Macrocyclic lactams as inhibitors of atrial natriuretic factors (ANF)-degrading neutral endopeptidase (NEP)

摘要

The invention relates to macrocyclic lactam derivatives of formula I wherein R is hydrogen or acyl; m is an integer from 4 to 9 inclusive; n is 1 or 2; p is zero, 1 or 2; X is -CONH- or -NHCO-; Y is S, O or CH₂; R₁ is -COOH; orR₁ is in which R₂ is hydrogen, lower alkyl, aryl-lower alkyl, amino-lower alkyl, hydroxy-lower alkyl, acyloxy-lower alkyl, lower alkoxy-lower alkyl, mercapto-lower alkyl, lower alkyl-(thio, sulfinyl or sulfonyl)-lower alkyl, or carboxy-lower alkyl, R₃ is hydrogen or lower alkyl, and q is zero or an integer from 1 to 5 inclusive; orR₁ is in which R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy or acyloxy, and r is 1 or 2; orR₁ is in which s is 1 or 2; orR₁ is in which R₅ and R₆ independently represent hydrogen, lower alkyl, C₅- or C₆-cycloalkyl, (hydroxy-, acyloxy or lower alkoxy-) lower alkyl, carbocyclic or heterocyclic monocyclic aryl, or (hydroxy-, acyloxy- or alkoxy-) lower alkyloxy-lower alkyl; or R₅ and R₆ together with the nitrogen to which they are attached represent pyrrolidino, piperidino, morpholino, piperazino or N-alkylpiperazino; and macrocyclic sulfur and oxygen containing lactam ring isomers in which a CH₂ group of (CH₂)_m in formula I is replaced by O or S, and Y represents CH₂; and pharmaceutically acceptable prodrug esters of any above said compound with a free carboxyl group; and pharmaceutically acceptable salts of any said compounds with a free acid or basic salt forming group; pharmaceutical compositions comprising said compounds; methods for the preparation of said compounds and for the preparation of intermediates; and methods of treating disorders in mammals which are responsive to the inhibition of neutral endopeptidases by administration of said compounds to mammals in need of such treatment.