Synthesis and biological activities of the optical isomers of (+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2- morpholinyl]methyl]benzamide (mosapride).
The enantiomers, (S)-(-)-1 and (R)-(+)-1, of (+/-)-4-amino-5-chloro-2-ethoxy- N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride) [(+/-)-1], a new and selective gastroprokinetic agent, were prepared from optically active [4-(4-fluorobenzyl)-2-morpholinyl]methylamines (S)-(-)-4 and (R)-(+)-4, respectively. The requisite (S)-(-)-4 and (R)-(+)-4 were prepared by optical resolution of [4-(4-fluorobenzyl)-2-morpholinyl]methyl p-toluenesulfonate [(+/-)-5] using (-)- and (+)-N-(p-toluenesulfonyl)glutamic acids, followed by amination of the tosyloxy groups of (R)-(-)-5 and (S)-(+)-5, respectively. The absolute configurations of (R)-(-)-5 and (S)-(+)-5 were determined on the basis of an asymmetric synthesis of (R)-(-)-5 from (S)-(+)-benzyl glycidyl ether [(S)-(+)-11]. Mosapride and its enantiomers, (S)-(-)-1 and (R)-(+)-1, were essentially equipotent in serotonin 5-HT4 receptor agonistic activity on the electrically evoked contractions in isolated guinea pig ileum.
Morie
T
T
Exploratory Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Kato
S
S
Harada
H
H
Yoshida
N
N
Matsumoto
J
J
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D005765:Gastrointestinal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism
D001549:Benzamides; D005765:Gastrointestinal Agents; D009025:Morpholines; C062720:mosapride