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

Chem Pharm Bull (Tokyo). 1992 Mar;40(3):652-60. doi: 10.1248/cpb.40.652.

Abstract

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 D2 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.

MeSH terms

  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / metabolism
  • Benzamides / pharmacology*
  • Dogs
  • Dopamine Antagonists
  • Gastric Emptying / drug effects*
  • Male
  • Mice
  • Morpholines / chemical synthesis
  • Morpholines / chemistry
  • Morpholines / metabolism
  • Morpholines / pharmacology*
  • Rats
  • Receptors, Dopamine D2
  • Spiperone / metabolism
  • Structure-Activity Relationship
  • Vomiting / chemically induced
  • Vomiting / prevention & control

Substances

  • Benzamides
  • Dopamine Antagonists
  • Morpholines
  • Receptors, Dopamine D2
  • Spiperone