# US 5,348,978 A · Angiotensin converting enzyme inhibitors

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- Number: US 5,348,978 A
- Document ID: US5348978A
- Status: Granted
- Kind: A
- Application number: 07/956,877
- Filed: 1992-12-10
- Granted: 1994-09-20
- Earliest claimed: 1990-06-22
- Assignees: Fisons Limited
- Inventors: Andrew J. G. Baxter; Premji Meghani
- Web page: https://patentgrep.com/patent/US5348978A

## CPC

- C07D 339/06: having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 229/36: with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
- C07C 233/83: of an acyclic saturated carbon skeleton
- C07C 323/52: the carbon skeleton being acyclic and saturated
- C07C 323/56: the carbon skeleton containing six-membered aromatic rings
- C07D 333/34: Sulfur atoms
- C07F 9/4075: {Esters with hydroxyalkyl compounds}
- C07C 2601/02: with a three-membered ring
- C07C 2601/08: the ring being saturated
- C07C 2601/14: The ring being saturated
- C07C 2603/74: Adamantanes
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Angiotensin converting enzyme inhibitors have the formula Z(CH.sub.2).sub.n CHR.sub.1 COOCHR.sub.2 COOH in which Z is --SR.sub.3, --COCHR.sub.4 NHCOR.sub.5, ##STR1## or --NHCHR.sub.7 COOH, R.sub.4, R.sub.5, R.sub.6, and R.sub.7, which may be the same or different, are each phenyl or alkylphenyl C.sub.7-12, R.sub.4 is hydrogen, alkyl C.sub.1-6, NHR.sub.8 or (CH.sub.2).sub.p R.sub.9, R.sub.2 is (CH.sub.2).sub.m XR.sub.10, alkyl C.sub.1-6 optionally substituted by a saturated 5- or 6-membered carbocyclic or heterocyclic ring, alkylhalo C.sub.1-6, alkylcyano C.sub.1-6, or alkyl phenyl C.sub.7-12, the phenyl being optionally substituted by NO.sub.2 or NH.sub.2, X is O, S(O).sub.q, C.dbd.O or NR.sub.11, and R.sub.10 is alkyl C.sub.1-6, alkylhalo C.sub.1-6, alkoxy C.sub.1-6, alkoxy C.sub.1-6 substituted by halogen, alkanoyl C.sub.1-6, S(O).sub.r R.sub.12, NR.sub.13 R.sub.14, phenyl, alkylphenyl C.sub.7-12, naphthalenyl or a 5-membered unsaturated heterocyclic ring, n is an integer from 0 to 6, m and p, which may be the same or different, are each an integer from 1 to 6, R.sub.9 is hydrogen, SR.sub.15 or phenyl optionally substituted by OR.sub.16, R.sub.3 and R.sub.15, which may be the same or different, are each hydrogen or alkanoyl C.sub.1-6, R.sub.8 is hydrogen or COOR.sub.17, q and r, which may be the same or different, are each 0, 1, or 2, R.sub.11, R.sub.13, R.sub.14, R.sub.16, and R.sub.17, which may be the same or different, are each hydrogen or alkyl C.sub.1-6, and R.sub.12 is hydrogen, alkyl C.sub.1-6 or phenyl. The compounds, and salts thereof, are useful as vasodilators.

## Claims

### Claim 1

Compounds of formula I,
Z(CH.sub.2).sub.n CHR.sub.1 COOCHR.sub.2 COOH
in which Z is --SR.sub.3,
R.sub.1 is hydrogen, alkyl C.sub.1-6, NHR.sub.8 or (CH.sub.2).sub.p R.sub.9,
R.sub.2 is (CH.sub.2).sub.m XR.sub.10,
X is O, S(O).sub.q, C=O or NR.sub.11, and
R.sub.10 is alkyl C.sub.1-6, alkylhalo C.sub.1-6, alkoxy C.sub.1-6, alkoxy C.sub.1-6 substituted by halogen, alkanoyl C.sub.1-6, S(O).sub.r R.sub.12, NR.sub.13 R.sub.14, phenyl, alkylphenyl C.sub.7-12, naphthalenyl or a 5-membered unsaturated heterocyclic ring,
n is an integer from 0 to 6,
m and p, which may be the same or different, are each an integer from 1 to 6,
R.sub.9 is hydrogen, SR.sub.15 or phenyl optionally substituted by OR.sub.16,
R.sub.3 and R.sub.15, which may be the same or different, are each hydrogen or alkanoyl C.sub.1-6,
R.sub.8 is hydrogen or COOR.sub.17,
q and r, which may be the same or different, are each 0, 1, or 2,
R.sub.11, R.sub.13, R.sub.14, R.sub.16, and R.sub.17, which may be the same or different, are each hydrogen or alkyl C.sub.1-6, and
R.sub.12 is hydrogen, alkyl C.sub.1-6 or phenyl,
and pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

A compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein X is S or O.

### Claim 3 (depends on 1)

A compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is methyl.

### Claim 4 (depends on 1)

A compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, wherein R.sub.10 is alkyl C.sub.1-6.

### Claim 5 (depends on 1)

A compound of formula I, as defined in claim 1, which is
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(methylthio)propanoic acid,
2(S)-2-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-methoxypropanoic acid,
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-((1-methylethyl)thio)propanoic acid, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a compound of formula I, as defined in claim 1, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent or adjuvant.

### Claim 7 (depends on 1)

A compound of formula I, as defined in claim 1, which is
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(phenylthio)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(phenylmethoxy)propanoic acid,
2(S)-(3-Mercapto2(S)-methyl-1-oxopropoxy)-4-(methylthio)butanoic acid,
3-Ethoxy-2(S)-(3-mercapto-2(S)-methyl-1-oxopropoxy)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(1-methylethoxy)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-phenoxypropanoic acid,
3-(1,1-Dimethylethoxy)-2(S)-(3-mercapto-2(S)-methyl-1-oxopropoxy)propanoic acid,
2(R)-(3-Mercapto-2(S)-methyl-1oxopropoxy)-3-(phenylsulphonyl)propanoic acid,
3-(Ethylthio)-2(R)(3-mercapto-2(S)-methyl-1-oxopropoxy)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)butanedioic acid 4-methyl ester,
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-((phenylmethyl)thio)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-((methylsulphonyl)amino)propan oic acid,
3-(Acetylamino)2(S)-(3-mercapto-2(S)-methyl-1-oxopropoxy)propanoic acid,
4-Amino-2(S)-(3-mercapto-2(S)-methyl-1-oxopropoxy)-4-oxobutanoic acid,
3-((1,1-Dimethylethyl)thio)-2(R)-(3-mercapto-2(S)-methyl-1-oxopropoxy)propa noic acid,
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(1-naphthalenylthio)propanoic acid,
2(S)-(3-Mercapto-1-oxopropoxy)-3-(phenylmethoxy)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-((phenylsulphonyl)amino)propan oic acid,
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(2-thienylethio)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(methyl(methylsulphonyl)amino) propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-4-phenoxybutanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-4-((1-methylethyl)thio)butanoic acid,
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-((2-methylpropyl)thio)propanoi c acid,
3-(Cyclopentylmethoxy)-2(S)-(3-mercapto-2(S)-methyl-1-oxopropoxy)propanoic acid,
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3((2,2,2,-trifluoroethyl)thio)pr opanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)butanedioic acid 4-(1-methylethyl) ester,
2(R)-(3-Mercapto-2(S) -methyl-1-oxopropoxy)-3-((1,1-dimethylpropyl)thio)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)butanedioic acid 4-(2,2,2,-trifluoroethyl) ester,
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(3-thienylthio)propanoic acid,
3-(Ethyl(methylsulphonyl)amino)-2(S)-(3-mercapto-2(S)-methyl-1-oxopropoxy)p ropanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(methyl((1-methylethyl)sulphon yl)amino)propanoic acid,
2(S)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-((1-methylethyl)(methylsulphon yl)amino)propanoic acid,
3-(Cyclopentylthio)2(R)-(3-mercapto-2(S)-methyl-1-oxopropoxy)propanoic acid,
3-(2,2-Dimethyl-1-oxopropoxy)-2(S)-(3-mercapto-2(S)-methyl-1-oxopropoxy)pro panoic acid,
3-1-Ethylpropylthio)-2(R)-(3-mercapto-2(S)-methyl-1-oxopropoxy)propanoic acid,
2(R)-(3-Mercapto-2(S)-methyl-1-oxopropoxy)-3-(propylthio)propanoic acid,
3-(Cyclopropylthio)-2(R)-(3-mercapto-2(S)-methyl-1-oxopropoxy)propanoic acid,
or a pharmaceutically acceptable salt thereof.