Amidino dervatives useful as nitric oxide synthase inhibitors

A method of inhibiting nitric oxide synthesis in a subject in need of such inhibition by administering a therapeutically effective amount of a compound having the formula:

• ##STR338## and salts or pharmaceutically acceptable esters thereof, wherein:
• X is selected from the group consisting of methylene, nitrogen, oxygen, S, SO, and SO.sub.2 wherein nitrogen and lower alkyl radicals may optionally be substituted with hydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups;
• n is 3;
• R.sup.1 and R.sup.2, are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, haloalkyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, alicyclic hydrocarbon, heterocycly, aromatic hydrocarbon, --CONR.sup.5 R.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --COR.sup.5, --SO.sub.2 R.sup.5, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, and sulfonamide, wherein all said radicals can be optionally substituted with one or more of the following:
• hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy,lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy, haloalkyl, --SO.sub.2 NR.sup.5 R.sup.6 and --SO.sub.2 R.sup.5 wherein all said substitutions may be optionally substituted with one or more of the following:
• amino, carboxyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy;
• R.sup.3, R.sup.4 are independently selected from the group consisting of hydrogen, hydroxy, and alkyloxy;
• R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, lower alkyl, and aryl.

A method of selectively inhibiting nitric oxide synthesis produced by inducible NO synthase over NO produced by the constitutive forms of NO synthase in a subject in need of such inhibition by administering a therapeutically effective amount of a compound having the formula:

• ##STR339## and salts and pharmaceutically acceptable esters thereof, wherein:
• X is selected from the group consisting of methylene, nitrogen, oxygen, S, SO, and SO.sub.2 wherein nitrogen and lower alkyl radicals may optionally be substituted with hydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups;
• n is 3;
• R.sup.1 and R.sup.2, are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, haloalkyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, alicyclic hydrocarbon, heterocycly, aromatic hydrocarbon, --CONR.sup.5 R.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --COR.sup.5, --SO.sub.2 R.sup.5, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, and sulfonamide, wherein all said radicals can be optionally substituted with one or more of the following:
• hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy, haloalkyl, --SO.sub.2 NR.sup.5 R.sup.6 and --SO.sub.2 R.sup.5 wherein all said substitutions may be optionally substituted with one or more of the following:
• amino, carboxyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy;
• R.sup.3, R.sup.4 are independently selected from the group consisting of hydrogen, hydroxy, and alkyloxy;
• R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, lower alkyl, and aryl.

A method of lowering nitric oxide levels in a subject in need of such by administering a therapeutically effective amount of a compound having the formula:

• ##STR340## and salts and pharmaceutically acceptable esters thereof, wherein:
• X is selected from the group consisting of methylene, nitrogen, oxygen, S, SO, and SO.sub.2 wherein nitrogen and lower alkyl radicals may optionally be substituted with hydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups;
• n is 3;
• R.sup.1 and R.sup.2, are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, haloalkyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, alicyclic hydrocarbon, heterocycly, aromatic hydrocarbon, --CONR.sup.5 R.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --COR.sup.5, --SO.sub.2 R.sup.5, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, and sulfonamide, wherein all said radicals can be optionally substituted with one or more of the following:
• hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy, haloalkyl, --SO.sub.2 NR.sup.5 R.sup.6 and --SO.sub.2 R.sup.5 wherein all said substitutions may be optionally substituted with one or more of the following:
• amino, carboxyl, carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy;
• R.sup.3, R.sup.4 are independently selected from the group consisting of hydrogen, hydroxy, and alkyloxy;
• R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, lower alkyl, and aryl.

A compound having the formula:

• ##STR341## and salts and pharmaceutically acceptable esters thereof, wherein:
• X is selected from the group consisting of methylene, nitrogen, oxygen, sulfur, SO, or SO.sub.2 ;
• n is 3;
• R.sup.1 and R.sup.2, are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower thioalkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, haloalkyl, carboalkoxy, carboaryloxy, carboalkylaryloxy, alicyclic hydrocarbon, heterocycly, aromatic hydrocarbon, --CONR.sup.5 R.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --COR.sup.5, --SO.sub.2 R.sup.5, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, alkyl sulfate, aryl sulfate, and sulfonamide, wherein all said radicals are optionally substituted with one or more of the following:
• hydroxy, alkyl, lower alkenyl, lower alkynyl, lower alkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, carboalkoxy, carboaryloxy, carboxy alkylaryloxy, haloalkyl, --SO.sub.2 NR.sup.5 R.sup.6 and --SO.sub.2 R.sup.5 wherein all said substitutions may be optionally substituted with one or more of the following:
• amino, carboxyl,carboalkoxy, carboaryloxy, carboxyalkylaryloxy and lower alkoxy;
• R.sup.3, R.sup.4 are hydrogen,hydroxy, and alkyloxy;
• R.sup.5 and R.sup.6 are independently selected from the group consisting of hydrogen, lower alkyl, and aryl
• with the proviso that the compound is not hexahydro-7-imino-1H-azepine-2-carboxylic acid.

A pharmaceutical composition comprising a compound having the formula:

• ##STR342## and salts and pharmaceutically acceptable esters thereof, wherein:
• X is methylene, nitrogen, oxygen, or sulfur wherein nitrogen and lower alkyl radicals may optionally be substituted with hydroxy, lower alkyl, lower alkoxy, amino, and haloalkyl groups;
• n is 3;
• R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, and haloalkyl wherein all said radicals may optionally be substituted with hydroxy, lower alkyl, lower alkoxy, halogen, nitro, amino, carboxyl, cyano, sulfonyl, and haloalkyl groups.