# US 4,396,616 A · Substituted enantholactam derivatives as antihypertensives

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- Number: US 4,396,616 A
- Document ID: US4396616A
- Status: Granted
- Kind: A
- Application number: 06/299,051
- Filed: 1981-09-04
- Granted: 1983-08-02
- Earliest claimed: 1981-09-04
- Assignees: Merck & Co., Inc.
- Inventors: Elbert E. Harris; David Taub; Eugene D. Thorsett
- Web page: https://patentgrep.com/patent/US4396616A

## CPC

- C07D 225/02: not condensed with other rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Substituted enantholactam dipeptides and derivatives thereof are disclosed which are useful as converting enzyme inhibitors and as antihypertensives.

## Claims

### Claim 1

A compound of the formula: ##STR6## in which R.sup.1 is hydrogen, lower alkyl, cycloloweralkyl having 3 to 7 ring C atoms, aminoloweralkyl, hydroxyloweralkyl, or substituted aryl wherein the substituent is halo, loweralkyl, aminoloweralkyl or loweralkoxy;
R.sup.2 is hydrogen, lower alkyl, aminolower alkyl, indolyl lower alkyl or phenyl lower alkyl;
R.sup.3 is hydroxy, or lower alkoxy;
R.sup.4 is hydrogen or lower alkanoyl;
R.sup.5 is hydrogen or lower alkyl; and,
the pharmaceutically acceptable salts thereof.

### Claim 2 (depends on 1)

The compound of claim 1 wherein
R.sup.1 is hydrogen or lower alkyl;
R.sup.2 is hydrogen or lower alkyl;
R.sup.3 is hydroxy or lower alkoxy;
R.sup.4 is hydrogen or lower alkanoyl; and,
R.sup.5 is hydrogen.

### Claim 3 (depends on 2)

The compound of claim 2 which is 1-(1-carboxyethyl)-3-mercaptomethylperhydroazocin-2-one.

### Claim 4 (depends on 2)

The compound of claim 2 which is 1-(1-methoxycarbonyl)-3-acetylthiomethylperhydroazocin-2-one.

### Claim 5

A method of treating hypertension which comprises administering to a patient in need of such treatment an antihypertensively effective amount of a compound of the formula: ##STR7## in which R.sup.1 is hydrogen, lower alkyl, cycloloweralkyl having 3 to 7 ring C atoms, aminoloweralkyl, hydroxyloweralkyl, or substituted aryl wherein the substituent is halo, loweralkyl, aminoloweralkyl, or loweralkoxy;
R.sup.2 is hydrogen, lower alkyl, amino lower alkyl indolyl lower alkyl or phenyl lower alkyl;
R.sup.3 is hydroxy, or lower alkoxy;
R.sup.4 is hydrogen or lower alkanoyl;
R.sup.5 is hydrogen or lower alkyl; and,
the pharmaceutically acceptable salts thereof.

### Claim 6 (depends on 5)

The method of claim 5 wherein
R.sup.1 is hydrogen or lower alkyl;
R.sup.2 is hydrogen or alkyl;
R.sup.3 is hydroxy or lower alkoxy;
R.sup.4 is hydrogen or lower alkanoyl; and,
R.sup.5 is hydrogen.

### Claim 7 (depends on 6)

The method of claim 6 wherein said compound is 1-(1-carboxyethyl)-3-mercaptomethylperhydroazocin-2-one.

### Claim 8 (depends on 6)

The method of claim 6 wherein said compound is 1-(1-methoxycarbonyl)-3-acetylthiomethylperhydroazocin-2-one.

### Claim 9

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensively effective amount of a compound of the formula: ##STR8## in which R.sup.1 is hydrogen, lower alkyl, cycloloweralkyl having 3 to 7 ring C atoms, aminoloweralkyl, hydroxyloweralkyl, or substituted aryl wherein the substituent is halo, loweralkyl, aminoloweralkyl, or loweralkoxy;
R.sup.2 is hydrogen, lower alkyl, amino lower alkyl, indolyl lower alkyl or phenyl lower alkyl;
R.sup.3 is hydroxy, or lower alkoxy;
R.sup.4 is hydrogen or lower alkanoyl;
R.sup.5 is hydrogen or lower alkyl;
and the pharmaceutically acceptable salts thereof.

### Claim 10 (depends on 9)

The composition of claim 9 wherein said compound is 1-(1-carboxyethyl)-3-mercaptomethylperhydroazocin-2-one.

### Claim 11 (depends on 9)

The composition of claim 9 wherein said compound is 1-(1-methoxycarbonyl)-3-acetylthiomethylperhydroazocin-2-one.

### Claim 12

A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier; an antihypertensively effective amount of a compound of the formula: ##STR9## in which R.sup.1 is hydrogen, lower alkyl, cycloloweralkyl having 3 to 7 ring C atoms, aminoloweralkyl, hydroxyloweralkyl, arloweralkyl, or substituted aryl wherein the substituent is halo, loweralkyl, aminoloweralkyl, or loweralkoxy;
R.sup.2 is hydrogen, lower alkyl, amino lower alkyl, indolyl lower alkyl or phenyl lower alkyl;
R.sup.3 is hydroxy, or lower alkoxy;
R.sup.4 is hydrogen or lower alkanoyl;
R.sup.5 is hydrogen or lower alkyl;
the pharmaceutically acceptable salts thereof; and, an antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metalazone, metoprololtartrate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, (S)-1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-3-{[4-(2-thienyl)-1H-imidazol- 2-yl]phenoxy}-2-propanol, polythiazide, the pivaloyloxyethyl ester of methyldopa, indacrinone and variable ratios of its enantiomers, rifetipine, verapamil, diltiazam, flumethiazide, bendroflumethiazide, atenolol, (+)-4-{3-{[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benz oic acid, bumetanide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, guinethazone, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procaine, as well as admixtures and combinations thereof.

### Claim 13 (depends on 12)

The composition of claim 12 wherein said antihypertensively effective compound is 1-(1-carboxyethyl)-3-mercaptomethylperhydroazocin-2-one.

### Claim 14 (depends on 12)

The composition of claim 12 wherein said antihypertensively effective compound is 1-(1-methoxycarbonyl)-3-acetylthiomethylperhydroazocin-2-one.

### Claim 15

A process for preparing compounds of the formula: ##STR10## wherein: R.sup.1 is hydrogen, lower alkyl, cycloloweralkyl having 3 to 7 ring C atoms, aminoloweralkyl, hydroxyloweralkyl, arloweralkyl, or substituted aryl wherein the substituent is halo, loweralkyl, aminoloweralkyl, or loweralkoxy;
R.sup.2 is hydrogen, lower alkyl, amino lower alkyl, indolyl lower alkyl, or phenyl lower alkyl;
R.sup.3 is hydroxy, or lower alkoxy;
R.sup.4 is hydrogen or lowr alkanoyl; and,
R.sup.5 is hydrogen or lower alkyl; which process comprises treating a compound of the formula ##STR11## with R.sup.4 -SH wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined above, followed by removal of acyl and ester groups, if necessary, to yield the desired product and, if desired, isolating the biologically more active isomer by chromatography, fractional crystallization, or by resolution with an appropriate, optically active base and, if desired, preparing a salt of the desired product by conventional means.

### Claim 16 (depends on 15)

The process of claim 15 wherein:
R.sup.1 is hydrogen or lower alkyl;
R.sup.2 is hydrogen or lower alkyl;
R.sup.3 is hydroxy or lower alkoxy;
R.sup.4 is hydrogen or lower alkanoyl; and,
R.sup.5 is hydrogen.

### Claim 17 (depends on 1)

The compound: ##STR12## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.5 are as defined in claim 1.

### Claim 18

The compound: ##STR13## and the corresponding carboxylic acid thereof.