Synthesis and gastrointestinal prokinetic activity of novel benzamide derivatives with amphoteric side chains

Novel benzamide derivatives (19-24, 32a-c, 43d-f), each possessing a cycloa minoalkanecarboxylic acid side chain, were synthesized and their gastrointe stinal prokinetic and dopamine D-2 receptor antagonist activities were eval uated, 4-[(4-Amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (19) exhibited the mast potent gastro- and colon-prokinetic activities, th rough intravenous administration to conscious dogs, and also showed the red uced dopamine D-2 receptor antagonistic activity. However, 13 showed only w eak gastrointestinal prokinetic activity after oral administration. Several ester prodrugs (44-62) of 19 were tested for pharmacological activities as well as physicochemical and metabolic stability; the butyl eater (46) was consequently selected as a promising gastrointestinal prokinetic agent with reduced side effects.