Synthesis and biological activity of 4-amino-5-chloro-2-ethoxy-3-hydroxybenzamides, metabolites of a new gastroprokinetic agent, mosapride.
To confirm the proposed structures of the minor metabolites of a potential gastroprokinetic agent, mosapride, 4-amino-5-chloro-2-ethoxy-3-hydroxy-N-(2-morpholinylmethyl)benzamide (3) and the N-(5-oxo-2-morpholinyl)-methyl analogue 4 were prepared. As the common intermediate, 2-ethoxy-3-hydroxy-4-nitrobenzoic acid (15) was prepared via the regioselective ethylation of 2,3-dihydroxybenzaldehyde (10) and subsequent nitration of the resultant 2-ethoxy-3-hydroxybenzaldehyde (11). The key intermediate 15 was converted into the benzamides 3 and 4. After enzymatic treatment of the isolated metabolites, their structures were identified by comparison with the synthetic compounds. Serotonin-4 receptor binding affinity of these metabolites was found to be lower than that of mosapride.
Kato
S
S
Discovery Research Laboratories I, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Morie
T
T
Yoshida
N
N
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001711:Biotransformation; D005765:Gastrointestinal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects; D018629:Spectrometry, Mass, Secondary Ion; D013055:Spectrophotometry, Infrared; D013268:Stimulation, Chemical
D001549:Benzamides; D005765:Gastrointestinal Agents; D009025:Morpholines; D011985:Receptors, Serotonin; C062720:mosapride