Synthesis and antihypertensive activity of stereoisomers of 4-piperidyl-1,3-dihydro-2-oxo-2H-benzimidazoles. Enhanced potencies of (+) isomers.
To elucidate the relationship between the pharmacological activity and stereochemical structure, we resolved 1-[2-(3-,4,5-trimethoxyphenyl)-2-hydroxy-1-methylethyl]-4-(1,3-dihydro-2-oxo-2H -benzimidazol-1-yl)piperidine (1 and 2) and 1-[2-(3,4-dimethoxyphenyl)-2-hydroxy-1-methylethyl]-4-(1,3-dihydro-2-oxo-2H-benzimidazol-yl)piperidine (3), which produced hypotensive effects mainly through their alpha-blocking actions. Threo isomers 1 and 3 were resolved via diastereomeric carbamates. Erythro isomer 2 was obtained by an oxidation and reduction sequence from optically active 1. No significant difference was found between the pharmacological activities of the threo and erythro isomers of the corresponding compounds. However, a clear difference was found between the pharmacological activities of the optical isomers. Difference was most clearly shown in the hypotensive actions of normotensive rats and in alpha-adrenergic blocking activities of isolated rat vas deferens. In these actions, (+) isomers were always more potent than the corresponding (-) isomers.
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D001681:Biological Assay; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009904:Optical Rotation; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D001562:Benzimidazoles; D007202:Indicators and Reagents; D010880:Piperidines