Dipeptidyl peptidase iv (dp-iv) inhibitors as anti-diabetic agents

Abstract

The present invention relates to a series of prodrugs of inhibitors of DP-IV with improved properties. The compounds can be used for the treatment of a number of human diseases, including impaired glucose tolerance and type II diabetes. The compounds of the invention are described by general formula (1); wherein Ris H or CN; Ris selected from CHR, CHCHRand C(R)(R)—X—(CH)R; Rand Rare each independently selected from H and Me; Ris selected from CON(R)(R), N(R)C(═O)R, N(R)C(═S)R, N(R)SORand N(R)R; Rand Rare each independently R(CH)or together they are —(CH)—Z—(CH)— or CH—o—CH—Z—CH—; Ris H or Me; Ris selected from R(CH), R(CH)O and N(R)(R); Ris R(CH); Ris selected from H, alkyl, optionally substituted aryl, optionally substituted aroyl, optionally substituted arylsulphonyl and optionally substituted heteroaryl; Ris selected from HNCH(R)CO, HNCH(R)CONHCH(R)CO, C(R)═C(R)CORand ROCO; R, Rand Rare selected from the side chains of the proteinaceous amino acids; Ris selected from H, lower alkyl (C–C) and phenyl; Ris selected from H and lower alkyl (C–C); Ris selected from H, lower alkyl (C–C), OH, O-(lower alkyl (C–C)) and phenyl; Ris selected from lower alkyl (C–C), optionally substituted phenyl and RC(═O)OC(R)(R); R, Rand Rare each independently selected from H and lower alkyl (C–C); Z is selected from a covalent bond, —(CH)—, —O—, —SO— and —N(R)—; Xis S or CH; Xis O, S or CH; a is 1, 2 or 3; b is 0–3; c is 1 or 2; and d is 0, 1 or 2.