BIOMAT Database Logo BIOMAT Database Logo

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). 2001

T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan. Ichikawa_Takashi@takeda.co.jp

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.

UI MeSH Term Description Entries
D007093 Imidazoles Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D009682 Magnetic Resonance Spectroscopy Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING). In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D002851 Chromatography, High Pressure Liquid Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed. Chromatography, High Performance Liquid,Chromatography, High Speed Liquid,Chromatography, Liquid, High Pressure,HPLC,High Performance Liquid Chromatography,High-Performance Liquid Chromatography,UPLC,Ultra Performance Liquid Chromatography,Chromatography, High-Performance Liquid,High-Performance Liquid Chromatographies,Liquid Chromatography, High-Performance
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000935 Antifungal Agents Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues. Anti-Fungal Agents,Antifungal Agent,Fungicides, Therapeutic,Antibiotics, Antifungal,Therapeutic Fungicides,Agent, Antifungal,Anti Fungal Agents,Antifungal Antibiotics
D001711 Biotransformation The chemical alteration of an exogenous substance by or in a biological system. The alteration may inactivate the compound or it may result in the production of an active metabolite of an inactive parent compound. The alterations may be divided into METABOLIC DETOXICATION, PHASE I and METABOLIC DETOXICATION, PHASE II.
D013058 Mass Spectrometry An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers. Mass Spectroscopy,Spectrometry, Mass,Spectroscopy, Mass,Spectrum Analysis, Mass,Analysis, Mass Spectrum,Mass Spectrum Analysis,Analyses, Mass Spectrum,Mass Spectrum Analyses,Spectrum Analyses, Mass
D013237 Stereoisomerism The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed) Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer

Related Publications

T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
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-triazo lone (TAK-187).
February 1997, Chemical & pharmaceutical bulletin,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Optically active antifungal azoles. IX. An alternative synthetic route for 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 and its analogs.
March 1999, Chemical & pharmaceutical bulletin,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]- 3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones.
March 1999, Chemical & pharmaceutical bulletin,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Optically active antifungal azoles. VI. Synthesis and antifungal activity of N-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazo l-1- yl)propyl]-N'-(4-substituted phenyl)-3(2H,4H)-1,2,4-triazolones and 5(1H,4H)-tetrazolones.
February 1996, Chemical & pharmaceutical bulletin,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-b utanol and its stereoisomers.
June 1993, Chemical & pharmaceutical bulletin,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Optically active antifungal azoles. II. Synthesis and antifungal activity of polysulfide derivatives of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H- 1,2,4-triazol-1-yl)-2-butanol.
June 1993, Chemical & pharmaceutical bulletin,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Design, synthesis and antifungal evaluation of 1-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-1H-1,2,4-triazol-5(4H)-one.
July 2011, European journal of medicinal chemistry,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Optically active antifungal azoles. V. Synthesis and antifungal activity of stereoisomers of 3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2- butanols.
March 1995, Chemical & pharmaceutical bulletin,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Optically active antifungal azoles. IV. Synthesis and antifungal activity of (2R,3R)-3-azolyl-2-(substituted phenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanols.
March 1995, Chemical & pharmaceutical bulletin,
T Ichikawa, and M Yamada, and M Yamaguchi, and T Kitazaki, and Y Matsushita, and K Higashikawa, and K Itoh
Optically active antifungal azoles. III. Synthesis and antifungal activity of sulfide and sulfonamide derivatives of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-b utanol.
January 1994, Chemical & pharmaceutical bulletin,
Copied contents to your clipboard!