Macrocyclic lactams as inhibitors of atrial natriuretic factors (ANF)-degrading neutral endopeptidase (NEP)
申请人:CIBA-GEIGY AG
公开号:EP0544620A1
公开(公告)日:1993-06-02
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; or
R₁ 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; or
R₁ is
in which R₄ is hydrogen, lower alkyl, lower alkoxy, hydroxy or acyloxy, and r is 1 or 2; or
R₁ is
in which s is 1 or 2; or
R₁ 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.
本发明涉及式 I 的大环内酰胺衍生物
其中 R 是氢或酰基;m 是 4 至 9(包括 9)的整数;n 是 1 或 2;p 是 0、1 或 2;X 是 -CONH- 或 -NHCO-;Y 是 S、O 或 CH₂;R₁ 是 -COOH;或
R₁ 是
其中 R₂ 是氢、低级烷基、芳基-低级烷基、氨基-低级烷基、羟基-低级烷基、酰氧基-低级烷基、低级烷氧基-低级烷基、巯基-低级烷基、低级烷基-(硫基、亚磺酰基或磺酰基)-低级烷基或羧基-低级烷基,R₃ 是氢或低级烷基,且 q 是零或 1 至 5(包括 5)的整数;或
R₁ 是
其中 R₄ 是氢、低级烷基、低级烷氧基、羟基或酰氧基,且 r 是 1 或 2;或
R₁ 是
其中 s 为 1 或 2;或
R₁ 是
其中R₅和R₆各自代表氢、低级烷基、C₅-或C₆-环烷基、(羟基-、酰氧基-或低级烷氧基-)低级烷基、碳环或杂环单环芳基或(羟基-、酰氧基-或烷氧基-)低级烷氧基-低级烷基;或 R₅ 和 R₆ 与它们所连接的氮一起代表吡咯烷基、哌啶基、吗啉基、哌嗪基或 N-烷基哌嗪基;以及大环硫氧内酰胺环异构体,其中式 I 中 (CH₂)m 的 CH₂ 基团被 O 或 S 取代,Y 代表 CH₂;以及上述任何化合物的药学上可接受的带有游离羧基的原药酯;以及任何上述化合物的药学上可接受的带有游离酸或碱性成盐基团的盐;包含上述化合物的药物组合物;制备上述化合物和制备中间体的方法;以及通过向需要治疗的哺乳动物施用上述化合物来治疗对中性内肽酶抑制有反应的哺乳动物疾病的方法。