Optically active antifungal azoles. XIII. Synthesis of stereoisomers and metabolites of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456)

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1- yl)propyl]-3-14-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R,2R)-1: TAK- 456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2R)-, (1S,2S)- and (1R,2S)-1] of this compoun d were prepared as authentic samples to determine the enantiomeric and dias tereomeric purity of TAK-456 as well as to compare their in vitro antifunga l activity. Pharmacokinetic studies of TAK-456 using rats identified the ex istence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydr oxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydro xylated compounds. 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metab olites by HPLC. In vitro antifungal activities of the three stereoisomers a nd the synthesized metabolites were considerably weaker than TAK-456.