Substituted enantholactam derivatives as antihypertensives

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.

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.

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.

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.