Optically Active Antifungal Azoles. VII. Synthesis and Antifungal Activity of Stereoisomers of 2-[(1R, 2R)-2-(2, 4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1, 2, 4-triazol-1-yl)propyl]-4-[4-(2, 2, 3, 3-tetrafluoropropoxy)phenyl]-3(2H, 4H)-1, 2, 4-triazolone (TAK-187)

Abstract

2-[(1R, 2R)-2-(2, 4-Difluorophenyl)-2-hydroxy-1-lmethyl-3-(1H-1, 2, 4-triazol-1-yl)propyl]-4-[4-(2, 2, 3, 3-tetrafluoropropoxy)phenyl]-3(2H, 4H)-1, 2, 4-triazolone [(1R, 2R)-1 : TAK-187] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S, 2S)-, (1R, 2S)- and (1S, 2R)-1] of this compound were prepared to clarify the relationship between the stereochemistry and the biological activities. In vitro and in vivo assays of antifungal activity revealed that TAK-187 [(1R, 2R)-1] is the most potent among the four stereoisomers. Furthermore, TAK-187 was found to exert a strong and selective inhibitory effect on the sterol synthesis in Candida albicans as compared with that in rat liver.