Optically Active Antifungal Azoles. XIII.Synthesis of Stereoisomers and Metabolites of 1-[(lR, 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)
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概要
- 論文の詳細を見る
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.
- 公益社団法人日本薬学会の論文
- 2001-09-01
著者
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Yamada Makiko
San-ei Gen F.f.i. Inc.
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Itoh K
Medicinal Chemistiy Research Laboratories I Pharmaceutical Research Division Takeda Chemical Industr
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Itoh K
Pharmaceutical Research Laboratories Iii Pharmaceutical Research Division Takeda Chemical Industries
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Yamada M
Pharmaceutical Research Division Takeda Pharmaceutical Company Limited
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Yoshida M
Tohoku Univ. Sendai Jpn
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Ichikawa Takashi
Pharmaceutical Research Division Takeda Pharmaceutical Company Limited
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ICHIKAWA Takashi
Medicinal Chemistry Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Indus
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YAMADA Masami
Medicinal Chemistry Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Indu
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YAMAGUCHI Masashi
Drug Analysis & Pharmacokinetic Research Laboratories, Pharmaceutical Research Division, Takeda Chem
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KITAZAKI Tomoyuki
Medicinal Chemistry Research Laboratories II, Pharmaceutical Research Division, Takeda Chemical Indu
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MATSUSHITA Yoshihiro
Medicinal Chemistry Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Indus
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HIGASHIKAWA Keiko
Medicinal Chemistry Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Indus
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ITOH Katsumi
Medicinal Chemistry Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Indus
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Itoh Katsumi
Medicinal Chemistiy Research Laboratories I Pharmaceutical Research Division Takeda Chemical Industr
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Higashikawa Keiko
Medicinal Chemistry Research Laboratories I Pharmaceutical Research Division Takeda Chemical Industr
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Ichikawa T
Pharmaceutical Research Division Takeda Pharmaceutical Company Limited
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Itoh K
Graduate School Of Pharmaceutical Sciences Chiba University:nisshin Seifun Group Inc.
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Itoh Kinuyo
Department Of Materials Chemistry & Frontier Research Center Graduate School Of Engineering. Osa
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Itoh Kunihiko
Dept. Pharmaceutical Sciences Akita University
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Kitazaki T
Pharmaceutical Research Division Takeda Pharmaceutical Company Limited
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