Renin-inhibiting amino acid derivatives

A pharmaceutical composition comprising an amount effective to inhibit renin of a compound of formula I or a pharmaceutically acceptable salt thereof:

• ##STR11## wherein:
• A is a radical of the formula II:
• ##STR12## in which R.sup.4 is a radical of the formula IV:
• R.sup.7 --S(O).sub.t -- (IV)
• wherein
• R.sup.7 is (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or substituted by one or more functional groups selected from the group consisting of oxo, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy and phenyloxy;
• (C.sub.1 -C.sub.6)-alkanoyloxy;
• halogen;
• hydroxysulfonyloxy;
• carboxyl;
• (C.sub.1 -C.sub.4)-alkoxycarbonyl;
• carbamoyl, mono-(C.sub.1 -C.sub.4)-alkylcarbamoyl or di-(C.sub.1 -C.sub.4)-alkyl-carbamoyl;
• cyano;
• amino;
• mono-(C.sub.1 -C.sub.4)-alkylamino or di-(C.sub.1 -C.sub.4)-alkylamino;
• acylamino or substituted amino in which the amino group is part of a pyridyl group;
• (C.sub.2 -C.sub.8)-alkenyl which is unsubstituted or substituted by one or more functional groups selected from the group consisting of oxo, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy and phenyloxy or (C.sub.2 -C.sub.8)-alkynyl which is optionally substituted by one or more functional groups selected from the group consisting of oxo, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy and phenyloxy;
• hydroxyl;
• (C.sub.1 -C.sub.6)-alkoxy;
• (C.sub.3 -C.sub.8)-cycloalkyl;
• (C.sub.5 -C.sub.10)-bicycloalkyl;
• (C.sub.8 -C.sub.10)-tricycloalkyl;
• (C.sub.3 -C.sub.8)-cycloalkyl-(C.sub.1 -C.sub.10)-alkyl;
• (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryloxy or (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.10)-alkyl, which are optionally substituted in the aryl moiety by one or two identical or different radicals selected from the group consisting of F, Cl, Br, hydroxyl, (C.sub.1 -C.sub.7)-alkoxy, (C.sub.1 -C.sub.7)-alkyl, (C.sub.1 -C.sub.7 )-alkoxycarbonyl, amino and trifluoromethyl;
• pyridyl;
• or amino, mono-(C.sub.1 -C.sub.4)-alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino, acylamino or substituted amino in which the amino is part of a pyridyl group;
• and
• t is 2;
• R.sup.5 is phenyl;
• 2-, 3- or 4-pyridyl;
• or 1- or 2-naphthyl;
• each of which is optionally substituted by a radical selected from the group consisting of hydroxyl, (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, Cl, F, Br, nitro, amino, acetamino, and trifluoromethyl or by a methylenedioxy radical;
• m is 1;
• n is 0 or 1;
• p is 0, 1 or 2;
• B is a radical, which is linked N-terminal to A and C-terminal ##STR13## of an amino acid selected from the group consisting of phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, .beta.-2-thienylalanine, .beta.-3-thienylalanine, .beta.-2-furylalanine, .beta.-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O-tertbultyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, .beta.-2-benzo[b]thienylalanine, .beta.-3-benzo[b]thienylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA, O-dimethyl-DOPA, 2-amino-4-(2-thienyl)butyric acid, benzodioxol-5-ylalanine, N-methyl-histidine, 2-amino-4-(3-thienyl)butyric acid, 3-(2-thienyl)serine, (Z)-dehydrophenylalanine, (E)-dehydrophenylalanine, 1,3-dioxolan-2-ylalanine, N-pyrrolylalanine, and 1-, 3- or 4-pyrazolylalanine;
• R.sup.1 is hydrogen, (C.sub.1 -C.sub.10)-alkyl, (C.sub.4 -C.sub.7)-cycloalkyl, (C.sub.4 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl or 1,3-dithiolan-2-yl-(C.sub.1 -C.sub.4)-alkyl;
• R.sup.2 is hydrogen;
• R.sup.3 is a radical of the formula III:
• --(CH.sub.2).sub.q --(CH.sub.2).sub.s --R.sup.6 (III)
• in which
• R.sup.6 is pyridyl;
• and
• q and s is each, independently of one another, 0, 1 or 2;
• and
• R.sup.9 is hydrogen.

A method of inhibiting renin comprising administering to a patient an amount effective to inhibit renin of a compound of formula I or a pharmaceutically acceptable salt thereof:

• ##STR14## wherein:
• A is a radical of the formula II:
• ##STR15## in which R.sup.4 is a radical of the formula IV:
• R.sup.7 --S(O).sub.t -- (IV)
• wherein
• R.sup.7 is (C.sub.1 -C.sub.10)-alkyl which is unsubstituted or substituted by one or more functional groups selected from the group consisting of oxo, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy and phenyloxy;
• (C.sub.1 -C.sub.6)-alkanoyloxy;
• halogen;
• hydroxysulfonyloxy;
• carboxyl;
• (C.sub.1 -C.sub.4)-alkoxycarbonyl;
• carbamoyl, mono-(C.sub.1 -C.sub.4)-alkylcarbamoyl or di-(C.sub.1 -C.sub.4)-alkyl-carbamoyl;
• cyano;
• amino;
• mono-(C.sub.1 -C.sub.4)-alkylamino or di-(C.sub.1 -C.sub.4)-alkylamino;
• acylamino or substituted amino in which the amino group is part of a pyridyl group;
• (C.sub.2 -C.sub.8)-alkenyl which is unsubstituted or substituted by one or more functional groups selected from the group consisting of oxo, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy and phenyloxy or (C.sub.2 -C.sub.8)-alkynyl which is optionally substituted by one or more functional groups selected from the group consisting of oxo, hydroxyl, (C.sub.1 -C.sub.6)-alkoxy and phenyloxy;
• hydroxyl;
• (C.sub.1 -C.sub.6)-alkoxy;
• (C.sub.3 -C.sub.8)-cycloalkyl;
• (C.sub.5 -C.sub.10)-bicycloalkyl;
• (C.sub.8 -C.sub.10)-tricycloalkyl;
• (C.sub.3 -C.sub.8)-cycloalkyl-(C.sub.1 -C.sub.10)-alkyl;
• (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryloxy or (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.10)-alkyl, which are optionally substituted in the aryl moiety by one or two identical or different radicals selected from the group consisting of F, Cl, Br, hydroxyl, (C.sub.1 -C.sub.7)-alkoxy, (C.sub.1 -C.sub.7)-alkyl, (C.sub.1 -C.sub.7)-alkoxycarbonyl, amino and trifluoromethyl;
• pyridyl;
• or amino, mono-(C.sub.1 -C.sub.4)-alkylamino, di-(C.sub.1 -C.sub.4)-alkylamino, acylamino or substituted amino in which the amino is part of a pyridyl group;
• and
• t is 2;
• R.sup.5 is phenyl;
• 2-, 3- or 4-pyridyl;
• or 1-or 2-naphthyl;
• each of which is optionally substituted by a radical selected from the group consisting of hydroxyl, (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxy, Cl, F, Br, nitro, amino, acetamino, and trifluoromethyl or by a methylenedioxy radical;
• m is 1;
• n is 0 or 1;
• p is 0, 1 or 2;
• B is a radical, which is linked N-terminal to A and C-terminal ##STR16## of an amino acid selected from the group consisting of phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, .beta.-2-thienylalanine, .beta.-3-thienylalanine, .beta.-2-furylalanine, .beta.-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methylhistidine, O-methyltyrosine, O-benzyltyrosine, O-tertbutyltyrosine, phenylglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, .beta.-2-benzo[b]thienylalanine, .beta.-3-benzo[b]thienylalanine, 2-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, norleucine, cysteine, S-methylcysteine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA, O-dimethyl-DOPA, 2-amino-4-(2-thienyl)butyric acid, benzodioxol-5-ylalanine, N-methyl-histidine, 2-amino-4-(3-thienyl)butyric acid, 3-(2-thienyl)serine, (Z)-dehydrophenylalanine, (E)-dehydrophenylalanine, 1,3-dioxolan-2-ylalanine, N-pyrrolylalanine, and 1-, 3- or 4-pyrazolylalanine;
• R.sup.1 is hydrogen, (C.sub.1 -C.sub.10)-alkyl, (C.sub.4 -C.sub.7)-cycloalkyl, (C.sub.4 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.4)-alkyl, (C.sub.6 -C.sub.14)-aryl, (C.sub.6 -C.sub.14)-aryl-(C.sub.1 -C.sub.4)-alkyl or 1,3-dithiolar-2-yl-(C.sub.1 -C.sub.4)-alkyl;
• R.sup.2 is hydrogen;
• R.sup.3 is a radical of the formula III:
• --(CH.sub.2).sub.q --(CH.sub.2).sub.s --R.sup.6 (III)
• in which
• R.sup.6 is pyridyl;
• and
• q and s is each, independently of one another, 0, 1 or 2;
• and
• R.sup.9 is hydrogen.