- Heterocyclic lactam derivatives as dual angiotensin converting enzyme and neutral endopeptidase 24.11 inhibitors
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A series of 13- and 14-membered ring lactam derivatives 9a,b, 10, 11, and 12a-c was prepared from L-cysteine. Compounds 9a,b and 12a,b were tested in vitro for inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibit
- Stanton,Sperbeck,Trapani,Cote,Sakane,Berry,Ghai
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- CERTAIN MACROCYCLIC LACTAM DERIVATIVES
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The invention relates to macrocyclic lactam derivatives of formula I STR1 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 CH 2 ; R 1 is--COOH; or R 1 is STR2 in which R 2 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, R 3 is hydrogen or lower alkyl, and q is zero or an integer from 1 to 5 inclusive; or R 1 is STR3 in which R 4 is hydrogen, lower alkyl, lower alkoxy, hydroxy or acyloxy, and r is 1 or 2; or R 1 is STR4 in which s is 1 or 2; or R 1 is STR5 in which R 5 and R 6 independently represent hydrogen, lower alkyl, C 5-or C 6-cycloalkyl, (hydroxy-, acyloxy or lower alkoxy-) lower alkyl, carbocyclic or heterocyclic monocyclic aryl, or (hydroxy-, acyloxy-or alkoxy-) lower alkyloxy-lower alkyl; or R 5 and R 6 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 CH 2 group of (CH 2) m in formula I is replaced by O or S, and Y represents CH 2 ; 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.
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