Synthesis and structure-activity relationships of 4-amino-5-chloro-2-ethoxybenzamides with six- and seven-membered heteroalicycles as potential gastroprokinetic agents.
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.
Morie
T
T
Exploratory Research Laboratory, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Kato
S
S
Harada
H
H
Yoshida
N
N
Fujiwara
I
I
Matsumoto
J
J
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005746:Gastric Emptying / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D001549:Benzamides; D005765:Gastrointestinal Agents; D006571:Heterocyclic Compounds