Bradykin B1receptor antagonists

A compound of formula

• 359
• wherein:
• (a) all of X, Y and Z are CH;
• or (b) one of X, Y and Z is N and the rest of X, Y and Z are CH;
• or (c) two of X, Y and Z are N and the other of X, Y and Z is CH;
• or (d) all of X, Y and Z are N;
• A is A1 or A2;
• A1 is R4R5N—C(O)—
• 360
• A2 is chosen from R7C(O)NH—, R7S(O)2NH—, R4NH—, and R4O—;
• Q is chosen from aryl, —CH2R13, —CH═N—OCH3 and
• 361
• heteroaryl other than 1-imidazolyl and 1-triazolyl;
• W is chosen from H, Cl, F, R8, C1-C4-alkylaryl, —OR8, —SR8, —NR9R10 and —NHC(O)R11, with the proviso that when two of X, Y and Z are N and Q is imidazolyl, W may not be H, Cl, F or R8;
• R1 is chosen from alkyl, cycloalkyl, alkenyl, C1-C3-alkylcycloalkyl, heterocyclyl, C1-C3-alkylheterocyclyl, aryl, C1-C3-alkylaryl, heteroaryl, C1-C3-alkylheteroaryl, (C1-C3-alkyloxy)alkyl, (C1-C3-alkyloxy)cycloalkyl, (C1-C3-alkylthio)alkyl, (C1-C3-alkylthio)cycloalkyl and (C1-C3-alkylsulfonyl)alkyl;
• R2 is H or C1-C3-alkyl, or R1 and R2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR12;
• R3 is H or C1-C6-alkyl, or, when n is zero, R2 and R3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;
• R4 is chosen from H, aryl, heteroaryl, C1-C4-alkyl substituted with from one to three aryl or heteroaryl residues,
• 362
• and J2 are independently chosen from H, F, Cl, CN, NO2 and CH3, and G is chosen from —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2—, —CH2O—, —CH2CH2O—, —OCH2CH2—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH2—, —CH2N(lower alkyl)-, —S—, —SO—, —SO2—, —CH2S—, —SCH2—, —CH2SO—, —SOCH2—, —CH2SO2—, and —SO2CH2—;
• R5 is H or C1-C3-alkyl, with the proviso that both R3 and R5 cannot be alkyl;
• R6 is aryl;
• R7 is aryl or C1-C3-alkylaryl;
• R8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C1-C4-alkylaryl, C1-C4-alkylheterocyclyl and C1-C4-alkylheteroaryl;
• R9 is chosen from H, alkyl, alkenyl, substituted alkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl, C1-C4-alkylcycloalkyl, (C1-C4alkoxy)alkyl, (C1-C4-alkoxycarbonyl)alkyl, (C1-C4-alkylthio)alkyl, heterocyclyl, C1-C4-alkylheterocyclyl, C1-C4-alkylaryl, and C1-C4-alkylheteroaryl;
• R10 is H or C1-C3-alkyl, or
• R9 and R10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO2 or NR12, said ring optionally substituted with —OH, —CN, —COOH or —COOCH3;
• R11 is aryl;
• R12 is chosen from H, C1-C3-alkyl, alkoxycarbonyl, methoxyacetyl and aryl;
• R13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;
• m is zero or one;
• and
• n is zero or one, with the proviso that when A is A2, m and n cannot both be zero.

A method of treating a condition resulting from inappropriate bradykinin receptor activity comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I

• 378
• wherein:
• (a) all of X, Y and Z are CH;
• or (b) one of X, Y and Z is N and the rest of X, Y and Z are CH;
• or (c) two of X, Y and Z are N and the other of X, Y and Z is CH;
• or (d) all of X, Y and Z are N;
• A is A1 or A2;
• A1 is R4R5N—C(O)—
• 379
• A2 is chosen from R7C(O)NH—, R7S(O)2NH—, R4NH—, and R4O—;
• Q is chosen from heteroaryl, aryl, —CH2R13, —CH═N—OCH3 and
• 380
• W is chosen from H, Cl, F, R8, C1-C4-alkylaryl, —OR8, —SR8, —NR9R10 and —NHC(O)R11, with the proviso that when two of X, Y and Z are N and Q is imidazolyl, W may not be H, Cl, F or R8;
• R1 is chosen from alkyl, cycloalkyl, alkenyl, C1-C3-alkylcycloalkyl, heterocyclyl, C1-C3-alkylheterocyclyl, aryl, C1-C3-alkylaryl, heteroaryl, C1-C3-alkylheteroaryl, (C1-C3-alkyloxy)alkyl, (C1-C3-alkyloxy)cycloalkyl, (C1-C3-alkylthio)alkyl, (C1-C3-alkylthio)cycloalkyl and (C1-C3-alkylsulfonyl)alkyl;
• R2 is H or C1-C3-alkyl, or R1 and R2 taken together form a 5- to 7-membered ring structure optionally containing O, S or NR12;
• R3 is H or C1-C6-alkyl, or, when n is zero, R2 and R3 taken together may form a 6-membered ring, which may be fused to a six-membered saturated or aromatic carbocycle;
• R4 is chosen from H, aryl, heteroaryl, C1-C4-alkyl substituted with from one to three aryl or heteroaryl residues,
• 381
• wherein J1 and J2 are independently chosen from H, F, Cl, CN, NO2 and CH3, and G is chosen from —CH2—, —CH2CH2—, —CH2CH2CH2—, —OCH2—, —CH2O—, —CH2CH2—, —OCH2CH2—, —O—, —N(lower alkyl)-, —N(lower alkyl)CH2—, —CH2N(lower alkyl)-, —S—, —SO—, —SO2—, —CH2S—, —SCH2—, —CH2SO—, —SOCH2—, —CH2SO2—, and —SO2CH2—;
• R5 is H or C1-C3-alkyl, with the proviso that both R3 and R5 cannot be alkyl;
• R6 is aryl;
• R7 is aryl or C1-C3-alkylaryl;
• R8 is chosen from alkyl, aryl, heteroaryl, substituted alkyl, C1-C4-alkylaryl, C1-C4-alkylheterocyclyl and C1-C4-alkylheteroaryl;
• R9 is chosen from H, alkyl, alkenyl, substituted alkyl, cycloalkyl, aryl, alkoxy, heteroaryl, fluoroalkyl, C1-C4-alkylcycloalkyl, (C1-C4-alkoxy)alkyl, (C1-C4-alkoxycarbonyl)alkyl, (C1-C4-alkylthio)alkyl, heterocyclyl, C1-C4-alkylheterocyclyl, C1-C4-alkylaryl, and C1-C4-alkylheteroaryl;
• R10 is H or C1-C3-alkyl, or
• R9 and R10 taken together may form a 5- to 7-membered ring structure optionally containing O, S, SO, SO2 or NR12, said ring optionally substituted with —OH, —CN, —COOH or —COOCH3;
• R11 is aryl;
• R12 is chosen from H, C1-C3-alkyl, alkoxycarbonyl, methoxyacetyl and aryl;
• R13 is chosen from —OH, —OTHP, 1-imidazolyl, and 1-pyrrolyl;
• m is zero or one;
• and
• n is zero or one, with the proviso that when A is A2, m and n cannot both be zero.