Novel benzamides as selective and potent gastrokinetic agents. IV. Synthesis and structure-activity relationships of 2-substituted 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chlorobenzamides.

A new series of 2-substituted 4-amino-N-(4-benzyl-2-morpholinyl)methyl]-5-chlorobenzamides (4-39) including a few 4-fluorobenzyl analogues were prepared and evaluated for their gastrokinetic activity by determining their effects on the gastric emptying activity of phenol red semisolid meal in rats. The C-2 substituent comprises alkoxy and variously substituted alkoxy groups. Among the derivatives, 4-amino-N-(4-benzyl-2-morpholinyl)methyl]-2-(n-butoxy)-5-chlorobenza mide (5), its 4-fluorobenzyl (6), and 3-methyl-2-butenyloxy analogues (22) were superior to cisapride and essentially equipotent to the 2-ethoxy analogue (1b, AS-4370 as its citrate) in gastrokinetic activity. These compounds, like AS-4370, had no dopamine D2 receptor antagonistic activity.