pyrrolidine and thiazolidin derivatives, their presentation and application for the treatment of hyperglycaemia and type ii diabetes

摘要

Spiro-cycloalkyl N-acyl pyrrolidine or thiazolidine derivatives (I), their optical isomers and acid addition salts are new. Spiro-cycloalkyl N-acyl pyrrolidine or thiazolidine derivatives of formula (I), and their optical isomers and acid addition salts, are new. X 1CR 4aR 4b, O, S(O) q1 or NR 5; R 4a and R 4bhydrogen or 1-6 C linear or branched alkyl or together complete a 3-7C cycloalkyl; q1 : 0-2; R 5hydrogen or 1-6C linear or branched alkyl, optionally substituted by hydroxy; m1 : 0-4; m2 : 1-4; n1 and n2 : 1-3; R 1hydrogen, carboxy, 1-6C linear or branched alkoxycarbonyl, carbamoyl (optionally substituted by 1 or 2 1-6C linear or branched alkyl), or 1-6C linear or branched alkyl (optionally substituted by hydroxy) or amino (optionally substituted by 1 or 2 1-6C linear or branched alkyl); R 2hydrogen or 1-6C linear or branched alkyl; Ak : 1-4C linear or branched alkylene, optionally substituted by one or more halo, particularly fluoro; p : 0-2; R 3hydrogen or cyano; X 2 and X 3S(O) q2 or CR 6aR 6b; R 6a and R 6bhydrogen or halo, preferably fluoro, or R 6a = hydrogen and R 6b = hydroxy; and q2 : 0-2. An independent claim is also included for the preparation of (I). [Image] ACTIVITY : Antidiabetic; Anorectic. MECHANISM OF ACTION : Inhibition of dipeptidyl-peptidase IV (DPPIV). The compound (2S)-1-({[9-(hydroxymethyl)-3-oxaspiro[5,5]undec-9-yl]amino}acetyl)-2-pyrrolidinecarbonitrile had IC 50 76.1 nM against porcine renal DPPIV, in an assay based on cleavage of Gly-Pro-p-nitroanilide.