URACIL DERIVATIVES AS ENZYME INHIBITORS

摘要

Novel uracil derivatives of formula (I) and esters and prodrugs thereof wherein R1 is H, C¿1-8? straight or branched-chain alkyl, C2-6 alkenyl, or (C1-3 alkyl-C3-6 cycloalkyl-C1-3 alkyl) optionally substituted by 1 or 2 substituents selected from -OR?8 or -NR8R9¿ (wherein R?8 and R9¿ are the same or different and are selected from H, C¿1-6? straight or branched-chain alkyl, and aralkyl); or a -CH2ZR?10¿, -ZCH¿2R?10, or CH¿2?ZR?10aZR10¿ group (wherein R10a is selected from C¿1-6? straight or branched-chain alkylene and R?10¿ is selected from C¿1-6? straight or branched chain alkyl) each of R?10a and R10¿ being optionally substituted by 1 or 2 substituents independently selected from -OR8 and -NR8R9 (wherein R?8 and R9¿ are as defined above) and Z is selected from O, S, -CH¿2?O-, or -CH2S-); R?2¿ is selected from O or S; R3 is selected from O, S, -SO, -SO¿2, -NR?8, C=O, or -C¿1-6? straight or branched-chain alkyl; R?4¿ is selected from H, C¿1-4? straight or branched-chain alkyl, halogen, -OR?11¿ (wherein R11 is C¿1-4? straight or branched-chain alkyl optionally substituted by halogen, aryl, C3-6 cycloalkyl, (C1-3 alkyl-C3-6 cycloalkyl), C2-6alkenyl or C2-6alkynyl), methylenedioxy, -CX3 (wherein X is halogen), NO2, or CN; R?5¿ is selected from H, halogen or -OR11; R6 is selected from H, or Y-Ar-R7(m) (wherein Y is selected from O, S, -SO, -SO2, -NR8, C=O, or -C¿1-6? straight or branched-chain alkyl, Ar is phenyl or naphthyl, m is 1-3 and R?7¿ is selected from R8, -CO2R?8, -COR8, -CONR8R9, R8aOR8¿ (wherein R8a is selected from C¿1-6? straight or branched-chain alkyl, and aralkyl), -CN, -CX3 (wherein X is halogen), -OR?8, OCX¿3 (wherein X is halogen), -SR8, -SO2R?8, -OR8a¿O- (when m=1), -NO¿2?, -NR?8R9¿, -NHCOR8, -NHSO¿2R?8, fluoro, chloro, bromo, or iodo, or a combination thereof); provided that when R1 is H, CH¿2?OCH2CH2OH or CH2OCH(CH2OH)2, R?2¿ is O, R3 is -CH¿2? then R?4, R5 and R6¿ are other than -OCH¿3?, -OCH2CH3, -OCH2Ph, or -O-iso-propyl, pharmaceutical compositions containing them, their uses in medicine and the preparation of such compounds are disclosed.