Amphoteric Drugs. I. Synthesis and Antiallergic Activity of [4-(Diphenylmethoxy)piperidino]-, [4-(Diphenylmethyl)piperazinyl]-and [4-(Diphenylmethylene)piperidino]alkanoic Acid Derivatives
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概要
- 論文の詳細を見る
A simple method of transforming classical antihistaminics into nonsedative antiallergic agents with strong effects in rat models is described. Various [4-(diphenylmethoxy)piperidino]- (series A), [4-(diphenylmethyl)piperazinyl]- (series B) and [4-(diphenylmethylene)piperidino]alkanoic acid derivatives (series C) were synthesized and examined for antiallergic activities and effects on the central nervous system (CNS), in comparison with the corresponding N-methyl derivatives (1a-c). N-Alkylcarboxylic acids (5a-c) showed stronger ingibitory effects on compound 48/80-induced lethality in rats than the corresponding N-methyl derivatives (1a-c). In particular, N-alkylcarboxylic acids (5a) in series A exhibited approximately 100-fold stronger inhibitory effects than 1a, and were the least effective in prolonging the sleeping time on hexobarbital-induced anesthesia in mice in all series. As a result of chemical modification in series A, it was found that introduction of a methyl group at the para-position on one benzene ring in the (diphenylmethoxy)piperidine system effectively reduced CNS side-effects without reducing antiallergic activityl. (+)-3-[4-[(4-Methylphenyl)phenylmethoxy]piperidino]propionic acid ((+)-5l), an optically active isomer of 5l, exhibited a stronger antiallergic effect (ED_<50>=0.17mg/kg, p.o.) than ketotifen and terfenadine in the 48h homologous passive cutaneous anaphylaxis (PCA) test, and moreover exhibited no CNS side-effects, such as prolongation of the sleeping time on hexobarbital-induced anesthesia, at an oral dose of 30mg/kg. Compound (+)-5l was thus proved to be a promising candidate as a nonsedative antiallergic agent.
- 社団法人日本薬学会の論文
- 1994-11-15
著者
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加藤 日出男
北陸製薬株式会社
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大橋 徹生
北陸製薬株式会社
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小川 信男
北陸製薬株式会社中央研究所研究開発本部
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安田 信吾
北陸製薬株式会社中央研究所研究開発本部
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岩崎 信彦
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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坂口 順
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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大橋 徹生
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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小川 信男
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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安田 信吾
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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越中 栄一
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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加藤 日出男
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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伊藤 安夫
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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澤西 啓之
the First Division of the Research Laboratory for Development of Medicine, Hokuriku University
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高原 栄二
Research and Development Division, Hokuriku Seiyaku Co., Ltd.,
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岩崎 信彦
Research And Development Division Hokuriku Seiyaku Co. Ltd.
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坂口 順
Research And Development Division Hokuriku Seiyaku Co. Ltd.
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高原 栄二
Research And Development Division Hokuriku Seiyaku Co. Ltd.
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澤西 啓之
北陸大・薬
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澤西 啓之
The First Division Of The Research Laboratory For Development Of Medicine Hokuriku University
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越中 栄一
Research And Development Division Hokuriku Seiyaku Co. Ltd.
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伊藤 安夫
Research And Development Division Hokuriku Seiyaku Co. Ltd.
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加藤 日出男
北陸製薬株式会社中央研究所
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