# US 5,703,106 A · Antagonists of endothelin receptors

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- Number: US 5,703,106 A
- Document ID: US5703106A
- Status: Granted
- Kind: A
- Application number: 08/718,593
- Filed: 1996-09-25
- Granted: 1997-12-30
- Earliest claimed: 1994-03-28
- Assignees: Japat Ltd.
- Inventors: Thomas Fruh; Thomas Pitterna; Toshiki Murata; Lene D. Svensson; Yoko Yuumoto; Junichi Sakaki
- Web page: https://patentgrep.com/patent/US5703106A

## CPC

- C07K 5/06078: {and aromatic or cycloaliphatic}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 27/02: Ophthalmic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/20: substituted additionally by nitrogen atoms, e.g. tryptophane
- C07K 5/06139: {with the first amino acid being heterocyclic}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention provides novel compounds having pharmacological properties represented by the general formula I ##STR1## processes for the manufacture, pharmaceutical compositions and the use of the compounds of formula I and salts thereof.

## Claims

### Claim 1

A compound of formula (I) ##STR46## Ar represents a direct bond or arylene; m is 0, 1, 2, or 3;
R.sub.1 is lower alkyl, cycloalkyl-lower alkyl, aryl-lower alkyl, cycloalkyl, aryl, aryl-cycloalkyl, lower alkoxy, or aryloxy;
R.sub.2 is hydrogen, lower alkyl, aryl-lower alkyl, cycloalkyl, or cycloalkyl-lower alkyl;
R.sub.3 represents hydrogen, hydroxy, amino, nitro, lower alkyl, cycloalkyl, or aryl-lower alkyl, provided that Ar is a direct bond, or represents aryl;
R.sub.3 ' represents hydrogen, lower alkyl, cycloalkyl, aryl-lower alkyl, or aryl; or
R.sub.3 and R.sub.3 ' together form a ring structure, provided that Ar is a direct bond;
R.sub.3 " is hydrogen, lower alkyl or aryl; or
R.sub.2 and R.sub.3 " together form the lower alkylene group --(CH.sub.2).sub.n -- wherein n is an integer of 1, 2 or 3; or
R.sub.2 and R.sub.3 " together form a group represented by the formula: --(CH.sub.2).sub.o --Ar.sub.1 -- or --Ar.sub.1 --(CH.sub.2).sub.o --, respectively, wherein o is zero or an integer of 1 or 2, and Ar.sub.1 is arylene;
C(.dbd.X) is C(.dbd.O), C(.dbd.S), C(.dbd.NH), C(.dbd.N-lower alkyl); C.dbd.NH--OH, or CH.sub.2; and Y is a direct bond, --NH--, ##STR47## oxygen, or methylene; or C(.dbd.X) is CHOH and Y is a direct bond or methylene;
R.sub.4 is lower alkyl, lower alkenyl, cycloalkyl, aryl-lower alkyl, aryl-lower alkenyl, or aryl;
R.sub.5 is hydrogen, lower alkyl, aryl-lower alkyl, cycloalkyl, or cycloalkyl-lower alkyl;
R.sub.6 represents lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, aryloxy-lower alkyl, aryl-lower alkyl, lower alkenyl, lower alkenyl which substituted by at least one substituent selected from the group consisting of carboxy, lower alkoxycarbonyl, hydroxy, lower alkoxy, amino, lower alkylamino and di-lower alkylamino, or represents aryl-lower alkenyl, aryl or lower alkyl which is substituted by carboxy or lower alkoxycarbonyl and also by amino, lower alkylamino or di-lower alkylamino; or
R.sub.5 and R.sub.6 together form the lower alkylene group --(CH.sub.2).sub.p -- wherein p is an integer of 3-5, or together form a group represented by the formulae: --(CH.sub.2).sub.q --Ar.sub.1 -- or --Ar.sub.1 --(CH.sub.2).sub.q --, wherein q is zero or an integer of 1 or 2, and Ar.sub.1 is arylene; and
Y.sub.1 represents --SO.sub.2 --, --O--, --NH--, --NH--CO--, --NH--CO--O-- or --NH--SO.sub.2 --; and wherein "aryl", it being a mono- or bivalent aryl radical or aryl moiety, respectively, represents, in each case, a corresponding carbocyclic or heterocyclic aryl radical or aryl moiety, respectively; or a salt thereof.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 of formula (I) wherein
Ar represents a direct bond or phenylene;
R.sub.1 is mono- or di-substituted phenyl ##STR48## in which one of A.sub.1 and A.sub.2 is or in which A.sub.1 and A.sub.2, independently of one another, are halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, phenyl-lower alkoxy, or nitro; or A.sub.1 and A.sub.2 together form --O--CH.sub.2 --O--;
R.sub.2 is hydrogen or lower alkyl;
R.sub.3 represents hydrogen, hydroxy, amino, nitro, phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, triazolyl, or pyridyl, each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, amino, hydroxy or nitro;
R.sub.3 ' and R.sub.3 ", independently of one another, represent hydrogen or phenyl which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, amino, hydroxy, or nitro; or
R.sub.3 and R.sub.3 ' together form fluorenyl, anthryl, or dibenzosuberyl, provided that Ar is a direct bond; or
R.sub.2 and R.sub.3 " together form the lower alkylene group --(CH.sub.2).sub.n -- wherein n is an integer of 1, 2 or 3;
C(.dbd.X) is C(.dbd.O), C(.dbd.NH), C(.dbd.N-lower alkyl); and Y is a direct bond, --NH--, ##STR49## oxygen, or methylene; R.sub.4 represents naphthyl, thienyl, 3,4-methylenedioxy-phenyl, indolyl or 1-lower alkyl-indolyl each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, or hydroxy, and m is 1, 2, or 3; or
R.sub.4 is lower alkyl, lower alkenyl, C.sub.3 -C.sub.8 -cycloalkyl, phenyl-lower alkyl, phenyl-lower alkenyl, or phenyl, and m is 0;
R.sub.5 is hydrogen or lower alkyl; and
R.sub.6 represents lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl in which phenyl is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, or hydroxy; lower alkenyl, lower alkenyl which substituted by at least one substituent selected from the group consisting of carboxy, lower alkoxycarbonyl, hydroxy, lower alkoxy, amino, lower alkylamino and di-lower alkylamino, or represents phenyl-lower alkenyl, phenyl, thienyl, furyl, thiadiazolyl, pyrimidyl or pyridyl, each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, nitro, carboxy, or lower alkoxycarbonyl; or
R.sub.5 and R.sub.6 together form the lower alkylene group of --(CH.sub.2).sub.p -- wherein p is an integer of 3-5; and
Y.sub.1 is --SO.sub.2 --, --O--, --NH--, --NH--CO--, --NH--CO--O--, or --NH--SO.sub.2 --;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound as claimed in claim 1 of formula (I) wherein
Ar represents a direct bond or phenylene;
R.sub.1 is mono- or di-substituted phenyl ##STR50## in which one of A.sub.1 and A.sub.2 is or in which A.sub.1 and A.sub.2, independently of one another, are halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, phenyl-lower alkoxy, or nitro;
R.sub.2 is hydrogen or lower alkyl;
R.sub.3 represents phenyl, thienyl, furanyl, pyrrolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, or pyridyl, each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, amino, hydroxy or nitro;
R.sub.3 ' and R.sub.3 ", independently of one another, represent hydrogen or phenyl which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, amino, hydroxy, or nitro; or
R.sub.3 and R.sub.3 ' together form fluorenyl, anthryl, or dibenzosuberyl, provided that Ar is a direct bond; or
R.sub.2 and R.sub.3 " together form the lower alkylene group --(CH.sub.2).sub.n -- wherein n is an integer of 1, 2 or 3;
C(.dbd.X) is C(.dbd.O), C(.dbd.NH), C(.dbd.N-lower alkyl); and Y is a direct bond, --NH--, ##STR51## oxygen, or methylene; R.sub.4 represents indolyl or 1-lower alkyl-indolyl each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, or hydroxy, and m is 1, 2, or 3;
R.sub.5 is hydrogen or lower alkyl; and
R.sub.6 represents lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl in which phenyl is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, or hydroxy; phenyl, thienyl, furyl, thiadiazolyl, pyrimidyl or pyridyl, each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, carboxy, or lower alkoxycarbonyl; or
R.sub.5 and R.sub.6 together form the lower alkylene group of --(CH.sub.2).sub.p -- wherein p is an integer of 3-5; and
Y.sub.1 is --SO.sub.2 --, --O--, --NH--, --NH--CO--, --NH--CO--O--, or --NH--SO.sub.2 --;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound as claimed in claim 1 of formula (I) wherein
Ar represents a direct bond or phenylene;
R.sub.1 is di-substituted phenyl ##STR52## in which A.sub.1 and A.sub.2, independently of one another, are halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, phenyl-lower alkoxy, or nitro; or A.sub.1 and A.sub.2 together form --O--CH.sub.2 --O--;
R.sub.2 is lower alkyl;
R.sub.3 represents hydrogen, hydroxy, amino, nitro, phenyl, thienyl, pyridyl, pyrazolyl, isoxazolyl, oxadiazolyl, isothiazolyL triazolyl, or thiadiazolyl, each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, amino, hydroxy, or nitro;
R.sub.3 ' and R.sub.3 ", independently of one another, represent hydrogen or phenyl which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, amino, hydroxy, or nitro;
C(.dbd.X) is C(.dbd.O), C(.dbd.NH), C(.dbd.N-lower alkyl); and Y is a direct bond, --NH--, ##STR53## oxygen, or methylene; R.sub.4 represents naphthyl, thienyl, 3,4-methylenedioxy-phenyl, indolyl or 1-lower alkyl-indolyl each of which is unsubstituted or substituted by halogen, lower alkyl, trifluoromethyl, lower alkoxy, or hydroxy, and m is 1 or 2; or
R.sub.4 is lower alkyl, lower alkenyl, phenyl-lower alkyl, C.sub.5 -C.sub.6 -cycloalkyl, or phenyl and m is zero;
R.sub.5 is hydrogen; and
R.sub.6 represents lower alkyl, lower alkenyl, halo-lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl or phenyl-lower alkenyl in which phenyl is unsubstituted or substituted by halogen, lower alkyl, trifluoromethyl, lower alkoxy, or hydroxy; lower alkenyl, phenyl or thienyl, each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, nitro, carboxy, or lower alkoxycarbonyl; and
Y.sub.1 is --SO.sub.2, --O--, --NH--,--NH--CO--, or --NH--CO--O--;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A compound as claimed in claim 1 of formula (Ia) ##STR54## wherein ring A is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, or hydroxy;
R.sub.1 is di-substituted phenyl ##STR55## in which A.sub.1 and A.sub.2, independently of one another, are lower alkyl, trifluoromethyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, or halogen;
R.sub.2 is lower alkyl;
R.sub.3 represents (i) hydrogen, hydroxy, amino or nitro or (ii) phenyl, thienyl, pyridyl, pyrazolyl, triazolyl, isoxazolyl, or isothiazolyl each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, amino, hydroxy, or nitro;
C(.dbd.X) is C(.dbd.O) or C(.dbd.NH), and Y is --NH-- or methylene;
R.sub.4 represents naphthyl, thienyl, 3,4-methylenedioxy-phenyl, or indolyl each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, or hydroxy, and m is 1 or 2; or
R.sub.4 is lower alkyl, lower alkenyl, phenyl-lower alkenyl, C.sub.5 -C.sub.6 -cycloalkyl, or phenyl, and
m is zero;
R.sub.5 is hydrogen or lower alkyl;
R.sub.6 represents lower alkyl, halo-lower alkyl, lower alkoxy-lower alkyl, lower alkenyl, or phenyl-lower alkenyl, or represents phenyl, or thienyl each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, nitro, carboxy or lower alkoxycarbonyl; and
Y.sub.1 is --SO.sub.2 --, --O--, --NH--, or --NH--CO--;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

A compound as claimed in claim 5 of formula (Ia), wherein ring A is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, or hydroxy;
R.sub.1 is di-substituted phenyl ##STR56## in which A.sub.1 and A.sub.2, independently of one another, are lower alkyl, trifluoromethyl, lower alkoxy, hydroxy, phenyl-lower alkoxy, or halogen;
R.sub.2 is lower alkyl;
R.sub.3 represents phenyl, thienyl, or isoxazolyl, each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, cyano, amino, hydroxy, or nitro;
C(.dbd.X) is C(.dbd.O) or C(.dbd.NH), and Y is --NH--or methylene;
R.sub.4 represents indolyl which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, or hydroxy, and m is 1 or 2; or
R.sub.5 is hydrogen or lower alkyl;
R.sub.6 represents lower alkyl, halo-lower alkyl or lower alkoxy-lower alkyl, or represents phenyl or thienyl each of which is unsubstituted or substituted by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, carboxy or lower alkoxycarbonyl; and
Y.sub.1 is --SO.sub.2 --, --O--or --NH--;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 5)

A compound as claimed in claim 5 of formula (Ia), wherein ring A is unsubstituted;
R.sub.1 is 3,5-di-lower alkyl-phenyl, preferably 3,5-dimethyl-phenyl;
R.sub.2 is C.sub.1 -C.sub.4 -alkyl;
R.sub.3 represents phenyl, isoxazolyl, preferably 5-isoxazolyl, or thienyl, preferably 3-thienyl, furthermore hydrogen or hydroxy;
C(.dbd.X) is C(.dbd.O); and Y is --NH--;
R.sub.4 represents indolyl, preferably 3-indolyl, and m is 1; or
R.sub.4 represents C.sub.1 -C.sub.4 -alkyl, preferably methyl, 2-propyl, 2-methyl-1-propyl, or 2-butyl, or C.sub.2 -C.sub.4 -alkenyl, preferably, allyl or methallyl, and m is 0;
R.sub.5 is hydrogen;
R.sub.6 represents C.sub.1 -C.sub.4 -alkyl, halo-C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.4 -alkyl, phenyl-C.sub.1 -C.sub.4 -alkyl, or phenyl or thienyl, preferably 2-thienyl each of which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, hydroxy, carboxy or C.sub.2 -C.sub.5 -alkoxycarbonyl, or represents C.sub.3 -C.sub.5 -alkenyl, preferably allyl;
Y.sub.1 is --SO.sub.2 --;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 5)

A compound as claimed in claim 5 of formula (Ia), wherein ring A is unsubstituted or substituted by halogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, trifluoromethyl, or hydroxy;
m is 1;
R.sub.1 is 3,5-di-lower alkyl-phenyl, preferably 3,5-dimethyl-phenyl;
R.sub.2 is C.sub.1 -C.sub.4 -alkyl;
R.sub.3 represents phenyl, isoxazolyl, preferably 5-isoxazolyl, or thienyl, preferably 3-thienyl;
C(.dbd.X) is C(.dbd.O); and Y is --NH-- or methylene;
R.sub.4 represents indolyl, preferably 3-indolyl;
R.sub.5 is hydrogen;
R.sub.6 represents C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.4 -alkyl, or phenyl or thienyl, preferably 2-thienyl each of which is unsubstituted or substituted by halogen, trifluoromethyl, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, hydroxy, carboxy or C.sub.2 -C.sub.5 -alkoxycarbonyl; and
Y.sub.1 is --SO.sub.2 --;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 5)

A compound as claimed in claim 5 of formula (Ia), wherein ring A is unsubstituted;
R.sub.1 is 3,5-dimethyl-phenyl;
R.sub.2 is C.sub.1 -C.sub.4 -alkyl such as methyl or ethyl;
R.sub.3 represents 5-isoxazolyl, 3-thienyl or phenyl;
C(.dbd.X) is C(.dbd.O); and Y is --NH--;
R.sub.4 represents 3-indolyl and m is 1; or
R.sub.4 represents C.sub.1 -C.sub.4 -alkyl, especially 2-propyl or 2-butyl, or C.sub.2 -C.sub.4 -alkenyl, preferably, allyl or methallyl, and m is 0;
R.sub.5 is hydrogen;
R.sub.6 represents C.sub.1 -C.sub.4 -alkyl, phenyl or 2-thienyl each of which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl, or represents C.sub.3 -C.sub.5 alkenyl, especially allyl; and
Y.sub.1 is --SO.sub.2 ;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 5)

A compound as claimed in claim 5 of formula (Ia), wherein ring A is unsubstituted or substituted by halogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy, trifluoromethyl, or hydroxy;
m is 1;
R.sub.1 is 3,5-dimethyl-phenyl;
R.sub.2 is C.sub.1 -C.sub.4 -alkyl such as methyl or ethyl;
R.sub.3 represents 5-isoxazolyl, 3-thienyl or phenyl;
C(.dbd.X) is C(.dbd.O); and Y is --NH--;
R.sub.4 represents 3-indolyl;
R.sub.5 is hydrogen;
R.sub.6 represents C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.4 -alkyl, or phenyl or 2-thienyl each of which is unsubstituted or substituted by C.sub.1 -C.sub.4 -alkyl; and
Y.sub.1 is --SO.sub.2 --;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 5)

A compound as claimed in claim 5 of formula (Ia), wherein ring A is unsubstituted;
R.sub.1 is 3,5-dimethyl-phenyl;
R.sub.2 is methyl;
R.sub.3 represents 5-isoxazolyl or 3-thienyl;
C(.dbd.X) is C(.dbd.O); and Y is --NH--;
R.sub.4 represents 3-indolyl and m is 1;
R.sub.5 is hydrogen;
R.sub.6 represents n-propyl, n-butyl, allyl, phenyl or 2-thienyl; and
Y.sub.1 is --SO.sub.2 --;
or a salt thereof, especially a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A compound according to claim 1 of formula (I') or (Ia'), respectively, having following formula ##STR57## wherein the stereochemistry is R/S, if Y is different from --CH.sub.2 --; or is R/R, if Y is --CH.sub.2 --.

### Claim 13 (depends on 1)

A compound according to claim 1, selected from the group consisting of:
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(biphenyl-4-yl)-(D)-a lanyl!-(L)-tryptophanamide;
N-(2-thienyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl )phenyl!-alanyl!-(L)-tryptophanamide;
N-phenoxy-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl)phenyl!-ala nyl!-(L)-tryptophanamide;
N-phenyl'-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl)phenyl!-ala nyl!-(L)-tryptophanhydrazide;
N-benzenesulfonyl-(R)-5-›N-(3,5-dimethylbenzoyl)-N-methyl-amino!-2-(R)-›(3- indolyl)-methyl!-4-oxo-6-(biphenyl-4-yl)-hexanoylamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-3-›4-(5-isoxazolyl)-phenyl!-(D)- alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(biphenyl-4-yl)-(D)-a lanyl!-(L)-tryptophanamide;
N-propanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(biphenyl-4-yl)-(D)-a lanyl!-(L)-tryptophanamide;
N-benzylsulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(biphenyl-4-yl)-(D)-al anyl!-(L)-tryptophanamide;
N-i-propanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(biphenyl-4-yl)-(D) -alanyl!-(L)-tryptophanamide;
N-(4-methylphenyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(biphenyl-4- yl)-(D)-alanyl!-(L)-tryptophanamide;
N-methanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(biphenyl-4-yl)-a lanyl!-(L)-tryptophanamide;
N-(4-chlorophenyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-(bipheny l-4yl)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-phenyl-(D)alanyl!-(L) -tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(4-hydroxyphenyl)-(D) -alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(b 3,5-dimethylbenzoyl)-N-methyl-3-(2-chlorophenyl)-(D)-alanyl!-(L)-tryptopha namide;
N-methanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-phenyl-(D)-alanyl!-(L )-tryptophanamide;
N-(2-thienyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thienyl)phe nyl!-(D)-alanyl!-(L)-tryptophanamide;
N-propanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thienyl)phenyl! -(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thienyl)phenyl! -(D)-alanyl!-(L)-tryptophanamide;
N-butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thienyl)phenyl!- (D)-alanyl!-(L)-tryptophanamide;
N-(2-methylphenyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thieny l)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-ethanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thienyl)phenyl!- (D)-alanyl!-(L)-tryptophanamide;
N-(2-ethoxy-ethane)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thien yl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2-trifluoro-ethane)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-th ienyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(4-methoxyphenyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thien yl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(4-carboxyphenyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thien yl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(4-ethoxycarbonylphenyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-( 3-thienyl)phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(4-fluorophenyl)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thieny l)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)phen yl!-(D)-alanyl!-(L)-tryptophanamide;
N-(4-H-1,2,4-triazol-3-sulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3- thienyl)-phenyl!-(D)- alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(4-nitrophenyl)-(D)-a lanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-phenoxyphenyl!-(D) -alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-pyridyl)-phenyl !-(D)-alanyl!-(L)-tryptophanamide;
N-(2-hydroxyethanesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxa zolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2-benzyloxyethanesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-iso xazolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2-pyridinesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl )-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-imidazolyl)-phe nyl!-(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(1,2,3-thiadiazol- 4-yl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(3-carboxybenzenesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isox azolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(3-ethoxycarbonylbenzenesulfonyl)-›N-(3,5-dimethylbenzoyl)- N-methyl-3-›4-(5-isoxazolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2-carboxybenzenesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isox azoyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2-ethoxycarbonylbenzenesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4- (5-isoxazolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2,6-dimethylbenzenesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-i soxazolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2,6-diethylbenzenesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-is oxazolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2,6-diisopropylbenzenesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-›4-(5- isoxazolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(3-carboxy-3-aminopropanesulfonyl)-›N-(3,5-dimethylbenzolyl)-N-methyl-3-› 4-(5-isoxazolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-(2-carboxy-2-aminoethanesulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4- (5-isoxazolyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(1,2,4-oxadiazol-3 -yl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-isoxazolyl)-phe nyl!-(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-tetrazolyl)-phe nyl!-(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(1-H-pyrrol-3-yl)- phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-furanyl)-phenyl !-(D)-alanyl!-(L)-tryptophanamide;
N'-(4-carboxy-5-trifluoromethylpyrimid-2-yl)-›N-(3,5-dimethylbenzoyl)-N-met hyl-(D)-3-›4-(3-thienyl)phenyl!-alanyl!-(L)-tryptophanhydrazide;
N'-(4-methoxycarbonyl-5-trifluoromethylpyrimid-2-yl)-›N-(3,5-dimethylbenzoy l)-N-methyl-(D)-3-›4-(3-thienyl)phenyl!-alanyl!-(L)-tryptophanhydrazide;
N'-(2-chlor-5-carboxyphenyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3- thienyl)-phenyl!-alanyl!-(L)-tryptophanhydrazide;
N'-benzoyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl)phenyl!-al anyl!-(L)-tryptophanhydrazide;
N-benzenesulfonyl-N-methyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-thieny l)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N'-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl)ph enyl!-alanyl!-(L)-tryptophanhydrazide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(4-aminophenyl)-(D)-a lanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-(4-cyanophenyl)-(D)-a lanyl!-(L)-tryptophanamide;
N'-butoxycarbonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl)phe nyl!-alanyl!-(L)-tryptophanhydrazide;
(57) N'-carboxymethoxycarbonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-th ienyl)phenyl!-alanyl!-(L)-tryptophanhydrazide;
N'-carboxyacetyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl)phen yl!-alanyl!-(L)-tryptophanhydrazide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-3-›4-(5-isoxazolyl)-phenyl!-(D)- alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-3,5-dimethylbenzoyl)-N-methyl-2-methylalanyl!-(L)-tryp tophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(2-thienyl)-phenyl !-(D)-alanyl!-(L)-tryptophanamide;
N-(1,3,4-thiadiazol-2-sulfonyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(3-t hienyl)-phenyl!-(D)-alanyl!-(L)-tryptophanamide;
N'-acetyl-IN-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl)phenyl!-ala nyl!-(L)-tryptophanhydrazide;
N'-ethoxycarbonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-(D)-3-›4-(3-thienyl)phe nyl!-alanyl!-(L)-tryptophanhydrazide; and
N'-(2-chloro-5-methoxycarbonylphenyl)-›N-(3,5-dimethylbenzoyl)-N-methyl-(D) -3-›4-(3-thienyl)phenyl!-alanyl!-tryptophanhydrazide.

### Claim 14 (depends on 1)

A compound according to claim 1, selected from the group consisting of:
N-butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl))-phe nyl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-(2-propene)sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl) -phenyl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)-phen yl!-(D,L)-alanyl!-(L)-isoleucineamide;
N-butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)-phen yl!-(D,L)-alanyl!-(L)-valineamide;
N-Butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-dimethyl-3-›4-(1,2,4-triazol-1- yl)-phenyl!-(D,L)-alanyl!-(L)-tryptophanamide; and
N-butanesulfonyl-IN-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(1,2,3-triazol-1-yl )-phenyl!-(D,L)-alanyl!-(L)-tryptophanamide.

### Claim 15 (depends on 1)

A compound according to claim 1, selected from the group consisting of:
N-methyl-N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxaz olyl)-phenyl!-(D,L)-alanyl!-(D,L)-tryptophanamide;
N-isopropanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)- phenyl!-(D,L)-alanyl!-(D,L)-tryptophanamide;
N-(4-hydroxy-benzene)-sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-is oxazolyl)-phenyl!-(D,L)-alanyl!-(D,L)-tryptophanamide;
N-(2-ethoxylethane)-sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isox azolyl)-phenyl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-(2-nitrobenzene)-sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxa zolyl)-phenyl!-(D,L)-alanyl!-(D,L)-tryptophanamide;
N-(3-nitro-benzene)-sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isox azolyl)-phenyl!-(D,L)-alanyl!-(D ,L)-tryptophanamide;
N-benzylsulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)-phen yl!-(L)-alanyl!-(L)-tryptophanamide;
N-n-butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)-ph enyl!-(L)-alanyl!-(L)-tryptophanamide;
N-n-butanesulfonyl-›N-(3,5-dimethoxybenzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-n-butanesulfonyl›N-(3,5-dimethylbenzolyl)-N-methyl-3-›4-(5-isothiazolyl)- phenyl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-n-butanesulfonyl-›N-(3-methyl-5methoxy-benzoyl)-N-methyl-3-›4-(5-isoxazol yl)-phenyl!-(D,L)- alanyl!-(L)-tryptophanamide;
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(L)-3-(2-naphthyl)-alanylamide;
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(L)-3-(3-naphthyl)-alanylamide;
N-(2-propene)-sulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazoly l)-phenyl!-(D ,L)-alanyl!-(L)-tryptophanamide;
N-vinylsulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-phen yl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-(3-phenyl-2-propene)-sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-i soxazolyl)-phenyl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-(3-butene)-sulfonyl-›N-(3,5-dimethyl-benzoyl)- N-methyl-3-›4-(5-isoxazolyl)-phenyl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-(3-nitro-benzene)-sulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isox azolyl)-phenyl!-(L)-alanyl!-(L)-tryptophanamide;
N-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-phe nyl!-(DL)-alanyl!-(L)-leucineamide;
N-butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)-phen yl!-(DL)-alanyl!-(L)-phenylglycinamide;
N-methallylsulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(L)-isoleucineamide;
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(D,L)-3-(3,4-methylenedioxy-phenyl)-alanylamide;
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L) -alanyl!-(D,L)-3-(3-thienyl)-alanylamide;
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(L)-cyclohexylglycineamide;
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(D,L)-(2-amino-5-phenyl)-pent-4-enoic acid amide;
N-n-butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(1,2,3-triazol-1- yl)-phenyl!-(D,L)-alanyl!-(L)-tryptophaneamide;
N-n-butanesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(1,2,3-triazol-2- yl)-phenyl!-(D,L)-alanyl!-(L)-tryptophanamide;
N-benzenesulfonyl-›N-(3,5-dimethylbenzoyl)-N-methyl-3-›4-(5-isoxazolyl)-phe nyl!-(D,L)-alanyl!-(L)-isoleucineamide;
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(L)-alanylamide;
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(5-isoxazolyl)-p henyl!-(D,L)-alanyl!-(L)-(2-amino)-pent-4-enoic acid amide;
N-benzoyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(3-thienyl)-phenyl!-(D,L) -alanyl!-(L)-tryptophanamide;
N-butanesulfonyl-›N-(3,4-methylenedioxybenzoyl)-N-methyl-3-›4-(5-isoxazolyl )-phenyl!-(D,L)-alanyl!-(L)-tryptophanamide; and
N-n-butanesulfonyl-›N-(3,5-dimethyl-benzoyl)-N-methyl-3-›4-(1-pyrazolyl)-ph enyl!-(D,L)-alanyl!-(L)-tryptophanamide.

### Claim 16 (depends on 1)

A pharmaceutical preparation comprising an effective amount of a compound according to claim 1, in free form or in form of a pharmaceutically acceptable salt, in addition to customary pharmaceutical adjuncts.

### Claim 17 (depends on 1)

A method of treating cerebral and coronary vasospasm, cerebral and coronary ischemia, subarachnoidal haemorrhage, various types of hypertension, pulmonary hypertention, cardiac failure, Raynand-syndrome, diabetes, benign prostatic hyperplasia, atherosclerosis or restenosis due to denudation following angioplasty, asthma, renal failure, dialysis, glomerular injury, hepatic failure, stomach and duodenal ulcer, ulcus cruris, various brain dysfunctions, migraine, occular diseases, glaucoma, endotoxin shock, or disseminated intravascular coagulation in a subject in need of such treatment, which method comprises administering to such subject a therapeutically effective amount of a compound according to claim 1, in the free form or in form of a pharmaceutically acceptable salt.

### Claim 18 (depends on 1)

A process for the manufacture of a compound of formula I according to claim 1 which comprises
a) reacting a compound of formula ##STR58## or a salt or a activated ester, reactive anhydride, or reactive cyclic amide thereof with a compound of formula HN(R.sub.5)--Y.sub.1 --R.sub.6 (IIb) or a salt thereof; or
b) reacting a compound of formula ##STR59## with a compound of formula Z.sub.1 --Y.sub.1 --R.sub.6 (IIIb) in which Z.sub.1 represents reactive esterified hydroxy; or,
c) for the manufacture of a compound of formula I in which C(.dbd.X) is different from methylene or CHOH and in which Y is different from a direct bond or methylene, reacting a compound of formula ##STR60## or a salt or a activated ester, reactive anhydride, or reactive cyclic amide thereof with a compound of formula ##STR61## d) reacting a compound of formula R.sub.1 --COOH (Va) or a salt or a activated ester, reactive anhydride, or reactive cyclic amide thereof with a compound of formula (Vb) ##STR62## and, optionally, free functional groups in starting material of each variant, with the exception of those participating in the reaction, being optionally in protected form, and any protecting groups present are removed;
and, optionally, converting a compound I obtainable according to the process or in another manner, in free form or in salt form, into another compound I, separating a mixture of isomers obtainable according to the process and isolating the desired isomer and/or converting a free compound I obtainable according to the process into a salt or converting a salt of a compound I obtainable according to the process into the free compound I or into another salt.