Novel benzamides as selective and potent gastrokinetic agents. 2. Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide citrate (AS-4370) and related compounds

• Published in: Journal of medicinal chemistry Vol. 34; no. 2; pp. 616 - 624
• Main Authors: Kato, Shiro, Morie, Toshiya, Kon, Tatsuya, Yoshida, Naoyuki, Karasawa, Tadahiko, Matsumoto, Junichi
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.02.1991
• Subjects: Animals; Benzamides - chemical synthesis; Benzamides - pharmacology; Chemical Phenomena; Chemistry; Cisapride; Dogs; Gastric Emptying - drug effects; Gastrointestinal Agents - chemical synthesis; Gastrointestinal Agents - pharmacology; Male; Metoclopramide - metabolism; Metoclopramide - pharmacology; Mice; Morpholines - chemical synthesis; Morpholines - pharmacology; Piperidines - metabolism; Piperidines - pharmacology; Rats; Serotonin Antagonists - metabolism; Serotonin Antagonists - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00106a023

The title compounds (19-55) with a 4-substituted 2-(aminomethyl)morpholine group were prepared and evaluated for the gastrokinetic activity by determining their effect on gastric emptying of phenol red semisolid meal in rats. Introduction of chloro, fluoro, and trifluoromethyl groups to the benzyl group of the parent compounds 1a and 1b enhanced the activity. Among compounds tested, 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl] methyl] benzamide (23b) showed the most potent gastric emptying activity (effects on phenol red semisolid meal in rats and mice, and on resin pellets solid meal in rats). The gastrokinetic activity of 23b citrate (AS-4370) compared very favorably with that of cisapride and was higher than that of metoclopramide. In contrast to metoclopramide and cisapride, AS-4370 was free from dopamine D2 receptor antagonistic activity in both in vitro ([3H]spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests.