公开(公告)号：EP1450794A1

公开(公告)日：2004-09-01

申请号：EP02801961.0

申请日：2002-10-23

申请人： Ferring B.V.

发明人： EVANS, David Michael ,  TARTAR, Andre

IPC分类号： A61K31/426 ,  C07D207/16 ,  C07D277/06 ,  C07D277/04 ,  C07D403/12 ,  C07D417/12 ,  C07D401/12 ,  C07D401/06 ,  A61K31/427 ,  A61K31/4025 ,  A61P3/10

CPC分类号： C07D213/82 ,  C07D277/04 ,  C07D401/06 ,  C07D401/12 ,  C07D403/12 ,  C07D417/12

摘要： 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 R1 is H or CN; R2 is selected from CH¿2R?5, CH2CH2R5 and C(R?3)(R4)-X2-(CH¿2)aR?5; R3 and R4¿ are each independently selected from H and Me; R5 is selected from CON(R?6)(R7), N(R8)C(=0)R9, N(R8)C(=S)R9, N(R8)SO¿2R1O and N(R?8)R1O; R6 and R7¿ are each independently R11(CH2)b or together they are -(CH2)2-Z-(CH2)2- or CH2-o- C6H4-Z-CH2-; R8 is H or Me; R9 is selected from R11(CH2)b, R11(CH2)bO and N(R?6)(R7); R10 is R11(CH¿2)b; R11 is selected from H, alkyl, optionally substituted aryl, optionally substituted aroyl, optionally substituted arylsulphonyl and optionally substituted heteroaryl; R12 is selected from H¿2?NCH(R?13¿)CO, H¿2?NCH(R?14¿)CONHCH(R15)CO, C(R?16)=C(R17)COR18 and R19OCO; R13, R14 and R15¿ are selected from the side chains of the proteinaceous amino acids; R16 is selected from H, lower alkyl (C¿1?-C6) and phenyl; R?17¿ is selected from H and lower alkyl (C¿1?-C6); R?18¿ is selected from H, lower alkyl (C¿1?-C6), OH, O-(lower alkyl (C1-C6)) and phenyl; R?19¿ is selected from lower alkyl (C¿1?-C6), optionally substituted phenyl and R?20¿C(=0)OC(R?21)(R22); R20, R21 and R22¿ are each independently selected from H and lower alkyl (C¿1?-C6); Z is selected from a covalent bond, -(CH2)c-, -O-, -SOd- and -N(R?1O)-; X1¿ is S or CH¿2; X?2 is O, S or CH¿2?; a is 1, 2 or 3; b is 0-3; c is 1 or 2; and d is 0, 1 or 2.