sulfuric acid, water and brine, successively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in inethylene chloride (10 ml) and to this was added DMAP

(N,N-

dimethylaminopyridjfle) (469 mng), PyBOP (benzotriazole..1.

ylx-rsproiio~opoiu hexafluorophosphate) (1.07 g) and (3)3hdoy4(-ahhlbtnmd (430 mng) at WO 97/03951 PCT/JP96/O1 995 46 room temperature. After being stirred overnight at the same temperature, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, aqueous ammioniumn chloride, aqueous sodium bicarbonate and brine, successively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (2"0 methanol in chloroform, as an eluent) to give (3S)-3-[(S--bnyoycroy-2(et butoxycarbonylamino)peltan 0 y 1 ]oxy-4- (2-naphthyl) butanainide (0.96 g).

NNR (CDCl 3 1 5) 7.80 (3H, in), 7.66 7.44 (2H, mn), 7.34 (9H, in), 5.86 (1H, br 5.54 (1H, in), 5.30 (1H, br 5.06 (2H, 5.00 (iN, d, J=l0Kz), 4.18 (1H, in), 3.14 (2H, dd, J=8.0, 2.46 (2H, in), 2.22 (2H, in), 1.5-1.6 (4H, in), 1.42 (9H, s) The following compounds (Examp~les 2 to 5) were obtained according to a similar manner to that of Exain l.

Exa inle 2 (3S) (3-Benzo fbifuranyl) -3-f (2S) -S-benzyloxycarbonyl 2- (tert-butoxycarbonylanino)penfl noflloxybutanamide NMP. (ODC 3 6) :7.64 (1H, mn), 7.53 (1K, 7.48 (1H, d, J=8Hz) 7.22-7.41 (7H, in), 5.82 (1H, br 5.64 (1H, in), 5.27 (1H, br 5.10 (2H, 4.97 (1K, in), 4.22 (1H, mn), 3.10 (2H, d, J=6Hz), 2.50 (2H, d, J=7Hz), 2.35 (2H, mn), 1.62-1.84 (4H, mn), 1.44 (9H, Example 3 (3S) -3-f (2S) -S-Benzyloxycarbonyl> -(tertbutoxycarbonylamino) pentanoyl] oxy-4- 4 -heitylphenyl) butanainide NMR (CDC1 3 7.30-7.39 (5H, mn), 7.09 (4H, 5.82 WO 97/03951 PCT/JP96/01995 47 (1H, br 5.43 (1H, 5.26 (1H, br 5.10 (2H, 5.01 (2H, 4.22 (1H, 2.97 (1H, dd, J=14, 7Hz), 2.89 (1H, dd, J=14, 7Hz), 2.55 (2H, dd, J=8, 7Hz), 2.32-2.45 (4H, 1.50-1.72 (6H, m), 1.44 (9H, 1.21-1.36 (8H, 0.88 (3H, t, J=7Hz) Example 4 (3S)-3-[(2S)-5-Benzyloxycarbonyl-2-tertbutoxycarbonylaminopentanoyl]oxy- 6 -nonyloxyhexanamide NMR (CDC1 3 6) 7.31-7.42 (5H, 5.90 (1H, br s), 5.25-5.34 (2H, 5.11 (2H, 5.05 (1H, d, J=8Hz), 4.23 (1H, 3.40 (2H, t, J=6Hz), 3.37 (2H, t, J=7Hz), 2.47 (2H, d, J=6Hz), 2.41 (2H, m), 1.49-1.92 (6H, 1.44 (9H, 1.21-1.37 (12H, 0.88 (3H, t, J=7Hz) Example 3 S)-3-[N-Methyl-{( 2 S)-5-benzyloxycarbonyl-2-(tertbutoxycarbonylamino)pentanoyl}amino]hexadecanamide NMR (CDC1 3 6) 7.25-7.4 (5H, 6.22 (1H, br s), 5.40 (1H, br 5.25 (1H, d, J=8.0Hz), 5.10 (2H, 4.75 (1H, 4.52 (1H, 2.90 (3H, 2.3- (4H, 1.45-1.75 (6H, 1.43 (9H, 1.15- 1.35 (22H, 0.88 (3H, t, ESI-MS 618 [M+H] PreDaration (3S)-3-[(2S)-5-Benzyloxycarbonyl-2-(tertbutoxycarbonylamino)pentanoyl]oxy-4-(2-naphthyl)butanamide (0.94 g) was dissolved in 4N hydrogen chloride in ethyl acetate (50 ml) at room temperature. After being stirred for 1 hour at the same temperature, the mixture was diluted with ethyl acetate and the resulting solid was collected by filtration to give 3

S)-

3 -[(2S)-2-amino-5- WO 97/03951 PCT/JP96/01995 -48 benzYloxycarbonylpentanoylj oxy-4- 2 -naphthyl)butananide hydrochloride (0.67 g).

NMR (DMSO-d 6 5) :8.60 (3H, br 7.88 (311, mn), 7.80 (1H, 7.3-7.55 (9H, mn), 6.90 (JH, br 5.50 (1H, in), 5.10 (2H, 3.94 (1H, mn), 3.10 (2H, mn), 2.42 di, J=7.5Kz), 2.28 (2H, mn), 1.72 (2H, in), 1.54 (2H, in) The following compounds (Preparations-36 to 41) were obtained according to a similar manner to that of Preparation Preparation 36 3

S)-

4 -(3-Benzo[blfuranyl)-3-[( 2 2 -aininopentanoyl] oxybutanainide NMR (DMSO-ci 6 5) :8.52 (2H, br 7.88 (1K, 7.72 (1H, dd, J=6, 3Hz), 7.56 (1H, cd, J=8Hz), 7.47 (1H, br 7.21-7.41 (7H, mn), 6.91 (1H, br 5.48 (1H, in), 5.08 (2H, 3.98 (1K, in), 2.96-3.09 (2H, mn), 2.45 (2K, di, J=6Hz), 2.36 (2H, t, J=7Hz), 1.47- 1.89 (4H, mn) Preiparation 37 (33) -3-1 (2S) -S-Benzyloxycarbonyl..ainopentanoyly 4 (4-heptylphenyl) butanaiice hydrochloride NIR (DMSo-d 6 :8.42 (2H, br 7.43 (1K, br s), 7.31-7.41 (5K, mn), 7.11 (4H, 6.87 (1H, br s), 5.38 (1K, mn), 5.07 (2H, 3.97 (1K, in), 2.87 (2K, mn), 2.29-2.40 (4K, mn), 1.42-1.83 (6H, in), 1.16-1.35 (8K, in), 0.85 (3K, in) P~raIrtion 3 8 2 S)-S5-Benzyloxycarbonyl-2-.ainopentanoyloxy-6 nonyloxyhexanaie hydrochloride NNR (DMSO-ci 6 :8.42 (2H, br 7.45 (1H, br s), WO 97/03951 PCT/JP96/01995 49 7.28-7.41 (5H, 6.87 (1H, br 5.23 (1H, m), 5.09 (2H, 3.99 (2H, 3.25-3.36 (4H, m), 2.31-2.44 (4H, 1.35-1.90 (10H, 1.10-1.32 (12H, 0.85 (3H, m) Preparation 39 (3St) 4- 2 naphthyl)butanamide hydrochloride NMR (CDC1 3 5) 8.66 (1H, br 8.46 (3H, br s), 7.56 (5H, br 7.1-7.4 (9H, 4.86 (2H, s), 4.42 (1H, 4.06 (1H, 3.22 (1H, 2.94 (1H, 2.76 (1H, 2.36 (1H, 1.16-2.0 (6H, m) Preparation 3 S)-3-[N-Methyl-{( 2 benzyloxycarbonylpentanoyl }aminohexadecanamide hydrochloride NMR (CDC1 3 5) 8.3-8.5 (3H, 8.14 (1H, br s), 7.2-7.4 (5H, 7.14 (1H, br 5.08 (2H, s), 4.85 1 H 4.14 1 H 2.85 (3H, 1.4-2.8 (10H, 1.1-1.3 (22H, 0.88 (3H, t, Preparation 41 (3S)-3-[(2S)-5-Benzyloxycarbonyl-2aminopentanoyl]aminohexadecanamide hydrochloride NMR (DMSO-d6, 5) 8.25 (1H, d, J=8Hz), 8.12 (2H, m), 7.29-7.34 (6H, 6.80 (1H, br 5.08 (2H, s), 4.04 (1H, 3.80 (1H, 2.38 (2H, 2.21 (2H, d, J=7Hz), 1.51-1.86 (4H, 1.10-1.47 (24H, m), 0.85 (3H, t, J=7Hz) Preparation 42 (2S)-5-Benzyloxycarbonyl-2-(tertbutoxycarbonylamino)pentanoic acid dicyclohexylammonium salt (1.07 g) was suspended with ethyl acetate and the mixture was washed with 0.5N sulfuric acid, water and brine, WO 97/03951 PCT/JP96/01995 successively. The organic layer was dried ver magnesium sulfate and concentrated in vacuo. The residue was disolved in methylene chloride (10 ml) and to this was added DMAP (469 mg), PyBOP (1.05 g) and 3 S)-4-(6ethyl s added DMA2 hydroxybutanamide (0.47 ethyl-2-naphthyl)-3 hydroxybutanamide (047 g) at room temperature. After being stirred overnight at the same temperature, the mixture was diluted with ethyl acetate and washed with IN hydrochloric acid, aqueous ammonium chloride, aueous sodium bicarbonate and brine, successively The organic layer was dried over magnesium sulfate and eogac l a y e r w a s d r i e d o v e r 0 magnesied sulfate and concentrated in vacuo. The residue was dissolved in 4N hydrogen chloride in ethyl acetate (20 ml) at room temperature After being stirred for 1 hour at the same temperature, the mixture was diluted with ethyl acetate and the resulting solid was collected by filtration to give (3s)- 3-((2S)-2-amin°-5-benzyloxycarbonylpentanoyl]oxy-4-(6-ethyl- 2-naphthyl)butanamide hydrochloride (0.70 g).

NMR (DMSO-d 6 :8.52 (3H, br 7.80 (2H, dd, J=8.

0 6

.H

b 7.72 (1H, 7.66 (1H, 7.48 2 br .3-7.4 (7H, 6.90 (iH, br 5.50 5.08 (2H, 3.94 (1H, 3.06 (2H, m), 274 (2H J=7.5Hz), 2.40 (2H, d, J=7.5Hz), 2.28 (2H, 1.4-1.8 (4H, 1.24 (3H, t, ExamPle _6 To a stirring solution of 3 S)-3-(2S)2am benzyloxyaca ipento(3S)- 3 -(2)-2-amino-5benzyoxycarbonylpentanoyl]oxy-4- (6-ethyl-2_ naphthyl)butanamide hydrochloride (20 -benzyn carboxylic acid (105 mg) and OBt (62 g) in DF (2 ml) wase-3added WSCD ,71 g a OIC 6 2 mg i n D MF (2 ml) was added WSp D (71 ig) at 00c. After being stirred at room temperature overnight, the mixture was diluted with ethyl acetate and washed with iN hydrochloric acid, aqueous ammonium chloride y d r o c h l acid, aqueous oniuccessivelyoride, aqueou sodium bicarbonate and brine, successively. The organic layer was dried over magnesium sulfate and-oncentrated in vacuo to give S benzylindol-3-ycarbonylamino)-5- WO 97/03951 PCT/3P96/01995 51 benzyloxycarbonylpentanoyljoxy-4-(6-ethyl-2-naphthyl)butanaiide (0.26 g).

NMR. (CDC1 3 6) 8.20 (1H, 8.1 (2H, 7.1-7.8 (19H, 6.66 (1H, d, J=1Oz), 6.1 (1H, br 5.6 (1H, 5.34 (2H, 5.08 (2H, 4.7 (1K, i), 3.1 (2H, 2.74 (2H, q, J=7.5Hz), 2.1-2.6 (4H, in), 1.4-1.9 (4H, 1.28 (3H, t, ESI-MS 724 [M+Hj The following compounds (ExamDes 7to 20) were obtained according to a similar manner to that of Examnrle 6.

Exaiole 7 (3S)-3-f(2S)-2-(l-Benzylindoi-2-ylcarbonylamino)-5benzyloxycarbonylpentanoyljoxy-4- 2 -naphthyl)butanamide NMR (CDC1 3 6) 7.72 (4H, 7.62 (11, 7.1-7.45 (14H, 7.02 (3H, 6.92 (1H, d, J=7.5Kz), 5.82 (1K, br 5.78 (2H, ABq), 5.54 (1H, 5.20 (1H, br 5.10 (2H, 4.54 (1K, 3.08 (2H, m), 2.05-2.45 (4H, 1.70 (2H, 1.44 (2K,

M)

ESI-MS 696 fM+Hj Examole 8 (3S)-3-[(2S)-2-(l-Benzylindol-3-ylcarbonylamino)S benzyloxycarbonylpentanoylioxy-4- (2-naphthyl)butanamide NMR (CDCl 3 6) 8.06 (1H, 7.7 (4H, 7.62 (1H, 7.2-7.4 (15H, 7.16 (1K, d, J=7.5Kz), 6.66 (1K, d, J=7.5Kz), 6.10 (1K, br 5.60 (1H, m), 5.34 (2H, 5.26 (1H, br 5.08 (2H, 4.66 (1K, 3.14 (2H, d, J=7.5Hz), 2.52 (2H, ABX), 2.1-2.3 (2H, 1.65-1.85 (2H, 1.45-1.6 (2H, Im) ESI-MS 696 fM+H] Example 9 WO 97/03951 PCT/JP96/01995 52 (3S)-3-[(2S)-5-Benzloxycarbonyl-2-(2quinolylcarbonylamino)pentanoyl]oxy-4-( 2 -naphthyl)butanaide NMR (CDC1 3 5) 8.70 (1K, d, J=lOHz), 7.3-8.5 (18H, 5.92 (1H, br 5.62 (1H, 5.32 (1K, br s), 5.10 (2H, 4.74 3.16 (2H, d, 2.52 (2H, in), 2.30 (2H, 1.6-2.0 (4I, m) ESI-MS 618

LM+H]

Examole (3S)-3-[(2S)-2-(3-Benzylnaphthalen-2-ylcarbonylamino)-5benzyloxycarbonylpentanoyii oxy-4-( 2 -naphthyl)butanamide NMR (CDC1 3 5) 7.05-7.86 (23H, 6.34 (1H, d, 5.80 (1K, br 5.58 (1K, 5.28 (1H, br 5.04 (2H, 4.50 (1H, 4.34 (2H, ABq), 3.16 (2H, d, J=7.5Hz), 2.48 2.16 (2H, m), 1.44-1.70 (2H, 1.28-1.40 (2H, m) ESI-MS 707 Exapinle 11 3 S)-4-(2-Naphthyl)-3-[( 2 S)-5-benzyloxycarbonyl-2-[2-( 2methoxycarbonylethyl)benzoylaminojpentanoyl oxybutanamide (CDC13, 6) 7.68-7.82 (3H, 7.65 (1K, br s), 7.21-7.46 (12H, 6.93 (1H, d, J=8Kz), 6.02 (1H, br 5.61 (1H, 5.31 (1H, br 5.08 (2K, s), 4.59 (1H, 3.59 (3H, 3.18 (2K, 3.05 (2H, 2.72 (2K, 2.54 (2K, d, J=7Kz), 2.16-2.34 (2H, 1.48-1.86 (4K, m) Exainle 12 (3S)-4-(2-Naphthyl)-3-f(2S) -S-benzyoxycarbonyl t-butoxycarbonylethyl)benzoylainojpentanoyl oxybutanamide NMR (CDC1 3 5) 7.68-7.81 (3K, 7.65 (1H, br s), 7.10-7.48 (13K, 6.10 (1K, br 5.60 (1H, i), 5.28 br 5.06 (2H, 4.56 (1K, 3.18 (2K, 2.93-3.13 (2H, 2.50-2.69 2.22 WO 97/03951 PCT/JP96/01995 53 (2H, 1.50-1.84 (4H, 1.36 (9H, s) Example 13 (3S)-4-(2-Naphthyi)-3-f(2S)-5-benzYioxycarbony1 2 carbamoylethyl)benzoyiaminojpentanoyljoxbutanamide NMR (DNSO-i 6 6) 8.85 (1H, d, J=7Hz), 7.79-7.88 (3H, Yn), 7.75 (1H, br 7.18-7.50 (12H, 6.68 (1H, br 6.82 (1H, br 5.42 (1H, 5.06 (2H, s), 4.31 (1H, ri), 3.13 (1H, dd, J=l4Hz, 5Hz), 3.02 (1H, cd, J=14, 6Hz), 2.92 (2H, d, J=16, 8Hz), 2.33-2.46 (4H, 2.23 (2H, 1.44-1.73 (4H, m) Examle 14 (3S)-3-f(2S)-5-Benzyloxycarbonyl-2-(2quinolylcarbonylainro)pentanoyl] oxy-4-( 4 -heptylphenyi)butanamide NMR (CDC1 3 6) 8.69 (1H, d, J=8Hz), 8.33 (1H, d, J=8Hz), 8.26 (1H, d, J=8Hz), 8.18 (1H, d, J=8Hz), 7.90 (1H, d, J=8Hz), 7.80 (1H, 7.75 (1H, i), 7.28-7.38 (5H, 7.11 (2H, d, J=8Hz), 7.02 (1H, d, J=8Hz), 5.85 (1H, br 5.49 (1H, 5.30 (1H, br 5.10 (2H, 4.76 (1H, in), 2.53-2.86 (2H, 2.35-2.53 (6H, 1.40-2.10 (6H, 1.15-1.34 (8H, 0.88 (3H, t, J=7Hz) Example 3 -Benzo[b]furanyl)-3-[(2S)-5-ben zyioxycarbonyi.

2-( 2 -guinolylcarbonylamin)pentanoyl]oxybutanamide NMR (CDC1 3 6) 8.68 (1H, d, J=8Hz), 8.34 (1H, d, J=8Hz), 8.27 (1H, d, J=8Hz), 8.19 (1H, d, J=8Hz), 7.91 (1H, d, J=8Hz), 7.81 (iH, d, J=8Hz, 7Hz), 7.62-7.71 (2H, 7.54 (1H, 7.43 (1H, i), 7.23-7.37 (7H, 5.86 (1H, br 5.58 (1H, i), 5.28 (1H, br 5.09 (2H, 4.75 (1H, 3.10 (2H, d, J=7Hz), 2.53 (2H, 2.38 (2H, 1.64- WO 97/03951 PCT/JP96/01995 54 2.03 (4H, m) E~xarple 16 (3S)-3-[(2S)-5-Benzyloxycarbony 2-(2quinolylcarbonylamino)pentanoyl] oxy-6-nonyloxyhexanamide R (CDC13, 6) 8.74 (1H, d, J=8Hz), 8.32 (1K, d, J=8Hz), 8.25 (1H, d, J=8Hz), 8.16 (1H, d, J=9Kz), 7.88 (1K, d, J=8Kz), 7.77 (1H, t, J=8Hz), 7.62 (1H, t, J=8Hz), 7.28-7.37 (5H, 5.93 (1K, br 5.36 (1H, 5.28 (1H, br 5.11 (2K, 4.78 (1H, 3.30-3.41 (4H, 2.41-2.53 (4H, 1.45-2.15 ri), 1.15-1.33 (12H, 0.86 (3H, t, J=7Hz) Examlle 17 2 S)-5-Benzyloxycarbonyl-2-(tert butoxycarbonylamino)pentanolj amino-4- 2 -naphthyl)butanamide NMR (CDC1 3 6) 7.74-7.82 (3K, 7.64 (1H, S), 7.3-7.5 (8H, 7.14 (1K, d, J=1O~z), 5.76 (1H, br 5.56 (1K, br 5.08 (1K, d, J=8.OHz), 5.06 (2K, 4.50 (1K, 4.00 (1K, 3.16 (1H, dd, J=12.0, 7.5Kz), 3.02 (1H, d, J=12.0, 7.5Hz), 2.42 (2H, ABX), 2.26 (2K, in), 1.6-1.75 (2H, 1.45-1.6 (2K, 1.4 (9H, s) ESI-MS 562 fM+K] Examle 18 (3S)-3-[(2S)-2-(l-Benzlindol-3-ylcarbonyamin benzyloxycarbonylpentanoyliamino-4- 2 -naphthyl)butanamide NTMIR (DMSO-d6, 6) 8.26 (1H, 8.20 (1H, d, J=8.0Kz), 8.02 (1K, d, J=8.Oz), 7.86 (1K, J=8.Oz), 7.64-7.74 (4K, 7.54 c, 7.1-7.4 (16H, 6.84 (1K, br 5.46 (2K, s), 5.06 (2H, 4.44 (1H, 4.30 (1K, 2.82-3.0 (2H, 2.2-2.4 (4H, 1.4-1.8 (4K, m) ESI-MS 695

LM+H]

WO 97/03951 PCT/JP96/01995 55 Example 19 (3S)-3-[N-Methyl-{(2S)-5-benzyloxycarbonyl-2-(2quinolylcarbonylamino)pentanoyl}amino]hexadecanamide NMR (CDC1 3 5) 8.90 (1H, d, J=8.0Hz), 8.1-8.35 (3H, 7.85 (1H, d, J=8.0Hz), 7.75 (1H, t, 7.62 (1H, t, J=8.0Hz), 7.25-7.35 (5H, 6.32 (1H, br 5.52 (1H, br 5.16 (1H, 5.10 (2H, s), 4.82 (1H, 3.00 (3H, 2.4-2.55 (4H, m), 1.4-2.05 (6H, 1.05-1.4 (22H, 0.88 (3H, t, ESI-MS 673 [M+H] Example (3S)-3-[(2S)-5-Benzyloxycarbonyl-2-(2quinolylcarbonylamino)pentanoyl]aminohexadecanamide NMR (CDC1 3 5) 8.71 (1H, d, J=8Hz), 8.32 (1H, d, J=8Hz), 8.25 (1H, d, J=8Hz), 8.15 (1H, d, J=9Hz), 7.88 (1H, d, J=8Hz), 7.78 (1H, t, J=8Hz), 7.63 (1H, t, J=8Hz), 7.26-7.36 (5H, 6.82 (1H, d, J=8Hz), 6.06 (1H, br 5.35 (1H, br 5.12 (2H, s), 4.62 (1H, 4.18 (1H, 2.37-2.54 (4H, m), 1.48-2.18 (6H, 1.02-1.36 (22H, 0.87 (3H, t, J=7Hz) Examile 21 To a stirring solution of 3

S)-

3 -[(2S)-2-(1-benzylindol- 3 -ylcarbonylamino)-5-benzyloxycarbonylpentanoyl]oxy-4-(6ethyl-2-naphthyl)butanamide (0.24 g) and anisole (717 mg) in methylene chloride (2.5 ml) was added aluminum chloride (442 mg) in nitromethane (2.5 ml) at room temperature. After being stirred for two hours at the same temperature, the mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, water and brine, successively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting solid was triturated WO 97/03951 PCT/JP96/0199 -56with ethyl ether to give 3 S)-3-[(2S)-2-(1-benzylindol-3- Ylcarbonylarnino) -5-carboxypentanoyl oxy-4- (6-ethyl-2naphthyl)butanamide (113 ug).

NMR (DMSO-d, 6) 8.28 (1H, 8.16 (2H, d, 3.0Hz), 7.1-7.8 (14H, 6.86 (1H, br 5.50 (2H, 5.40 (1H, 4.40 (1H, 3.04 (2H, ABX), 2.74 (2H, a, J=7.5Hz), 2.34 (2H, d, 2.18 (2H, t, J=7.5Hz), 1.5-1.8 (4H, 1.24 (3H, t, .The following compounds (ExamPles 22 to 32) were obtained according to a similar manner to that of Example 21.

Example 22 (3S)-3-[(2S)-2-(l-Benzylindol-3-ylcarbonylamino)-5carboxypentanoyljoxy-4-(2-naphthyl)butanaiide NMR (DMSO-d 6 6) 8.28 (1H, 8.20 (2H, d, 7.8 (3H, 7.54 (1H, d, J=7.5Hz), 7.1- 7.6 (11H, 6.86 (1H, br 5.46 (2H, 5.40 (1K, 4.40 (1K, 3.05 (2H, AEX), 2.32 (2H, d, 2.16 (2H, t, J=7.5Hz), 1.70 (2H, 1.55 (2H, m) ESI-MS 606 [M±K] Example 23 (3S)-3-Il (2S)-S-Carboxy-2- 2 -quinolylcarbonyaminno)pentanoyljoxy-4-(2-naphthyl)butanamide NM (CDCl 3 6) 8.72 (i1, d, J=lOHz), 7.15-8.3 (13H, 7.04 (1H, br 6.50 (1K, br 5.60 (1K, i), 4.76 (1H, 2.9-3.2 (2K, 2.44 (2K, 2.24 (2K, 1.35-2.1 (4K, m) ESI-MS 528 [M+K1 Example 24 3 -Benzvlnaphthalen-2-ylc WO 97/03951 PCT/JP96/01995 57 carboxypentanoylioxy-4-(2-nahthyl)butanaice NYR (DMSO-d 6 6) 8.84 (1K, d, J=8.OHz), 7.06-7.98 (19H, in), 6.88 (1H, 5.42 (1K, 4.34 (1K, m), 4.28 (2H, ABq), 3.10 (2H, ABX), 2.36 (2H, d, J=7.5Kz), 2.10 (2K, t, J=7.5Hz), 1.4-1.75 (4K, m) ESI-MS 617 IM+Hl ExainPle (3S)-4-(2-Naphthyl)-3-[(2S)-S-carboxy-2-[2-(2inethoxycarbonylethyl)benzoylaiinojpentanoyljoxybutanamide NMR (DMSO-1 6 6) 8.75 (1K, d, J=8Kz), 7.80-7.91 (3H, 7.78 (1K, br 7.22-7.50 (8K, 6.86 (1H, br 5.42 (1H, in), 4.32 (1H, in), 3.50 (3H, s), 2.90-3.18 (4K, 2.63 (2H, dd, J=8, 7Kz), 2.35 (2K, c, J=7Kz), 2.23 (2K, t, J=7Kz), 1.44-2.72 (4H, in) Exainple 26 (3S)-4-(2-Naphthyl)-3-f(2S)-5-carboxy-2-[2-(2carboxyethyl)benzoylaiino]pentanoylioxybutanai e NMR (DMSO- 6 6) 8.74 (1K, c, J=7Hz), 7.80-7.92 (3H, 7.77 (1H, br 7.22-7.53 (8K, 6.87 (1H, br 5.42 (2K, 4.32 (1K, 3.15 (1H, dd, J=14, 6Kz), 2.86-3.08 (3K, 2.57 (2K, 2.37 (2H, d, J=7Hz), 2.13 (2H, t, J=7Kz), 2.42-1.72 (4H, Ex aipe 27 (3S)-4-(2-Naphthyl)-3-f(2S)-5-carboxy-2-f2-(2carbaioylethyl)benzoylariino]pentanoyljoxybutanamie NYIR (DMSO-d 6 5) 8.86 (1K, d, J=7Hz), 7.80-7.92 (3H, in), 7.75 (1K, br 7.15-7.53 (10K, 6.88 (1H, br 6.73 (2K, br 5.42 (1K, 4.32 (1H, m), 2.82-3.18 (4K, 2.35-2.47 (4K, 2.21 (2K, t, J=7Kz), 1.42-1.77 (4K, m) WO 97/03951 PCT/JP96/01995 58 Example 28 2 S)-5-Carboxy-2 2 -quinolylcarbonylamino)pentanoyl]oxy-4-(4-heptylphenyl)butanamide N1MR (DMSO-d 6 6) 8.95 (1H, d, J=8Kz), 8.62 (1H, d, J=8Hz), 8.20 (1H, d, J=9Hz), 8.17 (1H, d, J=8Hz), 8.12 (1H, d, J=8Hz), 7.90 (1K, t, J=8Hz), 7.74 (1H, t, J=8Hz), 7.37 (1H, br 7.08 (1H, d, J=8Kz), 6.92 (1H, d, J=8Hz), 6.80' (1H, br 5.33 (1H, m), 4.51 (1K, in), 2.87 (lH, d, J=14, 6Hz), 2.78 (1H, dc, J=14, 7Hz), 2.19-2.40 (4H, 1.84 (2H, m), 1.53 (2H, in), 1.36 (2K, 1.10-1.30 (8H, 0.83 (3H, t, J=7Hz) Example 29 2 S)-5-Carboxy-2- 2 -quinolycarbonylamino pentanoyl oxy-6-nonyloxyhexanaide NMR

(CDC'

3 8.84 (1H, d, J=8Hz), 8.32 (1H, d, J=8Kz), 8.26 (1K, d, J=8Kz), 8.17 (1H, c, J=8Hz), 7.88 (1K, c, J=8Hz), 7.78 (1H, 7.63 (1H, m), 7.13 (1K, br 6.25 (1K, br 5.43 (1K, i), 4.83 (1K, 3.31-3.46 (4H, 2.34-2.77 (4H, i), 1.90-2.20 (2H, 1.40-1.88 (10K, 1.14-1.37 (12K, in), 0.86 (3H, t, J=7Hz) Example (3S)-3-[(2S)-2-(l-Benzylindol-3-ylcarbonylamino)-5carboxypentanoyljamino-4-(2-nahthyl)butanaice NMR (DMSO- 6 5) 8.24 (1K, 8.20 (1K, d, J=8.Oz), 8.04 (1H, d, J=8.OHz), 7.84 (1H, d, J=8.0Kz), 7.64-7.74 (4H, 7.54 (1H, c, 7.1-7.4 (11H, 6.84 (1K, br 5.44 (2H, s), 4.42 (1H, in), 4.30 (1H, 2.8-3.0 (2H, 2.26 (2K, c, J=7.5Kz), 2.16 (2H, t, J=7.5Hz), 1.4-1.75 (4K, m) ESI-MS 605

[M+K]

WO 97/03951 PCT/JP96/01995 59 Exam-ole 31 (3S)-3--N-Methyl-f(2S) -5-carboxy- (2quinolycarbonylamino)pentanoyl aminojhexacecanamide INM-R (CDC13, 5) 9.00 (1H, d, J=8.0Hz), 8.26 (2H, s ABa), 8.16 (1K, d, J=8.0Kz), 7.86 (1H, d, 7.75 (1H, t, J=8.OHz), 7.60 (1K, t, J=8.O0z), 7.10 (1H, br 6.80 (1K, br 5.20 (1K, 5.10 (1H, 3.05 (3H, 2.58 (1H, dc, J=15.0, 2.34-2.50 (3H, 1.4-2.1 (6H, 1.0-1.35 (22H, 0.86 (3H, t, ESI-MS 583 [M+l] Examole 32 (3S)-3-f(2S)-5-Carboxy-2- 2 -quinolylcarbonylamino)pentanoylaiinohexadecanamide NMR

(DMSO-

6 8.75 (1K, d, J=9Hz), 8.09 (1H, c, J=9Hz), 8.17 (2H, c, J=8Hz), 8.10 (1K, d, J=8Hz), 8.07 d, J=9Hz), 7.88 (1H, t, J=8Hz), 7.73 (1H, t, J=8Hz), 7.27 (1H, br 6.79 (1H, br 4.55 (1H, 4.06 (1H, 2.12-2.30 (4H, 1.32-1.91 (6H, 0.95-1.30 (18H, 0.83 (3H, t, J=7Hz) Examole 33 A Solution of 3 S)-3-[(2S)-2-(l-benzylindl- 2 ylcarbonylamino)-5-benzyloxycarbonylpentanoylioxy-4-(2naphthyl)butanamide (0.22 g) in water (0.4 an methanol (4 ml) was hydrogenate over 10% palladium on carbon (40 ig) under atmospheric pressure of hydrogen for two days at room temperature. Then the catalyst was filtered off with celite and filtrate was concentrated under reduced pressure. The resadue was triturated with ether and chloroform to give (3S)-3-[(2S)-2-(l-benzylindl-2-ylcarbonylamino)-5carboxypentanoyl]oxy-4- 2 -naphthyl)butanamide (168 mg).

NMR (DMSO-d 6 5) 8.92 (1H, c, 7.05-7.85 (18H, 6.86 (1K, br 5.80 (2H, ABq), 5.40 WO 97/03951 PCT/1P96/O 1995 Mn), 4.32 (lH, Mn), 3. 02 (2H, AB3X) 2.50 (2H, 2.32 (2H, d, J=7.5Hz), 2.1-5 (211, t, 1.65-1.8 (2H, mn), 1.4-1.65 (2H, in) ESI-MS 606

LM+HJ

A mixture of 3 S)-4-(3-benzobfuranyl) 3 benzyloxvcroy2(-uinolylc.> nyamn 1] anyloxybutanamide (184 ing), cyclohexene (0.31 ml), and palladium on carbon (130 ing) in dioxane (1 ml) was refluxed for 2.5 hours. After filtration with celite, and filtrate was partitioned between ethyl acetate (20 ml) and water MI) The organic phase was washed with brine, dried over mnagnesium sulfate, and concentrated in vacuo. The residue was triturated in diethyl ether (5 ml) to give benzo[bifuranyl) 3 2 S)-5-carboxy2-(2 quinolvlcarbonylamino)ptaoy oxybutanamide (107 mng).

NM'R (DMSO-d 6 6) 9.02 (1H, d, J=8Kz), 8.61 (1K, d, J=8Kz), 8.21 (1K, d, J=8Hz), 8.17 (1K, d, J=8Kz), 8.12 (1H, d, J=8Hz), 7.91 (1H, t, J=8Kz), 7.70-7.79 (2K, mn), 7.52 (1K, dd, J=7, 2Kz), 7.41 (1K, br s), 7.12-7.34 (2K, in), 6.89 (1H, br 5.45 (1H, in), 4.53 (1K, mn), 3.03 (2H, mn), 2.42 (2K, in), 2.23 (2H, t, J=7Hz), 1.86 (2H, mn), 1.55 (2K, mn) Exainole A solution of (3S)-4-(2-naphthyl)3-( 2 benzyloxycarbonyl.

2 2 -t-butoxvcarbonylethyl) benzoylai~inopentanoyloxbutanm (160 mng) in 4N hydrogen chloride in ethyl acetLate (1 ml) was stirred at room temperature for four hours. Then, the mixture was concentrated in vacuo, dissolved in ethyl acetate (20 ml), washed with water (20 ml x 2) and brine (20 ml), and dried over magnesium sulfate. After evaporation, the residue was triturated in diisopropyl ether to give 3 S)-4-(2-naphthyl)- WO 97/03951 PCT/JP96/O1 995 61 3-f (2S) -5-benzyloxycarbony>> 2 2 -carboxyethyl) benzoylaminolpentanoyij oxybutanaiie (91 mng).

NMR (CDCJ.J, 7.66-7.80 (3K1, mn), 7.60 (1H, br s), 7.17-7.46 (12H, mn), 7.04 (1K, di, J=8Hz), 6.33 (1H, br 6.21 (1H, br 5.60 (1H, mn), 5.05 (2H, s), 4.62 mn), 2.92-3.20 (4H, mn), 2.50-2.69 (4H, mn), 2.19-2.32 (2H, mn), 1.45-1.81 (4H, mn) Preparation 43 (R)-3Hydrxyhxadeanamidewas obtained according to a simil1ar manner to that of PreQaratin 23.

NYIR (DMSO-d6, 5) 26 (1K, br s) 6. 88 (1K, br s) 4.58 (1H, di, J=5Kz), 3.75 (1H, in), 2.11 (2H, d, J=6 Hz), 1.14-1.40 (24H, in), 0.84 (3H, t, J=7Hz) Pre~paration 44 To a solution of 3

R)-

3 -hydroxyhexaciecanamide (6.4 g) and triethylainine (6.57 ml) in dichioroinethane (130 ml) and dimethylsulfoxiie (130 ml) was added methanesulfonyl chloride (2.74 mnl) This mixture was stirred at room temperature for 6 hours, and the resulting precipitate was filtered off. The lilauor was concentrated, and dissolved in ethyl acetate (500 ml) This solution was washed with 1N-hydrochloric acid (800 ml x saturated sodium carbonate (500 ml), and brine (200 ml) Drying over magnesium sulfate and concentration, the resi~due was chroinatographei on a silica gel, eluting with a mixture of dichloroinethane and methanol (50 to give (3R) -3-(mtanslonlxyhxdeaaid (4.16 g).

NMR (CDC1 3 6) :5.68 (1H, br 5.45 (1K, br 5.04 (1K, in), 3.04 (3H, 2.62 (2H, d, J=7Kz), 1.81 (2H, in), 1.35-1.50 (22K, in), 0.87 (3H, t, J=7Hz) Preiaration A solution of (3R) -3-(mtaeufnlxyhxdcnmd (4.16 g) and sodium azide (1.55 g) in dimethy1forinamide WO 97/03951 PCT/JP96/01995 62ml) was heated at 60°C for 2 hours. The cooled mixture was partitioned between ethyl acetate (300 m) and water (500 l) Tine 00organic phase was washed with water (300 ml), and brine (200 ml). Dried, concentrated under vacuum, the residue was purified on a silica gel (200 cc) to give (3S)-3azidohexadecanamide (2.20 g).

NMR (CDC1 3 5) 5.62 (1H, br 5.40 (1H, br 3.85 (1H, 2.42 (1H, dd, J=15Hz, 6Hz), 2.34 dd, 8Hz), 1.18-1.64 (24H, 0.88 (3H, t, =7 Hz) Preoartipn 46 A mixture of (3S)-3-azidohexadecanamide (2 palladium on carbon (320 mg) was hydrogenated at atmospheric pressure for 10 hours. The catalyst was filtered off with celite, and the liquor was concentrated under reduced pressure The residue was triturated in diisopropyl ether (30 ml) to give 3 S)-3-aminohexadecanamide.

NMR (DMSO-d6,5) :7.36 (1H, br 6.72 (1H, br s), 2.89 (lH, 2.08 (1H, dd, J=14Hz, 5Hz), 1.94 (1H, dd, J=14Hz, 8Hz), 1.13-1.52 (24H, 0.85 (3H, t, J=7Hz) (3S)-3-aminohexadecanamide thus obtained was dissolved in 4N hydrogen chloride in ethyl acetate (15 ml), and concentrated under reduced pressure. The residue was triturated in diisopropyl ether to give (3S)-3aminohexadecanamide hydrochloride (1.55 g) Prepratipn 47 To an ice-cooled solution of 3 S)-3-aminohexadecanamide (300 mg) and propionaldehyde (71 pl) in methanol (6 ml) was added sodium cyanoborohydride (61 mg). After 2 hours, propionaldehyde (71 pl) and sodium cyanoborohydride (61 mg) was added. The solvent asution was stirred overnight. Then, the solvent was evaporated, diluted with water (20 ml), and WO 97/03951 PCT/JP96/01995 63 extracted with chloroform (20 ml). The organic phase was washed with brine (20 ml), dried over magnesium sulfate and evaporated to dryness. The residue was purified on a silica Sgel (20 cc) eluting with 1 1 0 methanol in chloroform to give 3 S)-3-(propylamino)hexadecanamide (240 mg).

NMMR (CDCl 3 5) 7.52 (1H, br 5.61 (IH, br 3.05 (1H, 2.34-2.88 (5H, 1.49-1.73 (4H, 1.16 -1.45 (22H, 0.99 (3H, t, J=7Hz), 0.88 (3H, m) Example 36 (3S) -3-[N-Propyl-(2S)-5-benzyloxycarbonyl-2-(tertbutoxycarbonylamino)pentanoyl}amino]hexadecanamide was obtained according to a similar manner to that of Exmle 1.

Preparatio (3S)-3-[N-Propyl-{(2S)- 2 benzyloxycarbonylpentanoyl}aminohexadecanamide was obtained according to a similar manner to that of Preparation Example 37 (3S)-3-[N-Propyl-{( 2 S)-5-benzyloxycarbonyl-2-(2quinolylcarbonylamino)pentanoyl}amino]hexadecanamide was obtained according to a similar manner to that of Example 6.

Example 38 (3S)-3-[N-Propyl-{(2S)-5-carboxy-2-(2quinolylcarbonylamino)pentanoyl}amino]hexadecanamide was obtained according to a similar manner to that of Examle 21.

NMR

(CDC

1 3 5) 8.83 (1H, d, J=9Hz), 8.12-8.34 (3H, 7.86 (1H, d, J=8Hz), 7.76 (1H, t, J=7Hz), 7.61 (1H, J=7Hz), 6.52 (2H, br 5.10 (2H, m), 3.08-3.50 (2H, 2.33-2.72 (4H, 1.47-2.16 (8H, 1.05-1.40 (22H, 1.00 (3H, t, J=7Hz), 0.87 (3H, t, J=7Hz) WO 97/03951 PCT/JP96/0199 64 The following compounds (Prepa;rationsq 4n and 50) were obtained according to a similar manner to that of Preparation Pregaration 49 Methyl 4- 4 -biphenylyl)-3-oxobutanoate rap: 8 0-82-C Methyl 3-oxo10-phenyldecanoate NYR (CDCl 3 6) :7.1-7.25 (5K, mn), 3.74 (3H, s), 3.44 (2H, 2.5-2.7 (4H, in), 1.5-1.7 (4H, mn), 1.2-1.4 (6H, mn) FAB-MS 277

[M+HJ

The following compounds (Peaaioss o 60) were obtained according to a similar manner to that of 3.

ZPartons Methyl -4-(4nhpy pey--yroyuaot NMR (CDC1 3 6) :7.12 (4H, 4.25 (1K, in), 3.70 (3H-, 2.7-2.9 (3H, mn), 2.4-2.6 (4H, in), 1.55-1.65 (2H, mn), 1.2-1.4 (8K, mn), 0.88 (3H, t, J=7Hz) Prepoaration 52 Methyl (3R) 4 -nbuty)pheny3hydrbutaot NMR (OD1 3 65) :7.1 (4H, 4.24 (1H, mn), 3.70 (3K, 2.7-2.85 (3K, mn), 2.4-2.6 (4H, in), 1.5-1.65 (2K, in), 1.25-1.45 (2K, mn), 0.90 (3H, t, J=7Kz) Methyl 4 -rethylphenyl) -J-hydroxybutanoate NM? (ODC1 3 6) 7.1 (4K, 4.22 (1H, mn), 3.68

(OH,

2.76 (21H, AEX), 2.48 (2H, ABX), 2.32 (3K, s) WO 97/03951 PCT/JP96/01995 Pre~aation54 Methyl (3S)- 3 -hydroxy-5-(2npty~pnaot NMR (ODC1 3 5) .74-7.83 (32, mn), 7.64 (1H, s), 7.38-7.50 (2H, Qn, 7.35 (1HK, d, J=8Hz), 4.06 (1.H, Qn, 3.71 (3K, 2.82-3.06 (3H, mn), 2.42-2.60 (2H, Qn, 1.77-2.03 (2H, in) Methyl (3S) (fldecyloxy) 3 -hydroxypentanoate NMR (ODC1 3 5) :4.24 (1H, in), 3.71 (3H, 3.56-3.68 (2H, in, 3.53 (1K, di, J=3Kz), 3.42 (2H, t, J=7Kz), 2.48-2.54 (2H, in, 1.69-1.86 (2H, Qn, 1.50-1.61 (2H, in, 1.18-1.38 (14K, in, 0.87 (3K, t, J=7Hz) Preparatjon_56 Methyl (3S) 4 -biphenyly1)-3-.hydroxybutaot Prepratin 57 Methyl (3R)- 3 -hydroxyiocecanoate NMR (ODC1 3 5) :4.0 (1K, Qn, 3.8 (3H, 2.82 (1K, d, J=3Kz), 2.44 (2K, ABX), 1.2-1.55 (14H, in, 0.88 (3H, t, J=7Kz) Methyl (3)3hdoyoaot NMR (ODC1 3 5) :4.0 (1K, mn), 3.72 (3K, 2.85 (1H, di, M2Kz), 2.45 (2K, ABX), 1.2-1.6 (10K, in, 0.86 (3K, t, J=7Kz) Preparation Methyl (3R)-3hdoyhpaot NMR (ODCd 3 5) :4.0 (1K, in, 3.7 (3K, 2.82 (1K, d, J=3Kz), 2.44 (2H, ABX), 1.2-1.55 (6K, in, 0.88 (3K, t, J=7Kz) WO 97/03951 PCT/JP96/01995 66 Preparation Methyl (3R) (G-ethyl-2-naphthyl) 3 -hydroxybutanoate NNR (CDC1 3 5) 7.74-7.84 (3H, mn), 7.66 (1H, 7.4- (2Hn, 7.34 (1H, di, J=8Hz), 4.36 (1W, mn), 3.7 (2H, ABX), 2.87 (1H, di, J=5H-z), 2.52 (2H, ABX) ESI-MS: 245 [M-iH] The following compounds (Preparations 61 to 72) were obtained according to a similar manner to that of Preparation 7.

Prepoarat;jon61 (3R) 4 -n-Hepty)pheny1.>-hyroxybutmide NNR (CDC1 3 6) :7.12 (4H, 5.88 (1H, br 5.46 (1H, br 4.22 (iN, in), 3.26 (1W, di, J=3Hz), 2.7- 2.9 (2H, mn), 2.54-2.62 (2H, mn), 2.38 (2H, ABX), 2.54-2.66 (2H, mn), 1.2-1.4 (8H, mn), 0.88 (3H, t, J=7Hz) Prenaration 62 (3R) 4 -n-Buty1)pheny1..>hyiroxybutmde NMR (DMSO-ci 6 6) :7.2.6 (1H, br 7.06 (4H, 6.78 (1W, br 4.76 (1W, di, J=5Hz), 4.02 (1H, mn), 2.60 (2W, di, J=7Wz), 2.5 (2W, mn), 2.10 (2W, di, J=7Wz), 1.45-1.6 (2W, mn), 1.2-1.35 (2W, mn), 0.88 (3H, t, j=7Wz) PreiparatonQ (3R) 4 -Methylphenyl) 3 -hydroxybutanaie NMR (DMSO-ci 6 6) :7.26 (1W, br 7.06 (4H, 6.78 (1W, br 4.76 (1H, di, J=5Hz), 4.00 (1W, mn), 2.60 (2W, di, J=7Wz), 2.24 (3H, 2.10 (2H, di, J=7Wz) Prelparation 64 3 -Wydroxy-4- (2-naphthyl) butanamicie WO 97/03951 PCT/JP96/01995 67 NMR (DMSO-d 6 6) 7.78-7.90 (3H, 7.70 (1H, s), 7-34-7.52 (3H, 7.30 (1H, br 6.82 (1K, br 4.90 (1K, d, 4.14 (1K, 2.74-2.90 (2H, 2.15 (2H, d, PreDaraion (3S)-3-Hydroxy-5-( 2 -naphthyl)pentanamide NMR (DMSO-d6, 6) 7.80-7.90 (3H, 7.69 (11, s), 7.36-7.52 (3K, 7.28 (1H, 6.80 (1H, br s), 4.79 (1K, d, J=5Hz), 3.85 (1H, 2.68-2.96 (2H, 2.21 (2K, d, J=6Kz), 1.60-1.84 (2K, m) Pre aration 66 (3S)-5-(n-Decyloxy)-3-hydroxypentanamide Rf 0.16 methanol in chloroform) Preparation 67 (3S -3-Hydroxy-10-phenydcecanide NMR (CDC1 3 5) 7.1-7.35 (5K, 5.80 (1K, br s), 5.50 (1K, br 3.98 (1K, 3.30 (1H, d, J=3Hz), 2.5-2.65 (2K, 2.2-2.45 (2K, 1.2-1.7 mn) FAB-MS 264

[M+KJ

Prearation 68 4 -Biphenylyl)-3-hydroxybutanamide NMR (DMSO-d 6 5) 7.25-7.7 (10K, 6.85 (1K, br s), 4.86 (1K, d, J=7.5Kz), 4.10 (1K, 2.52 (2K, s), 2.15 (2K, d, FAB-MS 256

EM+H

Preparation 69 (3R)-3-Hydroxydodecanamide NMR (CDC1 3 5) 5.85 (1K, br 5.52 (1K, br s), 4.0 (1K, 3.3 (1K, d, J=3Hz), 2.4 (2K, ABX), WO 97/03951 PCT/JP96/j1995 68 1.2-1.6 (16H-, mn), 0.90 (3H, t, J=7Hz) Pre~arption (3R)- 3 -HWydroxynonanaiie NM'R (ODC1 3 5) :5.85 (1H, br 5.52 (1W, br (1H, in), 3.3 (1HW, br 2.38 (2H, ABX), 1.2-1.7 mn), 0.88 (3H, t, J=7Hz) Preparation 71 (3R)- 3 -Hydroxyheptanaie N MR (ODC1 3 5) :5.85 (1H, br 5.6 (1H, br (1H, mn), 3.32 (1H, br 2.38 (2H, ABX), 1.2-1.8 (8H, in), 0.88 (3H, t, J=7Hz) kPpaAtI1n 7_2 (3R) (6Ethyl-2-naphthyl) 3 -hydroxybutananide MRP (DMSO-d 6 5) :7.76 (2H, dd, J=8, 4Wz), 7.64 (2W, 7.34 (2W, di, J=8Hz), 7.28 (2H, br 6.80 (1W, br 4.86 (1W, d, J=4Hz), 4.14 (1W, mn), 2.8 (2H, d, J=7.5Hz), 2.74 (2H, q, J=7.5Wz), 2.16 (2H, d, 1.26 (3H, t, 4 -(flButyl)phenyijacetic acid was obtained according to a similar mnanner to that of Paration MR (ODC1 3 5) :7.10-7.22 (4H, mn), 3.60 (2W, 2.58 (2W, dci, J=B, 7Wz), 1.41-1.64 (2H, in), 1.27-1.42 (2H, in), 0.92 (3H, t, J=7Wz) The fol'lowing comnpoundis (Preparations 74 to 77) were obtained according to a simnilar inanner to that of Pexparation 14.

Preparation 74 Methyl 4- 4 -n-butyl)phenyl3oxobutante WO 97/03951 PCT/1P96/0I 995 69 NMR (ODC1 3 5) 7.05-7.15 (4H, in), 3.76 (2H, 3.70 3.42 (2H, 2.58 (2H, t, J=7Hz), 1.65 (2H, mn), 1.25-1.4 (2H, mn), 0.92 (3H, t, J=7HZ) Preparation Methyl 4- 4 -iethylrhenyl)- 3 -oxobutanoate NI'4R (CDC1 3 5) :7.0-7.15 (4H, mn), 3.74 (2H, 3.68 (3H, 3.42 (2H, 2.3 (3K, s) Preiparation 76 Iethyl 5- (2-naphthyl) 3 -oxopentanoate INMR (ODdi 3 :7.74-7.83 (3H, mn), 7.63 (1K, br s), 7.38-7.49 (2H, in), 7.32 (1H, d, J=8Hz), 3.72 (3H, 3.46 (2H, 3.09 (2H, t, J=7Kz), 2.97 (2H, t, J=7Hz) Preparation 77 Methyl 5- (n-decyloxy) 3 -oxopentanoate NMR (ODC1 3 5) :3.74 (3H, 3.67 (2H, t, J=7Hz), 3.51 3.39 (2H, t, J=7Hz), 2.78 (2H, t, J=7Hz), 1.46-1.58 (2K, in), 1..18-1.36 (14K, mn), 0.87 (3H, t, J=7Hz) The following compounds (Preparatipns 78 to 85) were obtained according to a similar inanner to that of Preparation 17.

(3R) -4-(4--etlpey -ehaeufnlxbtnmd NM?.R (CDCl 3 5) :7.05-7.2 (4K, in), 5.6 (1H, br 5.4 (1H, br 5.12 (1K, in), 3.08 (2K, d, J=7Kz), 2.70 (3H, 2.52-2.62 (4K, in), 1.5-1.65 (2K, in), 1.2- 1.35 (8H, mn), 0.88 (3H, t, J=7Hz) Preparation 79 WO 97/03951 PCT/JP96/01995 70 4 -n-Buty1)phenyl-3-methanesulfonyloxybutid INR (CDC1 3 5) 7.05-7.2 (4K, 5.64 (1H, br s), 5.54 (1K, br 5.14 (1H, 3.08 (2H, d, J=7Hz), 2.70 (3H, 2.54-2.64 (4H, 1.5-1.65 (2H, m), 1.25-1.4 (21, 0.92 (3H, t, J=7Hz) Preparation (3R)-4-(4-Methyphenyl) 3 -ethanesulfonloxybutanaide NMR (CDC1 3 5) 7.05-7.15 (4H, 5.60 (1K, br s), 5.44 (1H, br 5.14 (1H, 3.08 (2K, d, J=7Kz), 2.70 (3H, 2.64 (2H, d, J=7Hz), 2.30 (3H, s) Preparation 8i (3R)- 3 -Methanesulfonyloxy-4.(2-naphthyl)butanamide Preparation 82 (3R)-3-Methanesulfonyvoxydodecanamide NMR (CDC1 3 5) 5.72 (1K, br 5.52 (1H, br s), 5.05 (1H, 3.04 (3H, 2.62 (2K, d, J=7Kz), 1.83 (2H, 1.2-1.5 (14K, 0.90 (3K, t, J=7Hz) Preparation 83 (3R)-3-Methanesulfonyloxynonanamide NMIR (CDC1 3 5) 5.84 (1K, br 5.76 (1H, br s), 5.02 (1H, 3.02 (3H, 2.6 (2H, d, J=7Kz), 1.7-1.9 (2H, 1.2-1.45 (8K, 0.88 (3H, t, J=7Hz) Prenaration 84 (3R)- 3 -Methanesulfonyoxyheptanamide NM. (CDCI 3 5) 5.9 (1H, br 5.8 (1H, br 5.04 (1K, in), 3.04 (3H, 2.62 (2H, d, J=7Hz), 1.7-1.9 (2K, 1.2-1.4 (4K, in), 0.90 (3K, t, J=7z) Preparation WO 97/03951 PCT/JP96/01 995 71 (3R) (6Ethyl-2-naphthyl) -3methanesulffonyloxybutanamide NMR (DMSO-d 6 7.8 (2H, di, J=8, 4Hz), 7.7 cd, J=8Hz), 7.48 (1H, br 7.28 (2H, dci, J=8, 3Hz), 7.04 (1H, br 5.22 (1H, in), 3.2 (2H, ABX), 2.95 (3H, 2.76 (2H, q, J=7Hz), 2.46 (2H, d, J=7Hz),, 1.26' (3H, t, J=7Hz) The following compounds (Pre-parations 86 to 93) were obtained according to a similar manner to that of Preparation 18-.

Preiparation 86; (3S) -3-Azido-4- 4 -n-heptylphenyl)butanamiie Preparation 87 (33) -3-Azido-4- 4 -n-butyjlphenyl)butanamiie PreiparatiLon- 88 (3S) -3--Azido-4- 4 -iethylphenyljbutanamide Prenaration 89 -3-Azicio-4- 2 -naphthyl)butanaice Pre-oaration (3S)- 3 -Azidododecanaie NI4R (CDCl 3 5) :5.66 (1H, br 5.55 (1H, br s), 3.84 (1H, mn), 2.3-2.5 (2H, mn), 1.58 (2H, t, J=7HZ), 1.2-1.5 (14H, in), 0.88 (3H, t, J=7Hz) Prepar-ation 91 (3S)- 3 -Azidononanamiie NM?. (CDCl 3 5) :5.65 (1H, br 5.55 (1K, br s), 3.86 (1H, mn), 2.4 (2H, ABX), 1.2-1.65 (10K, in), 0.88 (3HK, t, J=7Hz) WO 97/03951 PCT/JP96/01 995 72 (3S)-3>Azidoheptanainide N14R (CDC1 3 3, 6) :5.65 (1H, br 5.55 (1K, br s), 3.82 (1K, mn), 2.4 (2H, ABX), 1.2-1.7 (6H, mn), 0.9 (3H, t, J=7Iiz) Pre-paratipn 93 (3S)-3-Azido-4- (E6ethy1-2-.naph1hy)butanaide The ffollowing compounds (Preparations 94 to 101) were obtained according to a similar manner to that off Preparatip

D

19.

Pre-para~tion 94 (3S) -3-Ainfl-4-(4nhpy zey~btnmd hvdrochloride NMR (DMSO-d 6 65) 8.04 (3H, br 7.62 (1H, br s), 7.05-7.2 (5H, mn), 3.56 (1H, in), 2.96 (1H, dd, J=12, 2.74 (1K, dd, J=12, 8Hz), 2.5-2.6 (2H, mn), 2.35 (2H, d, J=7Hz), 1.5-1.65 (2H, mn), 1.2-1.35 (8H, mn), 0.86 (3H, t, J=7Hz) (3S) 3 -Ainino-4- 4 -n-butylpheny.) butanamide hydrochloride NMR (DMSO-d 6 65) :8.06 (3H, br 7.62 (1K, br s), 7.1-7.2 (5H, in), 3.58 (1K, mn), 2.96 (1H, dd, J=12, 8Hz), 2.74 (1H, dd, J=12, 5Hz), 2.54 (2H, t, J=7Hz), 2.36 (2H, d, J=7Hz), 1.48-1.62 (2H, in), 1.22-1.38 (2K, mn), 0.90 (3H, t, J=7Hz) Preparation 96 (3S) -3-Ainino-4- 4 -rethylphenyl) butanamide hydrochloride NNMR (DMSO-d 6 6) 8.06 (3H, br 7.62 (1H, br s), 7.05-7.2 (5K, mn), 3.56 (1H, mn), 2.96 (1H, dd, J=12, 5Hz), 2.74 (1K, dd, J=12, 8Hz), 2.74 (2H, t, WO 97/03951 PCT/JP96/OI 995 73 J=7Kz), 2.34 (2H, di, J=7Hz), 2.28 (3H, s) Prelopration 97 (3S) -3-.Ainino-4- 2 -naphthyl) butanaiie NM?. (CD 3 OD-0DC1 3 3, 6) :7.75-7.87 (3H, in), 7.64 (1H, 7.42-7.54 (2H, mn), 7.32 (1K, di, J=BKz), 7.1.

(0.25H, br 5.62 (0.25H, br 3.54 (1H, in), 2.98 (1H, cid, J=14, 6Kz), 2.76 (1K, dd, J=14, 8Kz), 2.46 (1H, dci, J=15, 3Kz), 2.26 (1H, dd, J=15, 8Kz) Preparation 98 (3S) -J-Aininododecanamide hydrochloride NMTR (DMSO-ci 6 6) :8.04 (3K, br 7.66 (1K, br s), 7.12 (1K, br 3.32 (1K, in), 2.42 (2K, d, J=7Kz), 1.38-1.6 (2K, mn), 1.15-1.38 (14K, mn), 0.84 (3K, t, J=7Hz) Pre~paration 99 (3S)- 3 -Ainononanaide hydrochloride NM?. (DM30-cl 6 6) 8.08 (3K, br 7.68 (1H, br s), 7.12 (1H, br 3.32 (1K, in), 2.44 (2K, ci, J=7Hz), 1.4-1.65 (2H, in), 1.2-1.4 (8H, in), 0.86 (3K, t, J=7Kz) Preparation 100 (33)- 3 -Arninoheptanainide NM?. (DMSO-d 6 6) :7.36 (1K, br 6.72 (1K, br s), 2.94 (1K, in), 2.10 (1K, dci, J=12, 5Kz), 1.96 (1K, cid, J=12, 8Kz), 1.15-1.4 (6K, mn), 0.84 (3H, t, J=7Hz) Pre-oarption 101 (33) -3-Ainino-4- (6-ethyl-2-napohthyl)butananide NM?. (DMSO-d 6 6) :7.8 (2H, in), 7.7 (2K, ci, J=7Kz), 7.62 (1H, br 7.36 (2K, in), 7.1 (1K, br 3.7 WO 97/03951 PCT/JP96/01995 74 (1W, 3.16 (iN, d, J=12, 5Hz), 2.95 (1W, dd, J=12, 7Hz), 2.76 (2H, q, J=7Hz), 2.4 (2H, d, J=7HZ), 1.26 (3H, t, J=7Hz) The following compounds (Prearations 102 to 127) were obtained according to a similar manner to that of LLeaalttio 47.

PreDarat ion 1 02 2 -Naphthyl)-3-(n-proy-ainn)butanamini NMR (CDCl 3 5) 8.20 (1H, br 7.76-7.86 (3H, i), 7.60 (1H, 7.4-7.5 (2H, 7.30 (1H, c, J=8Hz), 5.34 (1H, br 3.26 (1H, 2.98 (2H, d, J=7, 2Hz), 2.65 (2H, t, J=7Hz), 2.52 (1H, d, J=12, 3Hz), 2.26 (1W, dd, J=12, 5Hz), 1.4-1.6 (2H, i), 0.88 (3H, t, J=7Hz) ESI-MS 271 [M+Hj Pre aration 10 3 (3S)-3-(n-Butyl)amino-4-(4 n -heptylphenyl)butanamide N-4R (CDC1 3 5) 8.26 (1W, br 7.0-7.2 (4H, m), 5.34 (1W, br 3.12 (1H, 2.76 (2H, d, J=7Hz), 2.54-2.7 (4H, 2.48 (1W, d, J=12, 3Hz), 2.20 (1H, d, J=12, 5Hz), 1.5-1.7 (6H, 1.2-1.5 (8H, mn), 0.85-0.95 (6H, m) Pre aration 104 (3S)-3-(n-Butyl)amino-4-(4-n-butylphenyl)butananmide N-4R (CDC1 3 5) 8.08 (1H, br 7.0-7.2 (4H, i), 5.38 (1H, br 3.15 (1H, 2.0-2.9 (9H, i), 1.25-1.65 (8H, 0.85-0.95 (6H, m) Preoaration 4 -n-Butvl)phenyl-3- (n-propylamino)butanamide NMR (CDC13, 5) 7.82 (1W, br 7.0-7.2 (4H, m), WO 97/03951 PCT/JP96/01995 75 5.46 (Il, br 3.20 (1K, in), 2.25-2.95 (9H, i), 1.25-1.65 (6H, 0.85-0.95 (6H, in) Preartion 106 4 -Methylphenyl) -3-(nPropylaiino) butanmde (CDC13, 5) 8.22 (1H, br 7.0-7.2 (4H, n), 5.34 (1H, br 3.12 (1H, 2.76 (2H, dd, J=7, 3Hz), 2.62 (2H, dt, J=7, 2Hz), 2.46 (1H, d, J=12, 3Hz), 2.32 (3H, 2.20 (1H, dd, J=12, 7Hz), 1.4- 1.55 (2H, 0.88 (3H, t, J=7Hz) PreDaration 107 (3S)-3-(n-Butyl)amino-4-(2-naphthy )butanamide NMR (CDC1 3 5) 8.20 (1H, br 7.76-7.86 (3H, m), 7.60 (1H, 7.4-7.5 (2H, ri), 7.30 d, J=8Hz), 5.34 (1H, br 3.24 (1K, 2.98 (2K, d, J=7, 2Hz), 2.65 (2H, t, J=7Hz), 2.52 (1K, dd, J=12, 3Hz), 2.24 (1H, dd, J=12, 5Hz), 1.2-1.5 (4K, m), 0.88 (3H, t, J=7Hz) Prearaion 108 (3S)-3-Ethylaino-4-( 2 -naphthy1)butanami de Prearaton 09 (3S)-3-Isopetylaminohxadecanamide NMR (CDC1 3 6) 8.12 (1K, br 5.38 (1K, br s), 2.86 (1K, 2.1-2.25 (2K, '.50 (1K, cd, J=12, 3Hz), 2.26 (1K, dc, J=12, 8Hz), 1.2-1.7 (27K, m), 0.8-0.9 (9K, im) ESI-MS 341

LM+K

Prearain (3S)-3-Isobutylaminohexadecanamide NM. (CDC1 3 5) 8.22 (1H, br 5.32 (1K, br s), 2.84 (1K, in), 2.35-2.6 (3K, 2.22 (1H, dc, J12, WO 97/03951 PCT/JP96/O1 995 76 8BHz), 12 .8 (25H, in), 0.92-0. 98 (6H, 0. 86 (3H, t, J=7Hz) ESI-MS 327 Preaatio ii (3s) (2-Naphthyl) (n-Pentylainino)butanamide NMR (ODC1 3 15) :8.20 (1H, br 7.76-7.87 (3H, in), 7.62 (1H, 7.42-7.52 (1H, in), 7.31 (1H, dci, J=8, 3Hz) 5.35 br s) 3.25 (iN, mn), 2. 98 (2H, di, J-7Hz), 2.67 (2H, t, J=7Hz), 2.53 (1H, dci, J=16, 3Hz), 2.24 (1H, dcl, J=16, 7Hz), 1.36-1.50 (2H, mn), 1.18-1.34 (4H, mn), 0.84 (3H, t, J=7Hz) ESI-MS :299

[M+H]

EPaation 1 2 (3S)- 3 -Ethylaninohexadecanamide Preparation 113 (3S) (flButylamino) hexadecanaice NM. (ODd1 3 5) :7.48 (iH, 5.65 (1N, 3.09 (iN, mn), 2.87 (1N, mn), 2.43-2.79 (3H, mn), 1.08-1.76 (28H, in), 0.96 (3H, t, J=7Hz), 0.88 (3H, t, J=7Hz) ESI-MS 327

[N+N]

Prarto11 (3S)- 3 -Phenethylamino) hexadecanaice NNR (ODC1 3 5) :7.95 (1H, br 7.1.5-7.35 (5H, in), 5.08 (iN, br 2.74-3.02 (4N, in), 2.38 (iN, dci, J=16, 3Hz), 2.24 (1H, dci, J=16, 8Hz), 1.08-1.69 (24N, in), 0.88 (3H, t, J=7Nz) ESI-MS 375

[M+H]

(3S) 2 -Pyridyinethylaino) hexaciecanaiice NNR (ODC1 3 :8.56 (1H, in), 8.12 (1N, hr s) 7. WO 97/03951 PCT/JP96/01995 77 (1H, dcl, J=8, 7Hz), 7.16-7.29 (2H, in), 5.31 (1H, br 3.95 (1H, 2.95 (1H, mn), 2.52 (1H, dd, J:=16, 4Hz), 2.24 (1H, dcl, J=16, 7Hz), 1.16-1.68 (24H, mn), 0.88 (3H, t, J=7Hz) ESI-MS: 362 LM+Hl Prenaration 116 (3S) -J-Benzylaninohexalecanaid NNR (CDC1 3 6) :8.09 (1H, br 7.23-7.39 (5H, mn), 5.28 (1H, br 3.83 (1H, d, J=14Hz), 3.76 (1H, cd, J=14Hz), 2.95 (1H, mn), 2.51 (1H, dcl, J=13, 4Hz), 2.24 (1H, dcl, J==13, 8Hz), 1.17-1.67 (24H, in), 0.88 (3H, t, J=7Hz) ESI-MS 361

[M+HJ

Pre~arati 1 7 (3S) (n-Pentylamino) dodecanaiie PreL-aain 18 (3S) (n-Propyanino)loecanaidec Pre~arat~ignl 9 (3S) -3-(n-Pentylamino) nonanaiie PreaatioLn 120 (3S) (n-Butylamino)nonanaice (3S) (n-Propylanino) nonanamicle Preraration 122 (35)-3JEthylaminononanaice ESI-MS: 201 [M+Hl WO 97/03951 PCT/JP96/01995 78 Prenaration 123 (3S) (n-Propylamino) heptanamide Preuaration 12-4 (3S) (f-Butylamino) hep~tanamide ESI-MS :201

[N+HJ

Preparation_ 125 10(3S) (n-Propyl) amino-4- (6-ethyi-2-naphthy)butanamide 2 (3S) (n-Butyl) amino-4- (6-ethyl-2-naphthyl)butananide Preiparatipn 127 (3S) (n-Pentylamino) hexadecanamide NR(ODC1 3 5) :7.80 (1H, br 5.52 (1H, br s), 3.00 (1H, in), 2.63-2.86 (2H, mn), 2.57 (1H, dd, J=13, 8Hz), 2.38 (1H, dd, J=13, 8Hz), 1.18-1.68 mn), 0.84-0.98 (6H, m) ESI-MS: 341

EM+H]

The following compounds (rpatos1 8o15 were obtained according to a similar manner to that of Peprto Prearation 2 8 3 (n-Butyl)-{ 2 pentanoyl }arino] 4 -n-heptylphenyl) butanainide hydrochloride ESI-MS 490

[M+H]

(3S) (n-Propyl) 2 S)-2-aiino4benzyloxycarbolbutanoyl }amino] 2 -naphthyl)butanamide hydrochloride ESI-MS :490 [M(free)+H] WO 97/03951 PCT/JP96/01 995 79 Pre~aration 130 3 (n-Butyl)-{ 2 pentanoyl }amino] 4 -n-butylphenyl)butanamide hydrochloride ESI-MS 524 LM(free)+H] Preparation 131 3 S)-3-N-(n-Propyl)-{ 2 S)-2-ami pentanoyl} amino] 4 -n-butvlphenyl) butanamide hydrochloride ESI-MS 510 [M(ffree)+H] Pre araion 132 3 2 pentanoyl. amino] 4 -methylphenyl)butanamide hydrochloride ESI-MS 468 [M(free)+j Preaaraion 13 3 (n-Butyl)-{ 2

S)-

2 pentanoyl lamino] -4-(2nptv~btnmd hydrochloride ESI-MS 518 [M(ffree)+H] -Peppati 1 34 (3S) [N-Ethyl-f (2S)-2a io--ezlxyabnl pentanoyl }amino] 2 -naphthya) butanamide hydrochloride ESI-MS 4-90 [N(free)+Hj 3 S)-3[N-Isopropyl{ 2)2ain--ezlbyabnl pent anoyl }amino] hexadecanamide hydrochloride ESI-ms 574 [M(ffree)+H] (3S) fN-Isobutyl (2S)-2a io--ezlxyabnl Pentanoyll}amino] hexadecanamide hydrochloride ESI-MS: 560 [M(ffree)+Hj WO 97/03951 PCT/JP96/01995 80 Preiparation 137 3 (n-Pentyl)-{ 2

S)-

2 pentanoyl amino] 2 -naphthyl)butanamnide hydrochloride ESI-MS 532 [M(free)+H] Preiparation 138 (n-Prop~yl)-( 2

S)-

2 pentanoyl }amino] (2-naphthyl) butanamide hydrochloride ESI-MS 504 LM(free)+H] Preparation 139 (3SV-3-LN-Ethyp.( (23) 2 pentanoyll}amino] hexadecanamide hydrochloride ESI-MS 532 [M(free)+H] Preparation 140 (1 3 S-3-N-(n-Propyl)- 2 pentanoy. }amino] hexadecanamide hydrochloride ESI-MS 560

[N+H]

(3S) N-Phenethyl-f((2s)-2a n--ez~oyabnl pentanoyllIamino] hexadecanamide hydrochloride ESI-Ms 608

[M+H]

Preparation 142 (3S) EN- (n-Pentyl)-{ (2S)-2aio5-ezlxyabnl pentanoyllIamino] hexadecanamide hydrochloride ESI-MS 574 LN(ffree)+H] 3

SV-

3 -N-Benzvl-{ (2s)-2aio b~zyoyabnl pentanoyllIamino] hexadecanamide hydrochloride ESI-MS: 594 [M(free)+H] WO 97/03951 PCT/JP96OI 995 (3S) -3-EN- 2 -PyridylImethyl).{ 2 carbonylpentanoyl }aminoj hexadecananide dihydrochioride ESI-MS 595 [N(free) P r e naratILn 14 (3S) -3-f (2S) 2 2 -na-chthyl)pentananide hydrochloride NMR (DMSO-d 6 65) :8.57 (2H, br 7.80-7.92 (3H, in), 7.73 (1H, 7.30-7.45 (8H, in), 6.92 br s), 5.30 (1K, mn), 5.09 (2H, 4.04 (1H, mn), 2.72-2.92 (2H, mn), 2.23-2.50 (4H, in), 1.52-2.07 (6H, in) Preratio 146 (3S)-3-f 2 ypnany oxylO0-phenyidecananide hydrochloride NMR (ODC1 3 6) :8.2 (2H, br), 7.1-7.4 (i1H, mn), 6.75 (1K, 5.3 (1K, mn), 5.08 (2H, 4.02 (1K, t, 2.54 (3K, mn), 2.40 (3K, in), 1.5-2.15 (8H, mn), 1.2-1.35 (8H, mn) Peparaion 1 47 3 E[N-Methyl-{ (2S) 2 amino] propanainide hydrochloride Pre-aatin 14 8 (3S) (n-Pentyl){ (2S) 2 Pentanoyll}amino] dodecanainide hydrochloride Preaaratio 149 (3S) EN- (n-P-ropyl (2S) 2 pentanoyj }amino] dodecanainide hydrochloride ESI-MS: 414 [M(free)+KJ WO 97/03951 PCT/JP96/01 995 82 (33) (n-Pentyl) 2 pent anoyll}amaino] nonanamide hydrochloride Preparation 151.

(3S) -3-fN- (n-Butyl) -f(23) 2 pentanoyll}aminol3nonanamide hydrochloride Preparation 152 (3S) (r-Propyl)- 2

S)-

2 pentanoyl laminolnonanamide hydrochloride LrE rpion 153 (3S) -3-[IN-Ethyl-{ (2S) 2 pentanoyllIamino] nonanamide hydrochloride ESI-MS: 358 [M(ffree)

E]

PrearAt!on-54 (3S) -3-EN- (n-Propyl) 2 pentanoyllIamino] heztanamide hydrochloride (3S) (n-Butyl) 2 S)-2-amino-s..methoxycarbonl pentany. Iamino] heptanamide hydrochloride ESI-ms 358 [M(free)+HlI Preopatin156 (3S) (n-Propyl)-{ (23) 2 pentanoyl.lamin-o]-4-(6eh 2npthlbtnmd hydrochloride Preaat- ion 157 (3S) (n-Butyl)-f(2)2aio--ezlxyabnl pentanoyl lamino] (6-ethyl-2-naphthyl) butanamide hydrochloride WO 97/03951 PCT/JP96/01995 83 The ffollowing CompDounds (Example3 o 43 were obtained according to a Similar manner to that offxap 1 Examp-le 39 -S-BenzYloxycarbonyp.

2 -(tertbutoxycarbonvi amino) pentanoylj oXy-1O-phenyldecananide NIR (ODd1 3 15) 4 mn), 5.-9 (1H, br s) 5. 3 (1H, br 5.22 (1H, Mn), 5.1 (2H, 5.06 (1K, d, 10J10.-z), 4.22 208 (2H, 2.3-2.5 (4H, 1.2-1. 9 (30H, mn) .FAB-MS 619 LM±Naj ExampLe (3S) -S-Benzyloxycarbony>.

2 -(tertbutoxycarbonylamino) pentanoyl] oxy-4- 4 -biohenylyl)butananide mp: 94-980C Example 4 3 S)-3-[N-(n.Buty1)( 2 S)-5-benzyloxycarbonyl.

2 -(tertbutoxycarbonylai~ino)ptan1 }amino] 4 -n-butyJlphenyl) butanamide ESI-MS 624 [m+Hj Ex-amplD e 2 13S) -3-f 2 S)-5-Benzyloxycarbony12-(tert- 2 -naphthy1)pentanamide 'N1TR (ODCd 3 7.74-7.84 (3H, in), 7.63 (1H, 7.28-7.51 (8K, in), .5.93 (1H, br 5.33 (1H, in), 5.30 br 5.12 (2H, 4.97 d, J=7Kz), 4-23 (1K, 2.84 (2K, t, J=7Hz), 2.52 (2K, d, J=6Hz), 2.33-2.42 (2K, mn), 2.04-2.18 (2H, mn), 1.60- 1.90 (4K, in), 0.95 (9K, s) Examole 3 (35) -3-f (2S) 5 -Benzyloxycarbonyl- 2 -(tert- WO 97/03951 PCT/JP96/01995 84 (ndecyloxy)pentanamd (CDC 3 6) 7 .31-7.40 (5H, 6.02 (1H, br s), 5.36 5.28 (1H, br 5.12 (2H, 5.06 (1K, d, J=8Hz), 4.23 (1K, 3.34-3.57 (4H, i), 2.59 (1K, dd, J=15, 6Hz), 2.51 dd, J=15, 7Hz), 1.49-201 (8H, 1.44 (9H, 1.21-1.36 (14H, in), 0.88 (3H, t, J=7Hz) The following compounds (Ea1 e 44 to 136) were obtained according to a similar manner to that of Example 6.

ExaMPle 4 4 (3S)-3-[(2S)-s5Benzyloxycarbon-- 2 (methoxycarbonylinethyl)benzoylaiinojpentanoyljoxy-4-( 2 -naphthyl)butanaiide NMIR (CDC1 3 6) 7.72-7.83 (3H, 7.65 (1K, s), 7.52 (1K, d, J=7Hz), 7.22-7.47 (12H, 5.93 (1H, br 5.59 (1K, 5.25(1H br 5.08 (2H, s), 4.59 (1H, 3.93 (1K, d, J=15Hz), 3.80 (1K, d, 3.67 (3H, 3.18 (2K, d, J=7Hz), 2.43-2.59 (2H, 2.16-2.34 (2H, 1.48-1.83 (4H, in) ESI-MS 639

[M+H

Examp1Q (3S)-3-(2S)-5-sBenzyloxycarbonyl-2-[2-(benzyloxy.

carbonylinethyl) benzoylaminoletaolax 4(-nahthyl)but anainide NMR

(CDC

3 6) 7.72-7.82 (3H, 7.66 (1H, 7.52 d, J=7Hz), 7.22-7.47 (17H, 5.89 (1K, br 5.57 (1H, 5.22 (1K, br 5.12 (2K, s), 5.07 (2H, 4.57 (1K, 3.97 (1K, d, J=16Hz), 3.86 (1H, d, J=16Hz), 3.17 (2H, d, J=7Hz), 2.42- 2.57 (2K, 2.13-2.31 (2H, 1.48-1.79 (4H, m) ESI-MS 715 LM KJ WO 97/03951 PCT/JP96/01995 Example 46 (3S)-3-E(2S)-5-Benzyioxycarbonyl-2-£2-((2E)-2inethoxYcarbonYlvinyl)benzoylaminojpentanoyij oxy-4- (2naphthyl)butanamide NTMR (CDC1 3 6) 7.98 (1H, d, J=16Hz), 7.60-7.77 7.29-7.53 (11H, 6.45 (1H, d, J=8Hz), 6.34 (1H, d, J=16Hz), 6.18 (1K, br 5.63 (1K, m), 5.37 (1K, br 5.09 (2H, 4.61 (1H, 3.75 (3K, 3.10-3.26 (2H, 2.54-2.69 (2H, m), 2.12-2.36 (2H, 1.46-1.86 (4K, n) ESI-MS 651

[M+HJ

Example 47 (3S)-3-[(2S)-5-Benzvloxycarbonyl-2-(3-benzylnaphthalen- 2-ylcarbonylamino)pentanoyljoxy-4-( 4 -n-heptylphenyl)butanaide NMR (CDC1 3 6) 7.93 (1H, 7.75-7.88 (2K, 7.66 (1H, 7.46-7.58 (2K, 7.27-7.38 (5K, m), 7.06-7.24 (9K, 6.33 (1K, d, J=7Kz), 5.75 (1H, br 5.46 5.23 (1H, br 5.08 s), 4.53 (1K, 4.47 (1K, d, J=16Kz), 4.28 (1H, d, J=16Hz), 2.88-3.04 (2K, 2.47-2.56 (2K, i), 2.37-2.45 (2K, 2.22-2.32 (2K, 1.38-1.82 (6K, in), 1.15-1.34 (8H, 0.82-0.92 (3K, m) ESI-MS 755

LM+H]

ExamPle 48 (3S)-3-[(2S)-S-Benzyloxycarbony1 2 2 -quinolylcarbonylamino)pentanoyljoxy-5-(2-naphthy)pentanainide NMR (CDC1 3 6) 8.73 (1K, d, J=8Hz), 8.33 (1K, d, J=8Hz), 8.26 (1K, d, J=8Kz), 8.18 (1K, d, J=8Hz), 7.90 (1K, d, J=8Hz), 7.61-7.83 (5H, 7.59 (1H, 7.25-7.46 (7K, 5.96 (1K, br 5.41 (1H, rn), 5.29 (1K, br 5.12 (2H, 4.77 (1K, m), 2.86 t, J=8Hz), 2.57 d, J=6Kz), 2.45 (2H, WO 97/03951 PCT/JP96/01995 86 ci, J=7Hz), 1.75-2.22 (6H, in) Examle 49 (3S)-3-f(2S)-S-Benzyloxycarbonyl-2-[1-( 4 -iethylbenzy)indo1-2-ylcarbonylaminopentanoyljoxy-4-( 2 -naphthyl)butanamide NYWR (CDC1 3 5) 7.67-7.78 (4H, 7.63 (1H, s), 7.27-7.45 (9H, 7.17 (iH, 6.86-7.05 (6H, m), 5.84 (1H, br 5.81 (1H, d, J=16Hz), 5.68 (1H, d, J=16Hz), 5.57 (lH, 5.16 (1H, br 5.11 (2H, 4.55 (lE, 3.08 (2H, 2.07-2.48 (4H, i) 2.25 (3H, 1.38-1.82 (4H, m) ESI-MS 710 [M+Hj Exanple (3S)-3-f( 2 s)-5Benzyloxycarbonyl- 2 4 -chlorobenzyl)- ±ndol-3-ylcarbonylaminopentanoyl]oxy-4-( 2 -na-hthyl)butanamide NMR (CDC1 3 5) 8.07 (1K, 7.67-7.78 (4H, 7.53 (1H, 7.21-7.47 (13H, 7.07 (2H, d, J=8Hz), 6.86 (1H, d, J=7Kz), 6.07 (1K, br 5.62 (1H, i), 5.32 (1H, br 5.30 (2H, 5.08 (2H, 4.70 (1H, 3.16 (2H, d, j=7Hz), 2.57 (1K, d, 4Hz), 2.48 (1H, d, J=15, 7Hz), 2.11-2.36 (2H, i), 1.45-1.90 (4H, m) ESI-MS 730 [M+Hj Exainmpla 51 (3S)-3-f(2S) S-Benzyloxycarbonyl 2 4 -methylbenzyl)- Jndol-3-ylcarbonylaminpentanoyljoxy-4-( 2 -naphthyl)butanamide NY?. (CDC1 3 5) 8.06 (1H, 7.67-7.77 (4H, 7.62 (1K, br 7.20-7.43 (11H, 7.13 (2H, d, J=8Hz), 7.07 (2H, d, J=8Hz), 6.73 (1K, d, J=7Hz), 6.13 (1H, br 5.59 (1H, 5.29 (2H, 5.27 WO 97/03951 PCT/JP96O1 995 87 (1K, br s) 5. 07 (2H, s) 4. 67 (1K, mn), 3. 15 (2H, di, J=7Hz), 2.57 (1H, dci, J=14, 4Hz), 2.48 (1H, dci, J=14, 7Hz), 2.32 2.07-2.28 (2H, in), 1.43- 1.88 (4H, in) ESI-MS 710 LM+Ki 2 -Pyriciyliethyl)- 2 2 2 -cauinolycarbofylan) pentanoyl .1amino) hexadecanamiie ESI-MS 750

[M+K)

xample 53 (3S) LN-Benzyl{ (2S) -S-benzyioxycarbonyl- 2 (2qioliabnyaiopentanovi }ami-nojhexaciecanamicie ESI-MS 749 [M+Kj EXaale 54 (n-Pentyl) 2 2 (2--runolicabonlamnoPentanoyl) amino Jhexaciecanai c ESI-ms 729

LM+H]

(3S) TN-Phenethyl (2s) -S-benzyioxycarbonyl- 2 (2aunllaroyaiopentanoyl Iamrino) hexaciecanaice £51-MS 763 LM K) (3S)3-[-(nButi)-(2S) -S-benzyloxycarbonyl.

2 2 -auinolylcarbonyl. inopentanoyl }amino) hexaciecanamaie ESI-MS 737

EM+H)

(33) (2S)5) Sbenzloxycarbonyl- 2 (2aioilabnyai pentanoyl Iamino) hexadecanaiie ESI-MS :687

[M+H)

WO 97/03951 PCT/JP96/01 995 Example 58 3 S-3-[N-(n-Propyl>{ 2 S)-2-(1-benzylindo.

3 ylcarbonylanino) -S-benzYioxycarbonvlpentanoy 1 o-4- (2naphthyjj butanamide ESI-MS 737

LM+H]

Example 59 3 S)-3-[N-(nPropyl){ 2 S)-5-benzyLoxycarbonyl 2 (l-(l naphthylmrethvi)infdol-3-viabnlmn~etaolaio--2 naphthyl) butanamide crbylmnpetoylan]-4(2 ESI-MS 787

[M+H]

Examuple 3 (n-Pentyl)-{ 2 S)-5-benzyloxycarbonyl-2 (1benzylindol-3.ycarbonyln)petny mnl4(2napohthyl) butanamide ESI-ms 765 [M+Hil Examplie 61 3 (n-Pentyl)-{ 2 S)-5-benzyloxycarbonyl-2 naphthylmethyl) ifdo3-ylcarbonlmn1.tnylaio--2 naphthyl) but anamide ESI-MS 815

[M+H]

Exampnle 62 3

S)-

3 -[N-Isobutyl( 2 S)-5-benzyloxycarbonyl- 2 quiflolylcarbonylamfl 0 pentanoyl }amino] hexadecanamide ESI-ms 715

LM+H-]

Z&Aala 63 3 S)-3-LN-Isopentyl-{( 2 S)-5-benzyloxycarbonyl- 2 quiflolylcarbonylajfQ) pentanoyl Iamino] hexadecanamide ESI-MS :729

[M+H]

Exampl-e 64 WO 97/0395 1 PCT/JP96/ol 995 89 (3S>K3-[N-Ethyl-f(2 S)-5-benzloxycarbonyl 2 benzylindol-3>ylcarbonyl. opnaoylmn]4(2na-phthyl) but anamide ESI-MS 723 LM H] Examole (3S)- 3 -LN-Ethy>{ 2 S)-5-benzyloxycarbonyl- 2 (1na-hthlmehylindl-3yicrboyiano)pentanoyllaminoj (2naphthyl) butanamide ESI-MS 773 [M+Iij Examle 66 (3S)- 3 2 S)-5-benzyloxycarbony- 2 (2chiorobenzyl) ifdol3-ylcarbonlamiopna.laio--2 naphthyl) but anainide ESI-MS 757 [M+Hj Expminle 67 3 (n-Butyl)-{ 2 S)-5-benzyloxycarbonyl- 2 (1benzvlindo>-3.ylcarbonlmn. naolamnl (2napchthyl) but anamide ESI-MS 751 [M H] 3 S)-3-[N-(nButyl)- 2 S)-5-benzyloxycarbonyl 2 2 chlorobenzyi) ifdolJ3-ylcarbonlamn. etnylaioflaphthyl) but anarnide ESI-MS 785 IM Hj ExpZLe--- 69 EN- (n-Propyl)-{ (l-benzylindol3 Ylcarbonylamino) -S-benzyloxycarbonvlpentanoy11 nc-4- (4maethylphenvl) butanamide ZExP -1Pe70 WO 97/03951 PCT/JP96/01 995 90 (3S) (n-Propyl)-{ (2S) -S-benzYloxycarbony1- 2 chlorobenzyi) idol 3 -ycarbonyamino)etany mnj4(4methyiphenyl) but anamide (n-Propyjj-{ 2 S)-5-benzYloxycarbony>- 2 (1benzylindo3ylcarbonlh.in etnylmnl4(4-n butyiphenyl) but anamide ESI-MS 743

[M+H-J

Exampl1 e 72 (3S) (n-Propyl)-{ 2 S)-5-benzyloxycarbonyl- 2 chlorobenzyl)infdol3-ylcarbonylamino)etany ai (4-nbutyiphenyl) but anamide ESI-ms 777

[M+H]

Exale 7 3 3 S)-3-[N-(nButya){ 2 S)-5-benzyloxycarbonyl- 2 (1benzyindol3ylcarbonlmnopentanoyl} amino] (4-nbutvlphenyl) butanamide ESI-M-S 757

EM+H]

Eaple 74 3 (n-Butyl)-{ 2 S)-S-benzyloxycarbonyl- 2 chlorobenzyl) indol-'3-1ylcarbonylamipenoyl aiol4(4-nbutyiphenyl) but anamide ESI-MS 791

[M+H]

Ele 7 3 S)-3-[N(nPropyl)( 2 S)-4-benzyloxycarbonyl 2 2 chlorobenzyl) indol-3-ylcarbonyamnobuaolmio-(2 niaphthyl) butanamide ESI-MS 757 [M-14H] ExaMpole 76 WO 97/03951 PCT/JP96/01995 91 3 (f-Butyl)-( 2 S)--1ethoxycarbonyl- 2 quinoJlylcarbonylamnjl) pentanoyl} amino] (4-nheptyiphenyl) butanaiie ESI-MS 667

[M+H]

Exainple 77 2 S)--etoxycarbonyl 2 (l( 2 chlorobenzyl) indo1-3ycarbnyainietnoytl aiol (4-nheptyiphenyi) butanaiie ESI-MS 757 [M+Hj Zxarole 78 2 S)-5-Benzyoxycarbony- 2 3 quifliolylcarbonylamjfQ) pentanoyl] oxy-1. Ophenycidecanaice NTTMR (CDC1 3 :9.34 (1H, 8.62 (1H, 8.16 (1H, di, J=10Kz), 7.90 (1H, di, J=lO~z), 7.82 (1H, in), 7.64 (1K, in), 7.1-7.4 (ilK, in), 5.94 (1H, br s), 5.50 (1H, br 5.35 (1H, in), 5.12 (2H, 4.80 (1K, in), 2.4-2.7 (6H, in), 1.5-2.15 (8H, in), 1.2-1.4 (8H, in) FAB-MS 652

LM+K]

Zxarn,,Le 7 9 (3S) -S-Benzyioxycarbonyi- 2 qunlycrb13aio etaoloxy-4- 2 -naphthyl) butanaiie NMR (ODC1 3 6) :9.32 (1K, di, J=2Kz), 8.56 (1H, di, J=2Hz), 8.15 (1K, di, J=l5Kz), 7.6-7.9 (7H, in), 7.25-7.4 (8H, in), 5.9 (1H, br 5.62 (1K, in), 5-.40 (1H, br 5.10 (2H, 4.68 (1H, mn), 3.15 (2H, di, J=7Hz), 2.45-2.6 (2H, in), 2.15-2.4 (2H, mn), 1.75-1.9 (2K, mn), 1.5-1.7 (2K, mn) FAB-MS4 618

LM+K]

(3S) -3-f (2S)-5-Benzyloxycarbonyi-2-(isoquinoin-3.

WO 97/03951 PCT/JP96/01995 92 Ylcarbonylamino)pentanoyl]oxy-4-(2-naphthyl)butanamide NMR (CDC1 3 6) 9.2 (1H, 8.66 (1H, d, 8.56 (1H, 8.1 (1K, d, J=l5Hz), 8.0 (1H, d, 7.6-7.85 (5H, 7.25-7.4 (8H, br 5.62 (1H, 5.35 br 5.10 (2H, 4.75 (1K, 3.15 (2H, d, J=7Hz), 2.45- 2.6 (2H, 2.15-2.4 (2H, 1.75-1.9 (2H, m), 1.5-1.7 (2H, m) FAB-MS 618

EM+H]

Expinale 81 (3S)-3-f(2S)-5-Benzvloxycarbonyl-2 (isoquinolin-l- Ylcarbonylaino)peltanoyl] oxy-4-(2-naphthyl)butanamide NTMIR (CDC13, 6) 9.5 (1H, d, J=15Hz), 8.65 (1H, d, J=15Hz), 8.5 (1K, c, J=lOHz), 7.6-7.9 (10H, m), 7.2-7.4 (5E, in), 6.04 (lH, br 5.58 (1H, m), 5.42 (1K, br 5.05 (2H, 4.7 (1H, 3.12 (2H, 2.5 (2H, 2.2-2.3 (2H, 1.5-1.9 (2H,

M)

FAB-MS 618

EM+H]

ExamPle 82 2 -Benzylbenzoyl) benzyoxycarbonylentanoyljoxy-4- (2-naphthyl)butanamide NM (CDC1 3 5) 7.05-7.8 (21H, 6.22 (1K, d, 5.82 (1K, br 5.55 (1K, 5.26 (1H, 5.05 (2K, 4.5 (1K, 4.2 (2K, ABq), 3.15 (2H, t, J=7Hz), 2.4-2.55 (2H, 2.05-2.25 (2H, 1.3-1.7 (4H, m) ESI-MS 657

[M+H]

Example 83 (3S)-3-f(2S)-5-Benzyloxycarbonyi 2 (2naphthYlcarbonylamino)petanoylloxy-4-( 2 -naphthyl)butanaice NMR

(DMSO-

6 6) 8.9 (1K, d, J1OHz), 8.52 (1K, s), WO 97/03951 PCT/JP96/019 9 93 7.3-8.05 (14H, 6.85 (1H, br 5.46 (1K, i), 5.08 4.44 (1KH, 3 -3.2 2.3- 2.4 (4H, 1.5-1.9 (4H, m) ESJ-MS 617 [M+Hi Extampe 84 2 -Benzoylawino- 5 benzYloxycarbonylpetanoyljoxy-4- 2 -aphthyl)buta.

NMR (CDcl, 6) 8.16 d, J=1Oz), 7.3-7.85 (11H, 6.9 (1K, d, J=8Iz), 5.94 (1K, br 5.6 (1H, 5.35 (11, br 5.1 (2H, 4.12 (1H, mi), 3 12 (2H d, J= 7H 2 .1-2 .6 (4 r) 1 5 .9 4H

M)

ESI-Ms 567

[M+H]

ExamPle (3S)-3-[(25)-s5Benzyloxycarbonyl-2-(2- Phenethylbenzoyl) aminopentanoyl oxy-4- 2 naphthyl)butanamide NMR (CDCj3, 6) 7.1-7g8 (21H, in), 6.25 (lI, d, J=IOHz), 5.78 U1H, br 5-6 (1H, 5.26 (IH, br 5.08 (21, 4.6 3.14 (2H, d, J=7Hz), 3.0-3.1 (2H, 2.85-2.95 (2H, 2.44 (2H, d, j=7Hz), 2.1-2.3 (2H, rn), 1.45-1.8 (4H, i) ESI-MS 671

[M+H]

Examle 86 (3S)- 3 3 -Benzylbenzoy befnzYloxycarbonylpetanoyii oxy-4- 2 -faphthy)butanamide NLR (CDCl 3 6) 8.1 (1K, 7.1-7.75 (20H, 6.92 d, J=8 2 5.92 (1K, br 5.55 (1K, 5.36 br 5.05 (2H, 4.56 (1K, 4.02 (2H, 3.1 (2K, d, J=7Hz), 2.4-2.55 (2H, 2.05-2.3 (2H, 1.4-1.8 (4H, in) ESI-MS 657

[M+H]

WO 97/03951 PCT/JP96/0I 995 94 Examiple 87 (3S) -3-f (2S) 3 -Benzylnaphthalen-2.ylcarbonyl) benzyloxycarbonylpentanoyl] oxy-4- (6-ethyl-2-naphthyl) but anamide NNR (CDC1 3 65) 7.05-7.85 (22H, mn), 6.32 di, J=l0Hz), 5.82 (1Hi, br 5.55 (lE, mn), 5.26 (1H, mn), 5.05 (2H, 4.45 (1H, mn), 4.32 (2H, ABq), 3.15 (2H, t, J=7Hz), 2.75 (2H, a, J=7liZ), 2.4-2.55 (2H, mn), 2.05-2.25 (2H, mn), 1.3-1.7 (4H, in), 1.26 (3H, t, J=7Hz) EST-MVS 735 [M+H] Example 88 3- [N-Mvethy1l{ (2S) 3 -benzylnaphthalen-2>ylcarbonyl).

amino-5-benzyloxycarbonylpentanoyl }amino] propanamide ESI-MS 580 fM+-I Examle 89 ylcarbonyl) amino-5-benzyloxycarbonylpentanoyl }amino] dodecanaiie ESI-MS 751 [M±H] Exampole (3S) (n-Propyl) (1-benzylinciol-3-ylcarbonyl) amino-5-rmethoxycarbonyipentanoy amino] dodecanamide ESI-MS 647 fM-iH] Example 91 3 S)-3-[N-(n-Propyl)-{( 2

S)-

2 -(-(2-chlorobenzyl)niol.3 ylcarbonyl) aiino-5-iethoxycarbonylpentanoyl }amino] dodecanamide ESI-MS 681 fMi-B{ Examplea 92Z WO 97/03951 PCT/JP96/0I 995 95 (3S)-3-[N-(n-Pentyi)- 2 S)-2-(1-benzylindo3y..

carbonyl) airrino--benzyoxycarbonylpentanoyl }amino] nonanamide ESI-MS 709 [M H] Ex-amile 93 (3S)-3-[N-(n-Butyl)q 2 S)-2-(l-benzylindol3ylcarbonyl) arinoSbenzyoxycarbony pentanoy 1}iolanaide ESI-MvS 695 [M+H] Expmnle 94 3 S)-3-[N-(n-Butyl){ 2 S)-5-benzyloxycarbonyl2-(1( 2 chlorobenzyl) indol-3-ylcarbonylamino) pentanoyl }aminoj nonanami de ESI-MS 729 [M+H] Examile EN- (n-Propyl)-{ (l-benzylindol-3-y..

carbonyl) amino-5-benzyloxycarbonylpentanoyl Iamino] nonanamide EST-MS 681. [M±Hl Example 96 (n-Prorylj-{ 2 S)-5-benzyloxycarbony>>[(1- (1naphthylmethyl) ifdoJ-3-ylcarbonyl) aminolpentanoyllamino] no nan ami de ESI-MS 731 [M-iH] Examiple 97 3 S)-3-[N-(n-Propyl){ 2 S)-5-benzyloxycarbonyl...>f(1-(2- Pyridylmethyl) indol-3-ylcarbonvi) aminolpentanoyllamino] nonanamide EST-MS 682 EM-iH] ExaMpI e9 8 (3S) -3-EN- (n-Propyl)-{ 2 S)-5-benzyloxycarbonyl..> (2chlorobenzyl) indol-3-ylcarbonyl) aminolpentanoyijamino>.

WO 97/03951 PCT/1P96/O1 995 -96 non anami de ESI-MS 715

[N+H]

Example- 99 3 S)-3--fN-(n-Propyl){ 2 S)-5-benzyJloxycarbonyl.

2 chlorobenzyl) ifdol-3-ylcarbonyl) aminojpentanoyl} amino] nonanamide ESI-Ms 715 [M-iH] Exam-ple 100 3 S)-3-[N-Ethylq 2

S-

2 -(-(2-chlorobelzy]2ifdol- 3 Micarbonyl) amino-5-methoxycarbonylpentano 1 }amino] nonanamide ESI-MS 625 [M-fH] Ex&ale 101I (3S) EN-Ethyl- (l-benzylindol.3 ylcarbonyl) amino-5-Inethoxycarbonylpentanoyl }amino] nonanamide ESI-MS 591 [M+H] ExampLe- 102 (n-Propyl)-{ 2 -chlorobenzyl)indol3- Ylcarbonyl) amino-5-benzyloxycarbonylpentanoyl Iamino] heptanamide ESI-MS 687 [M+H] Example 103 3

S)-

3 -[N-(n-Propyl) -{(2S)-2--(l-(l-naphthylmethyl)indo..

3 -ylcarbonyl) noheptanamide ESI-MS 703

[M+H]

Exampnle 104 3 (n-Butyl)-{ 2 -chlorobenzyl)indol.3- Ylcarbonyl) amino-5-methoxycarbonylpentanoyl }aminoj heptanamide WO 97/03951 PCT/JP96/0199 97 ESI-MS 625

LM+HJ

Exa iplek 105 3 -Ylcarbonyl) a ohentanamide ESI-MS 641

[M+H]

3 S-3-[N-(n-Propyl).{ 2 2 (l( 2 pyridyllnethyl) indol-3-ycarboniamno)etany mnl4(6ethyl-2-napchthyl) butanamide EST-MS 766

LN±H]

Exaple 107 (3S) (n-Propyl)-( (1-benzylindol-3 Ylcarbonyl) a o-4- (6ethyl-2-naphthyl) butanamide ESI-MS 765 LM+Hj Examole 108 (n-Butyjj-{ 2 2 (1be-nzyiindol3ylcarboy) aminojpentanoyl}aminoj- 4 -(6-ethyl-2napohthyl) butanamide ESI-MS 779 [I'M+Hj 3 (n-Buty1)-{ 2 S)-5-benzyloxycarbony..

2 (2chlorobenzy ±ndol-3-yicarbonyl) arinojpentanoy}am-no]- 4 ethyl-2-naphthyl) butanarnide ESI-MS 813 [M-fHl (3S)-3-N-(2-Pyridymthyl){ 2 S)-5-benzyioxycarbony-2- (tert-butoxvcarbonyam±) pentanoyl laminoihexadecanamide WO 97/03951 PCT/3P96/01 995 98 ESI-MS 695 [M+EjJ Example Ill (3S) [N-Benzyl-{ (2S) -5-benzyloxycarbonyl-2. (tertbutoxycarbonylamino) pent anoyl }amino] hexadecanamide ESI-MvS 694 [M+Hi] Exaple 112 (n-Pentyl)-{ (2S) -5-benzyloxycarbonyl2-.(tertbutoxycarbonylamino) pent anoyl Iamino Ihexadecanamide ESI-DMS 674 [M+H] Examule 113 3

S)-

3 -[N-Phenethy>{ (2S) -5-benzyloxycarbonyl..> (tertbutoxycarbonylamino) pentanoyl lamino] hexadecanamide ESI-MS 708 [M+H] Exainmle 114 3 (n-Butyl)-{ 2 S)-5-benzyloxycarbonyl2.(tertbutoxycarbony1 amino) pentanoyl }amino] hexadecanamide ESI-MS 660 [M+H] Examuple 115 (3S)- 3 -[N-Ethyl-{ (2S) -5-benzyloxycarbonyl.2-.(tertbutoxycarbonyl amino) pentanoyl Iamino] hexadecanamide ESI-MS 632 LM+H] Example 116 (n-Propyl)-{ (2S) -5-benzyloxycarbony>> (tertbutoxycarbonrylamino) pentan-oyl }aminoj (2-naphthyl) butanamide EST-IMS 604

[M+H]

Example 117 3 (n-Pentyl)q 2 S)-5-benzyloxycarbonyl-2-.(tertbutoxycarbonylamino)pentanoyl}.] no-4- (2-naphthyl) butanamide WO 97/03951 PCT/JP96/01995 99 ESI-MS 632 [M+HJ Exa mle 118 3 S)-3-[N-Isobuty.( 2 S)-5-benzyloxycarbonyl- 2 -(tertbutoxycarbolylamilo) Pentanoyl }amino] hexadecanamide ESI-MS 660 EM+H] Examile 119 3

S)-

3 -[NIsopentyl{ 2 S)-S-benzyloxycarbonyl- 2 -(tertbutoxycarbonylamino) pentanoyl Iamino] hexadecanamide ESI-MS 674 [M H] Expinole 120 [N-Ethyl- (2S) -5-benzyloxycarbonyl.2.(tertbutoxycarbonylamino) pentanoyllanino] 2 -naphthyl)butanamide ESI-MS 590

[M+H]

Exa inle 121 (3S) (n-Butyl)-{ (2S) -S-benzyloxycarbonyl-2-.(tertbutoxvcarbonyaino)pentanl}. no-4- 2 -naphthyl) butanamide ESI-MS 618

[M+H]

Examole 122 3 (n-Prooyl)q 2 S)-5-benzyloxycarbonyl2-2(tert butoxycarbonyl amino)pentany11 ~ro-4- 4 -methylphenyl) butanarride ESI-NS 568 [M+H] Example 13 (3S)- 3 -[N-(n-Propyi){ 2 S)-5-benzvioxycarbonyl-2-(tertbutoxvcarbonylamino)pentanoyl iamino] 4 -n-butylphenyjj but anamide ES2-MS 610 [M+H] Exaale124 WO 97/0395 1 PCT/JP96/01 995 100 3 S)-3-FN- (n-Propyjj-{ 2 S)-4-benzyloxycarbonyl- 2 -(tertbutoxycarbonylamno)butol }amino] 2 -naphthyl) butanamide ESI-MS 590

[M+H]

Lxam pp1e 12 EN- (n-Butvlj-{ (tert-butoxycarbonyl)amin lamino] 4 -n-heptylpheiyl) butanamide ESI-MS 590

[M+H]

ExpMaLe 1_26 3- [N-Methyl-f{(2S) -S-benz-vloxycarbonyl- 2 -(tertbutoxyvcarbonyl amino) pentanoyllIamino] propanamide ESI-MS 436 [M HJ Exam2Le 2-7 3 S)-3-[N(n-Pentyl){ 2 S)-5-benzyloxycarbony- 2 -(tet butoxycarbonyl amino) pentanoyl }amino] dodecanamide ESI-MS 618 LM+-i Expmale 12_8 3 (n-Propyl)-{ (tert-butoxycarbonyl)amino S-methoxycarbonvlpentanoyl }amino] dodecanamide ESI-MS 514

[M+H]

Exaple129 (n-Pentyl)-{ 2 S)-5-benzyoxycarbony2(ttbutoxycarbonylamino) pentanoy- I amino] nonanamide ESI-MS 576

[M+E]

aKale 130 3 S-3.-[N-(n-Butyl){ 2 S)-5-benzyloxycarbony>2-(tertbutoxycarbonylamnino) pentanoyl lamino) nonanalnide ESI-MS 562 [M Hl WO 97/03951 PCT/1P96/01995 102. Example 131 3 (n-Propyl)-{ 2 S)-5benzyoxycarbonyl2(ttbutoxycarbonylamino) pentanoy. }amino] nonanamide ESI-MS 548 [M-tH] Exampnle 132 (3S) [N-Ethyl-{ (2S) (tert-butoxycarbonyl)amino-s methoxycarbonyipentanoyil}amino] nonanamide ESI-MS 458 [M+Hl Example 133 3 (n-Propyl){ 2 S)-5-benzyloxycarbonyl- 2 -(tertbutoxycarbonylamino) pentanoy. }amino] heptanamide ESI-:MS 520

[M+H]

Example 134 (k 3 (n-Butyl)-{ (tert-butoxycarbonyl) amino- }amino] heptanamide ESI-MS 458

EM+-]

Examiple 135 2 S)-5-benzyloxycarbonyl-2-(tertbutoxvcarbonyiamino)pentaov}amino] (6-ethyl-2-naphthyl) but anamide ESI-MS 632

[M+H]

ExampLe 3 6 3 (n-Butyl) 2 S)-5-benzyloxycarbonyl-2-(tertbutoxycarbonylamino) pentanoya} amino] (6-ethyl-2-naphthyl) butanamide ESI-MS 646

[M+H]

The ffollowing compounds (Eapls131o 9 were obtained according to a similar manner to that of Exam-ole 21.

WO 97/03951 PCT/JP96/01995 102 Examnle 137 3 S)-3-N-(n-Propyl){ 2 S)-4-carboxy>L-(>-( 2 chlorobenzyl) indol-3-ylcarbonyl) aminojbutanoy1}amino 0 4 naphthyl) but analnide ESI-MS :667

[M+H]

rvnp :85-92 0

C

Expmvole 138 3 S)-3[N(nButy)(2S)cabox--(chlorobenzyl) ifdl-3-ylcarbonyl) aninolpentanoyllamino>.

4 (4n-butylphenyl) butanamide ESI-MS 701 [M+H] nip :166-1680C Example 139 3 (n-Butylj-{ 2 S)-5-carboxy-2-[(1-benzylindol-3ylcarbonyl) aminolpentanoyllaiinoi 4 -nbutylphenyl) butanamide ESI-MS 667 [M+HJ MnO 77-820C ExainaLa 140 3

S)-

3 -[N-(n-Pro-ryl){ (2S)-5-carboxy2(1-(2 chlorobenzyl) indol-3-ylcarbonyl) aminolpentanoyl}amino>4.(4flbutylphenyl) butanamide ESI-M~S: 685 nip :83-87*C Eaale 141 3 S)-3-[Nq-(nPropy1)- 2 S)-5-carboxy2-(l-benzylindol- 3 -ylcarbonyl) ami-iolpentanoyl }aninoj 4 -n-butylphenyl) but anamilde ESI-ms 651 EM-HJ nip :82-88'C WO 97/03951 PCT/JP96/O1 995 103- Example 142 chlorobenzyl)indfl-3-ylcarbonyl) aminolpentanoyllamino]- 4 methyiphenyl) but anamide ESI-MS :643

EM-H]

mp :79-96 0

C

Examle 143 3 S)-3-N-(n-Propyly)j 2 S)-2-(1-benzylinol.3ylcarbonyl) amino-5-carboxypentanoyl}amino14-(4metLhyiphenyl) but anamide ESI-MS 609

EM-H]

mp :83-92C Example 144 chlorobenzyl) ±ndol-3-ylcarbonyl) aminolpentanoyllamino>- 4 naphthyl) butanamide ESI-MS :693

[M-H]

mD 104-110 0

C

Examle 145 3 2 S)-5-carboxy-2-[(l.benzylindol- 3 ylcarbonyl) aminolpentanoyllamino] 2 -naphthyljbutanamide ESI-MS :659

EM-H]

mp :90-960C Exampole 14 6 (3S)-3-[N-Ethyl-q 2 S)-5-carboxy-2-(.( 2 chlorobenzyl) ifdol-3-ylcarbonyjj aminolpentanoyllamino>-4.(2naphthvl) but anamide ESI-MS :665

EM-H]

mp :110-1140C Exdale 147 WO 97/03951 PCT/1P96/01995 104 (3S) [N-Ethyl-{ (2S) -5-carboxy-2- (1naphthylmethyi)indfl03-ylcarbonyl) amino] pentanoyll amino] -4- (2-naphthyl) but anamide ESI-MS :681

[M-H]

mDp 118-126 0

C

Exa mle 148 (3S) EN-Isopentyl (2S) -S-carboxy-2- (2qu-irnolylcarbonylarjfl 0 pentanoyl }amino] hexadecanamide ESI-MS 639 [M+H] Exampie 1_49 3

S)-

3 -N-Isobutyl-{ 2 S)-5-carboxy-2-(2.

quino-iylcarbonlamflQ) oentanoyl }aminoj hexadecanamide ESI-MS: 625

LM+H]

mp 65-66*C Example 150o (3S) LN-Phenethvl- -5-carboxyV-2- (2auinoiyvlcarbonylamilo) pentanoyl laminolhexadecanamide ESI-MS 673 [M+H] Example- 151 3 S)-3-[N-Ethy1{ 2 S)-5-carboxy2(lbenzylindo1 3 ylcarbonvlamino)pentanoyl }amino] 2 -naphthyl)butanamide ESI-MS: 631 [M-H] mnp :110-1120C Expmle 152 (3S) (n-Pentyl)-{ (2S)-5-carboxy-2-[f(1-benzylindol- 3 -ylcarbonyl) aminolpentanoyl}amino] (2-naphthyl) butanamide EMI-MS: 675 [M+H] ME)p 89-93C EAal-eI 153 WO 97/03951 PCT/JP96/01995 105 3

S)-

3 -[N-(n-Pentvi){f(2S)-.5carboxy 2 f(l-(l narhthylmethyl) ifdol-3-ylcarbonyl) aminojpentanoyllamino] -4- 2 -naphthyl) butanamide ESI-MS :725 [N+Ii] mp 12-1160C Exam-ole 154 3

SV-

3 -[N-(n-Propyl)- 2 S)-5-carboxy-2-(..(i.

naphthylmethyl) ifdol-3-ylcarbonyl) aminoipe-ntanoyl Jamino] -4- (2-naphthyl) butanamide ESI-MS :697 [M-fH] mip :123-1260C Exa inole 155 (n-Propyl)-{ (1-benzylindol-3ylcarbonyl) amino-5-carboxypentanoyi }amino] (2naphthyl) but anamide ESI-MS :647

[M+H-I

mp 91-940C Exarvole 156 3 S)-3-N-(2-Pyridyinmethyl){ (2S)-5-carboxy-2-(2.

q-uinolylcarbonylamf 0 pentanoyl }amino] hexadecanamide dihydrochloride ESI-MS: 660 [M-tH] MD:74-81 0

C

Examp-le 157 (3S) -3-[fN-Ethyl-f{(2S) -5-carboxy-2- (2auinolyicarbon~ylamino)pentanoy 1 }amino] hexadecanamide ESI-MS 660 [M-iH] 3 S)-3-[N-(n-Propyl)q (2S)-5-carboxy-2-(2auinolylcarbonvla -ino)peltan 0 y 1 laminoihexadecanamide WO 97/03951 PCT/JP96/01995 -106 hydrochloride MC 5 9 -620C Example 159 3 2 S)-5-carboxy-.>(2quinolylcarbonylamjfQ) pentanoyl Iami-no]hexadecanamide ESI-MS 625 Examvole 160 (3S)- 3 -[N(nPentyl)- 2 S)-5-carboxy-2( 2 quinolylcarbonylamfQ) pentanoyl }aminolhexadecanamide ESI-ms 639

LM+H]

Example 11 (3S) EN-Benzyl-{ (2S) -S-carboxy-2- (2quinolycarbonylamfQ) pentanoyl Iamino] hexadecanamide ESI-MS 659

[M+H]

Ex ampl 62 3 S)-3[N(2-.Pyridylmethl){ 2 S)-5-carboxy..2-(2quinolylcarbonylamjfQ) pentanoyl Iamino] hexadecanamide ESI-MS 660

[M+H]

Examp l 6 3 (3S)-3-f (2S) -S-Carboxy-2-[l{>( 4 -methylbenzyl) indol-3- Ylcarbonyllaminolpentanoyij oxy-4- (2-naphthyl) butanamide NN-R (DMSO-d 6 5) :8.13-8.28 (3H, in), 7.70-7.86 (4H, in), 7.34-7.57 m),7.08-7.23 (6H, in), 6.85 (1H, br 5.42 (2H, 5.39 (lIH, mn), 4.40 (1H, mn), 27.96-3.16 (2H1, in) 2.29-2.38 (2H, in) 2.25 (3H1, s) 2.11-2.20 (2H1, in), 1.44-1.83 (4H1, mn) zST-MS 620

[M+H]

ExamP 164 (3S)-3-f 2 S)--Carbox2.l-l.(4hlorbezl~id WO 97/03951 PCT/P96/01995 107 ylcarbonyl)aminojpentanoyijoxy-4-( 2 -naphthyl) butanamide MI'R (DMSO-d 6 6) 8.12-8.28 (3H, 7.72-7.87 (4H, 7.32-7.57 (6H, 7.10-7.31 (4H, 6.85 (1H, br 5.49 (2H, 5.42 (1H, 4.42 (1K, i), 2.95-3.16 (2H, 2.29-2.38 (2H, 2.12-2.22 (2H, 1.45-1.84 (4K, m) ESI-MS 640

[M+H]

Example 165 (3S)-3-f(2S)-5-Carboxy-2-(l-( 4 -methylbenzyl)indol-2- Ylcarbonyllaminojpentanoyljoxy-4-( 2 -naphthyl)butanaide ESI-MS 620

[M+K]

86-90 0

C

Exainle 166 (3S)-3-f(2S)-5-Carboxy-2-( 2 -auinolylcarbonylamino)pertanoyl oxy-5-( 2 -naphthyl)pentanaiide NMR (DMSO-d 6 5) 9.12 (1K, d, J=8Kz), 8.60 (1H, d, J=8Hz), 8.22 (1H, t, J=8Kz), 8.20 (1H, d, J=9Hz), 8.12 (1H, d, J=8Hz), 7.90 (1H, t, J=8Hz), 7.68-7.86 (4K, 7.62 (1K, br 7.38-7.46 (3K, 6.88 (1H, br 5.20 (1H, 4.54 (1H, 2.70-2.86 (2H, mn), 2.42-2.49 (2H, 2.27 (3H, t, J=7Kz), 1.87-2.04 (4K, 1.53-1.67 (2K, m) ExpiDmle 167 3 carboxypentanoyi3oxv-4-(4-n-he)t ylphenyl)butanamie NMR (DMSO-d6, 5) 8.82 (1K, d, J=7Hz), 7.95 i), 7.93 (1H, 7.85 (1H, 7.75 (1H, 7.47-7.59 (2H, 7.38 (1H, br 7.05-7.28 (9K, 6.86 (1H, br 5.32 (1K, 4.37 (1H, d, J=14Hz), 4.33 (1K, 4.29 (lH, d, J=14Hz), 2.78-2.96 (2H, 2.24-2.40 (2K, 2.12-2.21 (2K, 1.42-1.75 (6K, in), 1.13-1.35 (8K, 0.78-0.88 (3K, m) WO 97/03951 PCT/JP96/01995 108 ESI-MS 665 fM+H] Example 168 -S-Carboxy-2-[2-((2E)-2-me t hoxycarbonya vinyl)benzoylaminolpentanoyljoxy-4-( 2 -naphthyl)butanaide N-YR (DMSO-c 6 6) 8.92 (1H, d, J=7Hz), 7.77-7.98 (6H, 7.42-7.57 (6H, 7.37 (1H, br 6.88 (1H, br 6.59 (1H, d, J=16Hz), 5.43 (1H, 4.23 (1H, 3.66 (3H, 3.16 (1H, dd, J=14, 6Hz), 3.06 (1H, d, J=14, 6Hz), 2.37 (2H, d, J=7Hz), 2.15 (3H, t, J=7Hz), 1.42-1.75 (4H, m) ESI-MS 561 [Mi-K Exampnle 169 (3S)-3-f(2S)-5-Carboxy-2-[2-(carboxynethyl)benzoylaiino]pentanoyljoxy-4-(2-naohthyl)butanaiide MR (DMSO-d, 6) 8.75 (1H, d, J=7Hz), 7.81-7.92 (3H, 7.77 (1K, 7.22-7.54 (8H, 6.86 (1H, br 5.42 (1K, 4.30 (1H, 3.83 (1H, d, J=16Hz), 3.71 (1H, c, J=16Hz), 3.13 (1K, cd, J=14, 3.03 (1H, d, J=14, 6Hz), 2.36 (2K, d, J=7Hz), 2.13 (3H, t, J=7Hz), 1.43-1.74 (4K, m) ESI-MS 535

[M±H]

Example 170 (3S)-3-f(2S)-5-Oarboxy-2-[2-(methoxycarbonyliethyl)benzoylamino]pentanoyljoxy-4-( 2 -naphthyl)butanaice NMR (DMSO-d 6 6) 8.71 (1K, d, J=7Hz), 7.75-7.92 (4H, 7.28-7.54 (8H, 6.87 (1K, br 5.42 (1H, 4.28 (1K, 3.91 (1K, c, J=16Kz), 3.81 (1H, d, J=16Hz), 3.53 (3K, 3.13 (1K, dd, J=14, 3.04 (1K, d, J=14, 6Hz), 2.36 (2H, d, J=7Kz), 2.14 (3K, t, J=7Kz), 1.42-1.74 (4K, m) ESI-MS 549 fM+K] WO 97/03951 PCT/JP96/01995 109 ExpinDle 171 (3S)-3-[(23)-S-Carboxy-2- (3-quino1ylcarbonylamino)pentanoyl] oxy-4-( 2 -naphthyl)butanamide NMR (CDC1 3

-CD

3 OD, 5) 9.36 (1H, 8.72 (1H, s), 8.15 (1H, d, J=l5Hz), 7.94 (1H, d, J=15Hz), 7.6-7.9 (61H, 7.3-7.45 (3H, 5.6 (11, 4.62 (1H, 3.15 (2H, d, J=7Hz), 2.4-2.6 (2H, 2.1-2.4 (21, 1.75-1.9 (2H, 1.5-1.6 (2H, m) Exainole 172 (3S)-3-[(2S)-5-Carboxy-2-(isoquinolin-3-ycarbolamino)pentanoyli oxy-4-(2-naphthyl)butanaiide NMR (CD01 3 5) 9. (1K, 8.7 (1H, d, 8.50 (1K, 7.9-8.05 (2H, 7.6-7.8 (5H, m), 7.25-7.4 (3H, 6.9 (1K, br 6.3 (1K, br s), 5.6 (11, 4.8 (11, 3.0-3.3 (2H, 2.4-2.6 (2H, 2.1-2.4 (2H, 1.75-1.9 (2H, 1.5-1.6 (2H, m) FAB-MS 528 [M+H] Examinle 173 2 S)-5-Carboxy-2-(isoauinolin-lylcarbonylamino)pentanoyl]oxy-4-(2-naphthyl)butanai e NMR (CDC1 3

-CD

3 0D, 5) 9.45 (1H, d, J1O~z), 8.72 (1H, d, J=lOHz), 8.4 (1H, d, J=7Hz), 7.6-7.9 (11H, i), (1K, br 6.4 (1H, br 5.6 (1H, 4.7 (1K, 3.0-3.3 (2H, 2.4-2.6 (2H, 2.1-2.4 (2H, 1.75-1.9 (2H, 1.5-1.6 (2H, m) FAB-MS 528 [M+K] Exainle 174 2 carboxypentanoyjoxy-4-(2-naphthyl)butanaide NM. (DMSO- 6 5) 8.75 (1H, d, J1OHz), 7.1-7.9 (17H, in), 6.88 (1K, br 5.4 (1H, 4.32 (1K, 4.1 WO 97/03951 PCT/JP96/01995 110 (2H, ABq), 2.95-3.15 (2H, 2.32 (2H, d, J=7Hz), 2.1 (2H, 1.4-1.7 (4H, in) ESI-MS 567 [M+Hj Exam~le 175 (3S)-3-f(2S)-5-Carboxy-2- 2 -naphthylcarbonylamino)pentanoyljoxy-4-( 2 -naphth1)butanamide NMR (DMSO-d 6 6) 8.9 (1H, d, J=10Hz), 8.52 (1H, s), 7.35-8.1 (14H, 6.9 (1H, br 5.45 (1H, m), 4.44 (1H, 3.0-3.2 (2H, 2.35 (2H, d, J=7Hz), 2.2 (2H, t, J=7Hz), 1.7-1.85 (2H, 1.5-1.7 (2H,

M)

EST-MS 527 fM+Hj Exampile 176 (3S)-3-f( 2 oxy-4-(2naphthyl)butanaiide NMR (DMsO-d 6 5) 8.74 (1H, d, 5=10Hz), 7.3-8.0 (13H, 6.88 (1H, br 5.4 (1H, 4.4 (1H, 3.2 (2H, 2.32 (2H, d, J=7Hz), 2.18 (2H, t, 5=7Hz), 1.4-1.8 (4H, m) ESI-MS 477

[M+H]

Exa ipie 177 (3S)-3-f(2S)-5-Carboxy-2- 2 -phenethylbenzoylaino)pentanoyljoxy-4-( 2 -naphthy)butanamide N-4R (CDC1 3 6) 8.8 (1H, d, 5=10Hz), 7.1-7.9 (17H, 6.85 (1H, br 5.44 (11, 4.36 (1H, m), 2.8-3.2 (6H, 2.35 (21, d, J=7Hz), 2.18 (2H, t, J=7Hz), 1.45-1.8 (4H, in) ESI-MS 581 [M+H] Exanale 178 3 carboxyentanoyljoxy-4-( 2 -naphthyl)butanaie WO 97/03951 PCT/JP96/01 995 NMR (DMSO-d 6 6 8.75 (1ii, di, J=l0HZ), 7.1-7.9 (17H, mn), 6.88 (1H, br 5.45 (1H, mn), 4.4 (1H, mn), 4.04 (2H, 2.95-3.15 (2H, In), 2.32 (2H, d, J=7Kz), 2.2 (2K, t, J=7Hz), 1.4-1.7 (4H, mn) ESI-MS 567 [M+HJ Examole 179 (3S) 2 -Benzylnaphthalen-2>ylcarbonyl) carboxypentanoylj oxy-4- (6-ethyl-2-naphthyl) butanamide N-XR (DMSO-d 6 6) :8.82 (1H, di, J=l0Hz), 7.1-7.9 (18H, mn), 8.86 (1H, br 5.4 (1H, mn), 4.32 (1K, mn), 4.26 (2K, ABar), 3.0-3.15 (2H, mn), 2.72 (2H, q, j=7Hz), 2.36 (2H, di, J=7Hz), 2.12 (2H, t, J=7Hz), 1.4-1.7 (4K, in), 1.22 (3H, t, J=7Hz) ESI-MS 645 [M+H] Example 180 3- EN-Methyl-{ (2S) 3 -benzylnaphthalen-2ylcarbonyl) ESI-MS :488

[M-K]

inp :147-157 0

C

Examp~le 181 vicarbonyl) aino-5-carboxypentanoyl} amino] dodecanamiie ESI-MS :661

[M+H]

mp :125-1270C Exainmle 182 3 S)-3-rN-(n-Pentyl)..{(2S)-2-(l-benzylnol3 ylcarbonyl) amino-5-carboxypentanoy amino] nonanamide ESI-MS :619

[M+H]

nip :127-1290C Exainle 183 WO 97/03951 PCT/JP96/01 995 112 3 2 S)-5-carboxy-2.[ (1-benzylinaol-3ylcarbonyl) amino] pentanoyl. }amino] nonanamide ESI-MS :605 [N-iH] mp 124-127 0

C

Example 184 (3S)-3-LN-(n-Butyi)- 2 5)-5-carboxy-2-[ (1-(2-chiorobenzyl) ifdol-3-ylcarbo-nyl) aminolpentanoyllaminojnonanamide EST-MS :6390

[M+H]

mp 153-1560C Examrole 185 3 S)-3-[N-(n-Propyl).{ (2S)-5-carboxy-2-[ (l-(3-chlorobenzyl) indol-3-vlcarbonyl) aminolpentanoyllaminolnonanamide ESI-MS :625

[M+H]

mp :106-1090C Exampole 186 3 S)-3-[N-(n-Propyl){ 2 S)--carboxy2[(-(l-naphthylmethyl) ifdcl-3-ylcarbonyl) amqinopenitanoyllaminolnonanamide ESI-MS :641

LM+H]

nmp :139-1410C Example 187 3

S)-

3 -[N-(fl-PrQDyl)-.{(2S)-5-carboxy-2-[ (1-(2-pyridylmethyl) indol-3-Ylcarbonyl) aminolpentanoyl}aminolnonanamide ESI-MS :592

LM+H]

mp 78-95 0

C

ExamDPe 18 8 (3S)-3-[N-(-Propyl>{ 2 S)--c-arboxy-2-[ (1-(2-chlorobenzyl) indol-3-ylcarbonyl) amrinolpentanoyl lamino] nonanamide 7SI-ms 625 [M+H] MID 175-1800C WO 97/03951 PCT/.JP96/01995 113 Examiple 189 3 S)-3L[N-inPropyly{ 2

S)-

2 -(1(2-chlorobenzyl)idlylcarbonyl) amino-5-carboxypentanoyvl }amino] heptanamide ESI-MS :597

[M+H]

MP 95-98 0

C

Examnle 190 3

S)

3 .J'-N-(n-Propyl)q 2 S)-2-(1-(lnaphthylmethyl)indol 3 -ylcarbonyl) airino-5-carboxypentanoyllamino hep~tanamide ESI-MS: 613 [M Hl 98-116-C Exaiple 191 (3S) (n-Propyl) (2S) -5-carboxy-2- (2pyridylmethyl) indo2.-3-yicarbonyl) aminolpentanoyl }amino] (6ethyl-2-napIhthyl) butanamide ESI-MS :676

EN+H]

r 110-1160C xmpe92 (3S) (n-Pro-oyl)-{ (l-benzylirndol-3ylcarbonyl)amnoS -carboxypentanol~am] 4 -(6-ethyl-2naphthvl) but anamide ESI-m's 673 [M-H] mp 05-116 0

C

Example 193 3 2 S)-2-(1-benzylindol.3- Ylcarbonyl) amino-5-carboxypefltanoy1}amino14-(6-ethyl-2naphthyl) but anamide ESI-MS :689 [Mi-HI nip 100-116 0

C

Example 194 3 2 S)-2-(-(2-chlorobenzyl)indol-3 WO 97/03951 PCT/JP96/01995 114 ylcarbonyvl) amino-5-carboxypentanoy1} amino] (6-ethyl-2naphthyl) but anamide ESI-MS :723 [M+H] nip 100-116'C The following compounds (Examples-195 to 199) were obtained according to a similar manner to that of Examp~le 33.

Examnle 195 (3S) -3-f (23) -5-Carboxy-2- (tert-butoxycarbonylamino) pentanoyl] oxy-5- (n-decyloxy) pentanamiide NIMR (CDC1 3 6) :6.90 br 6.24 (1H, br s), 5.40 mn), 5.20 (1K, d, J=8Hz), 4.27 (1K, mn), 3.32-3.57 (4H, mn), 2.40-2.72 (2H, in), 2.30-2.40 (2H, mn), 1.48-2.03 (8H, mn), 1.44 (9K, 1.16-1.35 (14K, mn), 0.87 (3H, t, J=7Hz) Examnle 196 (33) -3-f (23) -5-Carboxy-2- (tert-butoxycarbonylamino) pentanovlloxy-6- (n-nonyloxy)hexanamide NM'R (CDCl 3 65) :6.77 (1K, br 6.15 (1K, br s), 5.33 (1K, in), 5.22 (1H, d, J=8Kz), 4.26 (1K, m), 3.32-3.46 (4K, mn), 2.45-2.56 (2K, in), 2.27-2.40 (2K, in), 1.47-1.93 (8K, mn), 1.44 (9K, 1.16-1.36 (14K, mn), 0.88 (3H, t, J=7Kz) Examiple 197 (3S) -3-f (2S) -5-Carboxy-2- 3 -quinolylcarbonylanino) pentanoyl] oxy-1O-phenyldecanamide NMR (ODC1 3 6) :9.34 (1H, 8.62 (1H, 7.55-8.2.5 (4H, in), 7.1-7.4 (1lK, in), 6.85 (1K, br 6.40 (1K, br 5.35 (1K, mn), 4.80 (1H, mn), 2.4-2.7 (6H, in), 1.5-2.15 (8H, mn), 1.2-1.4 (8K, mn) FAB-MS :562 [M+H] WO 97/03951 PCT/JP96/01995 115 Example 198 (3S)-3-[(2S)-(tert-Butoxycarbonyl)amino-5- NMIR (CDC1 3 5) 7.1-7.3 (6H, 6.20 (1H, br s), 5.26 1H 5.20 (1H, d, J=15.0Hz), 4.28 (1H, m), 2.3-2.65 (6H, 1.5-1.9 (8H, 1.45 (9H, s), 1.2-1.4 (8H, m) Example 199 (3S)-3-[(2S)-2-(tert-Butoxycarbonyl)amino-5carboxypentanoyl]oxy-4-(4-biphenylyl)butanamide NMR (DMSO-d 6 5) 7.3-7.7 (10H, 7.22 (1H, d, J=15.0Hz), 6.84 (1H, br 5.32 (1H, 3.88 (1H, 2.8-3.0 (2H, 2.3 (2H, 2.14 (2H, m), 1.3-1.7 (13H, m) FAB-MS 499 [M+H] Example 200 To a stirring solution of (3S)-3-[N-(n-propyl)-{(2S)-2- (1-benzylindol-3-ylcarbonyl)amino-5-methoxycarbonylpentanoyl}amino]dodecanamide (0.23 g) in methanol (4.5 ml) was added 1N sodium hydroxide (0.71 ml) at room temperature and allowed to stand overnight. The mixture was diluted with IN hydrochloric acid (2 ml) and concentrated under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried with magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl ether to give 3 S)-3-[N-(n-propyl)-{( 2

S)-

2 -(1-benzylindol-3- (114 mg).

ESI-MS 633 [M+H] mp 155-160"C The following compounds (Examples 201 to 207) were WO 97/03951 PCT/JP96/01995 116 obtained according to a similar manner to that of Exampole 200.

Example 201 (n-Propryl)-{ (1-(2-chlorobenzyl) indol-3yicarbonyl) amino-5-carboxy-Dentanoyl lamino] dodecanamide 7SI-MS 667 [M±H] MP:145-150*C- Example 202 3 (2S)-5-carboxy-2-[ chlorobenzvl) indol-3--ylcarbonyl) amino]pentanoyl}amino] (4n-heptvlrphenyl) butanamide ESI-MS :743 [M4+H] mr): 79-810C Examople 203 (2S)-5-carboxy-2-(2-uinolyl.

carbonylamino)pentanoyl} amino] 4 -n-heptylphenyl)butanamide ESI-MS 631 [M-iH] Example 204 (3S)-3-[N-Ethyl-{ 2 S)-2-(l-(2-chlorobenzyl)indol.3.

ylcarbonyl) amino-5-carboxypentanoyl }amino] nonanamide ESI-MS :611 [M-iH] mp 80-183,C Examiple 205 (3S) [N-E-thyl-f{(2S) (l-benzylindol-3ylcarbonyl) amino-5-carboxypentanoyl }aminolnonanamide ESI-MS :577 [M+H] m*O 80-8511C Examnle 206 2 S)-2-(l-(2-chlorobenzyl)indol-3- WO 97/03951 PCT/JP96/0I 995 117 ylcarbonyl) amino-5-carboxypentanoyl }amino] heptanamide ESI-MS :611

LM+H]

nip :105-1100C Example 207 1( 3

S)-

3 -[N-(n-Butvi).q 2

S)-

2 -(1-(1-naphthylmethyl)indol- 3 -ylcarbonyl) amino-5-carboxypentanoyl lamino] heptanamide ESI-MS :627 [M+Hl nip 105-1130C E xamipl- 20 8 (3S) 3 -EN-Ethyl- -S-carboxy-2- 2 -quinolylcarbonylamino)pentanoyllam-inolhexadecanamide (300 mg) was dissolved in 4N hydrogen chloride in ethyl acetate (2 ml) at room temperature. After being stirred at the same temperature for minutes, the solvent was removed under reduced pressure and the resulting solid was triturated with ethyl acetate to give 3 S)-3-[N-ethyl-{ 2 S)-5-carboxy-2-(2.

auinolylcarbonylamino) pentanoyl Ia-mino] hexadecanamide hydrochloride (194 nTig) Exampile 209 3

S)-

3 2 S)-5-carboxy-2- (2auinolylcarbonylamino) pentanoyl Iamino] hexadecanamide hydrochloride was obtained according to a similar manner to that of Example 208.

Examplie 210 3

S)-

3 2 S)-2-(1-benzylindo..3 ylcarbonyl) was obtLained according to a similar manner to that of Example21.

ESI-MS 591 [M H] nip 147-1570C

Claims

1. A fatty acid derivative represented by the following formula: 2 R i -NH 0 X R3 R 4 wherein R' is Cl-C 4 alkoxycarbonyl; phenyl (Ci-C 4 alkanoyl or naphthyl (C 1 -C 4 alkanoyl, 15 each of which may have 1 to 3 substituent(s) g: selected from the group consisting of carboxy C 4 alkyl, CI-C 4 alkoxycarbonyl (C 1 -C 4 alkyl which may be substituted by phenyl, Ci-C 4 alkoxy carbonyl (C 2 -C 4 alkenyl, carbamoyl (C 1 -C 4 alkyl and phenyl (Ci-C 4 alkyl; or heterocyclic (Ci-C 4 alkanoyl which may have 1 to 3 substituent(s) selected from the group consisting of pyridyl (Cl-C 4 alkyl, naphthyl (Ci-C 4 alkyl and phenyl (Cl-C 4 alkyl which may have 1 to 3 substituent(s) selected from the group consisting of Cl-C 4 alkyl and halogen, in which the heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), R 2 is carboxy (Cl-C 4 alkyl or esterified carboxy (Cl-C 4 alkyl, R 3 is hydrogen; phenyl (Ci-C 4 alkyl which may have 1 to 3 substituent(s) selected from the group consisting of '2 Ci-C 4 alkyl, C 7 -C,6 alkyl and phenyl; JPERMJCL 64696-96 CIA 5/5/99 a. a a a a a a a a a a. a a a a a a a. a a a a a. a a a a

119- naphthyl (C,-C 4 alkyl which may be substituted by C 1 -C 4 alkyl; phenyl (C 7 -C 1 6 alkyl; heterocyclic (Cl-C 4 alkyl, in which the heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) C 1 ,-C 1 alkoxy (C 1 -C 4 alkyl; C-I-C6 alkyl; or C 7 -CI6 alkyl, R 4 is carbamoyl (Cl-C 4 alkyl, and X is -NH- or -N- [wherein R5 is C,-C 5 alkyl, phenyl (Cl-C 4 alkyl, or pyridyl (C,-C 4 alkyll, R with proviso that X is (wherein R' is as defined above), when R3 is alkyl or C 7 -C.6 alkyl, or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1, wherein RI is (Cl-C 4 alkoxycarbonyl; phenyl (CI-C 4 alkanoyl or naphthyl (C,-C 4 alkanoyl, each of which may have 1 to 3 substituent(s) selected from the group consisting of carboxy (Cl- C 4 alkyl, (Cl-C 4 alkoxycarbonyl (Cl-C 4 alkyl which may be substituted by phenyl, (C 1 -C 4 alkoxycarbonyl (C 2 -C 4 alkenyl, carbamoyl (Cl-C 4 aikyl or phenyl (Cl-C 4 alkyl; heterocyclic (C 1 -C 4 alkanoyl which may have 1 to 3 substituent(s) selected from the group consisting of pyridyl (CI-c 4 alkyl, naphthyl (C,-C 4 alkyl and phenyl (CI-C 4 alkyl which may have 1 to 3 fW T P 0 PEPA IJC'r64696-96 CLA -5 -5 99 120 substituent(s) selected from the group consisting of (C 1 -C 4 alkyl and halogen, in which the heterocyclic moiety is indolyl, guinolyl or isoquinolyl, R 2 is carboxy (CI-C 4 alkyl, methoxycarbonyl (Cl-C 4 alkyl, or benzyloxycarbonyl (Cl-C 4 alkyl, 3 is hydrogen; phenyl (C 1 -C 4 alkyl which may have 1 to 3 substituent(s) selected from the group consisting of (Cl-C 4 alkyl, (C 7 -0 1 9 alkyl and phenyl; naphthyl (Cl-C 4 alkyl which may be substituted by (C 1 -C 4 alkyl; :phenyl (C- 7 -C 1 6) alkyl; benzofuranyl (Cl-C 4 alkyl; 16 alkoxy (CI-C 4 alkyl; (C3-C 6 alkyl; or (C 7 -C 19 alkyl, 4 is carbamoyl (CI-C 4 alkyl, and R 20 X is -NH- or -N- [wherein R' is (C,-C 5 alkyl, phenyl (C 1 -C 4 alkyl, or pyridyl (CI-C 4 alkyl I, with proviso that X is (wherein R' is as defined above), when R 3 is alkyl or (C 7 alkyl, 3. A compound of claim 2, wherein R' is indolyl (Cl-C 4 alkanoyl which may have a substituent selected from the group consisting of pyridyl (CI-C 4 alkyl, naphthyl (CI-C 4 alkyl, phenyl (Cl-C 4 alkyl, C,-C 4 alkyiphenyl (C 1 -C 4 alkyl, and halophenyl (Cl-C 4 alkyl, R 2 is carboxy 4 akl !I)!,I'R11J: 64669(1Q6 -5i I 5 1 121 R 3 is alkyl or 6 alkyl, R' is carbamoyl (C 1 -Cj) alkyl, and X is -N- [wherein R' is C 1 -C 5 alkyl] 4. A compound of claim 3, which is selected from the group (3S)-3-[N-(n-Propyl)-{(2S)-5-carboxy-2-{(l-(2- chlorobenzyl) indol-3-ylcarbonyl) aminolpentanoyl}- amino] nonanamride, chlorobenzyl) indol-3-ylcarbonyl) carboxypentanoyl}amnino] heptanamide, (3S)-3-[N-(n-Propyl)-{ (2S)-2-(1-benzylindol-3- ylcarbonyl) dodecanamide, chlorobenzyl) indol-3-ylcarbonyl) carboxypentanoyl }amino] dodecanamide, (3S)-3-[N-Ethl-{(2S)-2-(1-(2-chlorobenzyl)indol-3- ylcarbonyl) aiino-5-carboxypentanoyl} amino] nonanamide, (3S)-3-[N-Ethyl-{ (2S)-2-(l-benzylindol-3- vlcarbonyl) amino-5-carboxypentanoyl} amino] nonanamide, (2S)-2-(1-(1--naphthylmethyl)- indol-3-ylcarbonyl) amino-5-carboxypentanoyllauino] heptanamide, and (3S)-3-[N-(n-Propyl)-{ (2S)-2-(1-benzylindol-3- ylcarbonyl) amino-5-carboxypentanoyl }amino] nonanaraide, or a pharmaceutically acceptable salt thereof. P ()PER R46V6-)6 5-5 9

122- A process for preparing a compound of the formula: R2 R3AR 4 wherein R' is CI-C4 alkoxycarbonyl; phenyl (C,-C 4 alkanoyl or naphthyl alkanoyl, each of which may have 1 to 3 substituent(s) selected from the group consisting of carboxy C4) alkyl, Ci-C 4 alkoxycarbonyl (C-C4) alkyl which 15 may be substituted by phenyl, C,-C4 alkoxy carbonyl (C2-C4) alkenyl, carbamoyl (Ci-C4) alkyl and phenyl (CI-C4) alkyl; or heterocyclic (C-C4) alkanoyl which may have 1 to 3 substituent(s) selected from the group consisting of pyridyl alkyl, naphthyl (Ci-C4) alkyl and phenyl (C-C4) alkyl which may have 1 to 3 substituent(s) selected from the group consisting of C,-C4 alkyl and halogen, in which the heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), R 2 is carboxy (C-C4) alkyl or esterified carboxy alkyl, R 3 is hydrogen; phenyl alkyl which may have 1 to 3 substituent(s) selected from the group consisting of Ci-C4 alkyl, C,-CI, alkyl and phenyl; naphthyl (Cl-C4) alkyl which may be substituted by CI-C4 alkyl; phenyl alkyl; P OP-KRMiJC (696-96 (LA 99 123 heterocyclic (CI-C 4 alkyl, in which the heterocyclic moiety is unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s); C 7 -CIg alkoxy (C 1 -C 4 alkyl; C 3 alkyl; or C,-Ci, alkyl, R 4 is carbamoyl (Ci-C 4 alkyl, and R X is -NH- or -N- [wherein R 5 is C,-Cs alkyl, phenyl (C 1 -C 4 alkyl, or pyridyl (CI-C 4 alkyl], C 9 9* R S 15 with proviso that X is (wherein R 5 is as defined above), when R 3 is C 3 alkyl or C 7 -CI alkyl, or a salt thereof, which comprises 1) reacting the compound of the formula R2 R-NH COOH wherein R 1 and R 2 are each as defined above, or a reactive derivative at the carboxy group or a salt thereof, with the compound of the formula X-H R 3 R 4 wherein R 3 R 4 and X are each as defined above, or a salt thereof, P OPER UC'64959-96 CI.k- 5 99 -124- 6. A pharmaceutical composition which comprises, as an active ingredient, a fatty acid derivative of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients. 7. Use of a fatty acid derivative of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. 8. A fatty acid derivative of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament. :i 9. A method for the prevention and/or the treatment of *pancreatitis, hepatitis, chronic renal failure, shock, arthritis, respiratory disease, heart disease, allergic disease, thrombosis, arteriosclerosis, pain, autoimmune disease, dermal disease, inflammatory bowel disease, .ophthalmic disease, nasal diseases, gout, trauma induced inflammation or liver diseases, which comprises o 20 administering a fatty acid derivative of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal. Use of a fatty acid derivative of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of pancreatitis, hepatitis, chronic renal failure, shock, arthritis, respiratory disease, heart disease, allergic disease, thrombosis, arteriosclerosis, pain, autoimmune disease, dermal disease, inflammatory bowel disease, ophthalmic disease, nasal diseases, gout, trauma induced inflammation or liver diseases. 11. A fatty acid derivative of claim 1 substantially as P OPFR, NC'64696-)6 (LA S 5'99 125 hereinbefore described with reference to any one of the Examples. 12. A process according to claim 5 substantially as hereinbefore described with reference to any one of the Examples. DATED this 5th day of May 1999 FUJISAWA PHARMACEUTICAL CO., LTD. o by DAVIES COLLISON CAVE e: Patent Attorneys for the Applicant 9 fte