Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxybenzamides with six- and seven-membered heteroalicycles as potential gastroprokinetic agents

Chem Pharm Bull (Tokyo). 1995 Jul;43(7):1137-47. doi: 10.1248/cpb.43.1137.

Abstract

A new series of 4-amino-5-chloro-2-ethoxybenzamides 3b--f and 5--8 bearing six- and seven-membered heteroalicycles was prepared and evaluated for gastroprokinetic activity. Compounds 3b--e, derived by replacement of the morpholine oxygen of 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5- chloro-2-ethoxybenzamide (3a) with other atoms (sulfur, nitrogen and carbon), generally exhibited a potent gastric emptying activity. N-(4-Benzyl-3-morpholinyl)methylbenzamide (5a) and its analogues 5b--e had weaker activity. However, N-(4-benzyl-3-morpholinyl)ethylbenzamide 8 was as potent as 3a. Benzamides 6a--e, having seven-membered heteroalicycles, showed fairly potent activity. Molecular superimpositions of 5a, 6a and 8 upon 3a using computer graphics suggested that the direction of the N-benzyl group greatly influences the gastric emptying activity, whereas the location of the alicyclic nitrogen is less critical.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / pharmacology*
  • Crystallography, X-Ray
  • Gastric Emptying / drug effects
  • Gastrointestinal Agents / chemical synthesis*
  • Gastrointestinal Agents / pharmacology*
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / pharmacology*
  • Male
  • Molecular Structure
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Gastrointestinal Agents
  • Heterocyclic Compounds