Novel Benzamides as Selective and Potent Gastrokinetic Agents. III. Synthesis and Structure-Activity Relationships of 4-amino-5-chloro-2-methoxy- and 2-Ethoxy-N-[(4-substituted 2-morpholinyl)methyl]-benzamides

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概要

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• A series of 4-amino-5-chloro-2-methoxy- and 2-ethoxy-N-[(4-substituted 2-morpholinyl)methyl]benzamides (11-64) were prepared and evaluated for gastrokinetic activity by determining their effects on the gastric emptying of phenol red semisolid meal in rats. The N-4 substituent includes alkyl, phenoxyalkyl, (4-fluorobenzoyl)alkyl, and heteroarylmethyl groups. The benzamide derivatives, having an isopropyl, isoamyl, neopentyl, 3-(4-chlorophenoxy)-propyl, or pyridylmethyl group at N-4,showed potent in vivo gastric emptying activity. In particular, 4-amino-5-chloro-2-ethoxy-N-[[4-(3-pyridylmethyl)-2-morpholinyl]methyl]benzamide (57b) was equipotent to the 4-fluorobenzyl analogue 1b (AS-4370 as its citrate) in the gastrokinetic activity on phenol red semisolid meal in rats and mice, and on resin pellet solid meal in rats. Moreover, compound 57b was free from dopamine D_2 receptor antagonistic activity in both in vitro ([^3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests. Structure-activity relationships of compounds with various substituents at N-4 are also discussed.

• 社団法人日本薬学会の論文
• 1992-03-25

著者

• 原田 博史

  Dainippon Pharmaceutical Co. Ltd.

• 賀登 志朗

  Research Laboratories, Dainippon Pharmaceutical Co., Ltd.

• 森江 俊哉

  Research Laboratories, Dainippon Pharmaceutical Co., Ltd.

• 原田 博史

  Research Laboratories, Dainippon Pharmaceutical Co., Ltd.

• 吉田 直之

  Research Laboratories, Dainippon Pharmaceutical Co., Ltd.

• 松本 純一

  Research Laboratories, Dainippon Pharmaceutical Co., Ltd.

• 森江 俊哉

  大日本製薬株式会社創薬研究所

• 松本 純一

  Exploratory Research Laboratories Dainippon Pharmaceutical Company Ltd.

• 吉田 直之

  大日本製薬(株)薬理研究所

• Kato Satoru

  Kanazawa Univ. Kanazawa Jpn

• Matsumoto J

  Discovery Research Laboratories Ii Dainippon Pharmaceutical Company Ltd.

• 松本 純一

  Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• 賀登 志朗

  大日本製薬株式会社創薬研究所

• Yoshida Naoko

  Institute For Medical And Dental Engineering Tokyo Medical And Dental University

• Kato S

  Discovery Research Laboratories I Dainippon Pharmaceutical Co. Ltd.

• Kato S

  Chemistry Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• 吉田 直之

  大日本製薬株式会社創薬研究所第一薬理研究部

• Yoshida Naotoshi

  Medicinal Plant Garden Faculty Of Pharmaceutical Sciences Hokkaido University

• 吉田 直之

  大日本製薬株式会社創薬研究所

• 松本 純一

  Exploratory Research Laboratories Dainippon Pharmaceutical Co. Ltd.

• Harada H

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Kato Satoru

  Department Of Molecular Neurobiology Graduate School Of Medicine University Of Kanazawa

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