Aza analogues of thalidomide: Synthesis and evaluation as inhibitors of tumor necrosis factor-alpha production in vitro

A synthetic entry to derivatives of the new classes of 5-phthalimidouracils and 5-phthalimidobarbituric acids is reported. These 5-phthalimidopyrimidi nes as well as phthalimido-2.4-difluorobenzenes were designed as analogues of thalidomide. a we ii known inhibitor of TNF-alpha production. A prelimin ary in vitro investigation of the compounds as inhibitors of, the TNF-alpha production was performed. Among the compounds of the present series, 5-eth yl-1-phenyl-5-(tetrafluorophthalimido)barbituric acid and 2-(2.4-difluoroph enyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione were proved to be pote nt inhibitors. Both compounds showed inhibitory activity in the lower micro molar range on the LPS-induced TNF-alpha production in human monocytes. (C) 2001 Elsevier Science Ltd. All rights reserved.