Substituted phosphonamides as antihypertensives
AssigneeMerck & Co., Inc.
InventorsWilliam J. Greenlee, Elbert E. Harris, Arthur A. Patchett, Eugene D. Thorsett
Life of this patent
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Abstract
There are disclosed substituted phosphonamides and related compounds which are useful as converting enzyme inhibitors and as antihypertensives.
Claims24
A compound of the general formula ##STR3## wherein:
- R.sub.1 is alkyl or substituted alkyl of C.sub.1 -C.sub.6 wherein the substituent is halo, amino, acylamino;
- aralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the aryl function is phenyl or naphthyl optionally substituted by halo or hydroxyl;
- or,
- heteroaralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the heteroaryl group can be indolyl or thienyl;
- R.sub.2 is H, lower alkyl of C.sub.1 -C.sub.4, aralkyl;
- R.sub.3 is lower alkyl of C.sub.1 -C.sub.6 optionally substituted by an amino group;
- R.sub.4 is H, lower alkyl of C.sub.1 -C.sub.6, aralkyl;
- X is (CH.sub.2).sub.n wherein n is 1 or 2;
- and,
- the pharmaceutically acceptable salts thereof.
The compound:
- N-(2-phenyl-1-ethylphosphonyl)-L-alanyl-L-proline.
The compound:
- N-(3-phenyl-1-propylphosphonyl)-L-alanyl-L-proline.
A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensivity effective amount of a compound of the formula:
- ##STR4## wherein:
- R.sub.1 is alkyl or substituted alkyl of C.sub.1 -C.sub.6 wherein the substituent is halo, amino, acylamino;
- aralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the aryl function is phenyl or naphthyl optionally substituted by halo or hydroxyl;
- or,
- heteroaralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the heteroaralkyl group can be indolyl or thienyl;
- R.sub.2 is H, lower alkyl of C.sub.1 -C.sub.4, aralkyl;
- R.sub.3 is lower alkyl of C.sub.1 -C.sub.6 optionally substituted by an amino group;
- R.sub.4 is H, lower alkyl of C.sub.1 -C.sub.6, aralkyl;
- X is (CH.sub.2).sub.n wherein n is 1 or 2;
- and,
- the pharmaceutically acceptable salts thereof.
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:
- ##STR5## wherein:
- R.sub.1 is alkyl or substituted alkyl of C.sub.1 -C.sub.6, wherein the substituent is halo, amino, acylamino;
- aralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the aryl function is phenyl or naphthyl optionally substituted by halo or hydroxyl;
- or,
- heteroaralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the heteroaralkyl group can be indolyl or thienyl;
- R.sub.2 is H, lower alkyl of C.sub.1 -C.sub.4, aralkyl;
- R.sub.3 is lower alkyl of C.sub.1 -C.sub.6 optionally substituted by an amino group;
- R.sub.4 is H, lower alkyl of C.sub.1 -C.sub.6, aralkyl;
- X is (CH.sub.2).sub.n wherein n is 1 or 2;
- the pharmaceutically acceptable salts thereof;
- and, a diuretic and/or other antihypertensive compound selected from the group:
- hydrochlorothiazide, timolol, methyldopa, the pivaloyloxyethyl ester of methyldopa, indacronine and variable ratios of its enantiomers, (+)-4-{3-{[2-(1-hydroxycyclohexyl)-ethyl]-4-oxo-thiazolidinyl}propyl}-benz oic acid as well as combinations and mixtures thereof.
A method for treating hypertension which comprises administering to a patient in need of such treatment an antihypertensively effective amount of a compound having the formula:
- ##STR6## wherein:
- R.sub.1 is alkyl or substituted alkyl of C.sub.1 -C.sub.6 wherein the substituent is halo, amino, acylamino;
- aralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the aryl function is phenyl or naphthyl optionally substituted by halo or hydroxyl;
- or,
- heteroaralkyl wherein the alkyl is C.sub.1 -C.sub.4 optionally substituted by amino or acylamino and wherein the heteroaralkyl group can be indolyl or thienyl;
- R.sub.2 is H, lower alkyl of C.sub.1 -C.sub.4, aralkyl;
- R.sub.3 is lower alkyl of C.sub.1 -C.sub.6 optionally substituted by an amino group;
- R.sub.4 is H, lower alkyl of C.sub.1 -C.sub.6, aralkyl;
- X is (CH.sub.2).sub.n wherein n is 1 or 2;
- and,
- the pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.