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-[4-(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 compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.