Synthesis of the Optical Isomers of 4-[1-(4-tert-Butylphenyl)-2-oxo-pyrrolidine-4-yl]methyloxybenzoic Acid (S-2) and Their Biological Evaluation as Antilipidemic Agent
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概要
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The enantiomers of (±)-4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-yl]methyloxybenzoic acid (S-2), a new antilipidemic agent having dual action on the plasma triglyceride (TG) and cholesterol (Cho) lowering effects, were prepared via separation by Chiralcel OJ column chromatography of their methyl ester and also by the same method as the described racemate's synthesis from optically active 1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-carboxylic acid respectively. These optically active carboxylic acids were prepared by the resolution of diastereomeric N-[(S)-(-)-[4-methyl-(α-methyl)benzyl]]-1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-carboxyamide using silica gel column chromatography, followed by deamination with N_2O_4. The absolute configurations for the enantiomers of S-2 were indirectly determined using X-ray analysis of the 4-bromo-2-fluorobenzamide of the (+)-4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-yl]-methyloxybenzoic acid. S-2 and its enantiomers showed an essentially equipotent activity on the fatty acid- and sterol-biosynthesis inhibition in vitro. On the other hand, in the in vivo activity, (S)-(+)-4-[1-(4-tert-butylphenyl)-2-oxo-pyrrolidine-4-yl]methyloxybenzoic acid (S-2E) was superior in the lowering abilities of the plasma TG and phospholipid(PL) and was chosen as a candidate for a novel antilipidemic agent. The difference in the in vivo activity among S-2 and its enantiomers was explained from the pharmacokinetics after administration p.o.
- 1999-11-15
著者
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KOBAYASHI Kimiko
The Institute of Physical and Chemical Research
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Ohno T
Biomedical Research Laboratories
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Ohno T
Department Of Chemical Analysis Pharmaceutical Research Laboratories Dainippon Pharmaceutical Co. Lt
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大野 智子
Department Of Chemical Analysis Pharmaceutical Research Laboratories Dainippon Pharmaceutical Co. Lt
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Ohno T
Laboratory Of Medicinal Resources School Of Pharmacy Aichi Gakuin University
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Ohno Tomie
Health And Welfare Course Hokkaido University Of Education Asahikawa Campus
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Yamada Haruo
Hanno Research Center Taiho Pharmaceutical Co. Ltd.
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Ohno Tetsuji
Biomedical Research Laboratories
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OHNO Tomoyasu
Hanno Research Center, Taiho Pharmaceutical Co., Ltd.,
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YANO Shin-go
Hanno Research Center, Taiho Pharmaceutical Co., Ltd.,
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SHIRASAKA Tetsuhiko
Hanno Research Center, Taiho Pharmaceutical Co., Ltd.,
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YAMAMOTO Akira
Tokushima Research Center, Taiho Pharmaceutical Co., Ltd.,
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OGAWA Kazuo
Hanno Research Center, Taiho Pharmaceutical Co., Ltd.,
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Kobayashi Kimiko
The Institute Of Physical And Chemical Research (riken)
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Shirasaka T
Hanno Research Center Taiho Pharmaceutical Co. Ltd.
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Yano Shin-go
Hanno Research Center Taiho Pharmaceutical Co. Ltd.
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Ogawa Kazuo
Hanno Research Center Taiho Pharmaceutical Co. Ltd. :(present Address)technological R & D Laboratories Taiho Pharmaceutical Co. Ltd.
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Yamamoto Akira
Tokushima Research Center Taiho Pharmaceutical Co. Ltd.
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