Novel 5-Hydroxytryptamine (5-HT_3) Receptor Antagonists. IV. Synthesis and Pharmacological Evaluation of the Oxidation Products of (-)-(R)-5-[(1-Methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole Hydrochloride (YM060 : Ramosetron)
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概要
- 論文の詳細を見る
In physicochemical and pharmacokinetic evaluations of (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride 1 (YM060 : ramosetron), which is a highly potent 5-hydroxytryptamine (5-HT_3) receptor antagonist, 4-hydroxy-6-[(1-methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole 2 was identified as a degradation product and metabolite of 1. The (-)-(4R, 6S)-isomer 2 was synthesized from the diketone derivative 3,via the stereoselective reduction of 3 followed by the stereocontrolled epimerization of the (-)-(4S, 6S)-isomer 10,the epimer of 2. The stereochemistry of 2 and 10 was determined by NMR and HPLC studies. Compounds 2 and 10 were found to be potent 5-HT_3 receptor antagonists, like 1. Among the other oxidation products, the diketone derivatives 3 and 7 and the dihydroxylated derivative 4 retained antagonistic activity similar to that of ondansetron. This is of interest, because they do not possess the amine group which is known to be necessary for high affinity to the 5-HT_3 receptor.
- 公益社団法人日本薬学会の論文
- 1996-09-15
著者
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斎藤 徹
Faculty Of Pharmaceutical Sciences Kanazawa University
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Miyata K
Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn
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Miyata K
Yamanouchi Pharmaceutical Co. Ltd. Tsukuba City Jpn
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Miyata Keiji
Inflammation Research Pharmacology Laboratories Institute For Drug Discovery Research Yamanouchi Pha
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Miyata Keiji
Neuroscience/gastrointestinal Research Laboratories Institute For Drug Discovery Research Yamanouchi
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Suzuki T
Drug Discovery Research Laboratory Sanwa Kagaku Kenkyusho Co. Ltd.
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Suzuki T
Laboratory Of Biopharmaceutics Faculty Of Pharmaceutical Sciences Chiba University
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Ohta Masato
Pharmaceutical Research Center Meiji Seika Kaisha Ltd.
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Saito Takako
Research And Development Laboratories Maruho Co. Ltd.
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Miyata Keiji
Neuroscience And Gastrointestinal Research Laboratory Institute For Drug Discovery Research Yamanouc
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Suzuki Toshikazu
Discovery Research Laboratory Tanabe Seiyaku Co. Ltd.
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Tokunaga Tatsuhiro
Molecular Chemistry Resarch Laboratories Institute For Drug Discovery Research Yamanouchi Pharmaceut
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Ohta Miyako
Division Of Biological Chemistry And Biologicals National Institute Of Health Sciences
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Miyata K
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.
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Ohta Mitsuaki
Neuroscience/gastrointestinal Research Laboratories Institute For Drug Discovery Research Yamanouchi
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MASE Toshiyasu
Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceut
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Miyata K
Inflammation Research Pharmacology Laboratories Institute For Drug Discovery Research Yamanouchi Pha
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Suzuki T
Research Unit Of Pharmaceutics College Of Pharmacy Nihon University
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Tokunaga T
Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.
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Miyata K
Hitachi Research Laboratory Hitachi Ltd.
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SUZUKI Takeshi
Gastrointestinal Research Laboratories Institute for Drug Discovery Research, Yamanouchi Pharmaceuti
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NAGASHIMA Shinya
Neuroscience
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TOKUNAGA Tatsuhiro
Gastrointestinal Research Laboratories Institute for Drug Discovery Research, Yamanouchi Pharmaceuti
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Mase T
Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn
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Miyata Keiji
Neuroscience & Gastrointestinal Research Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.
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