Synthesis and analgesic-antiinflammatory activities of ethyl 2-[3-(1-phenoxy( methoxy)carbonyl-4-aryl-(alkyl)-1,4-dihydropyridyl)]acetates

Reaction of ethyl 2-(3-pyridyl)acetate 4a or ethyl 2-methyl-2-(3-pyridyl)acetate 4b, with phenyl chloroformate or methyl chloroformate, afforded the intermediate pyridinium salt 5 which undergoes regioselective nucleophilic attack at C-4 upon reaction with a Grignard reagent in the presence of a cuprous iodide catalyst at -23 degrees to yield the corresponding ethyl 2-[3-(1-phenoxy(methoxy)carbonyl-4-aryl(alkyl)-1,4-dihydropyridyl)]acetates 6a-f in 64-96% chemical yield. No product arising from reaction of the ester substituent of the pyridinium salt 5 with the Grignard reagent was observed. The H-1 nmr spectra of 6a-f exhibit ed dual resonances for the 1,4-dihydropyridyl H-2, H-5 and H-6 protons at 25 degrees in deuteriochloroform. These dual resonaces were attributed to two different rotameric configurations resulting from restricted rotation about the nitrogen-to-carbonyl carbamate bond due to its double bond character. Compound 6 generally exhibited superior analgesic and antiinflammatory activities, compared to the reference drugs aspirin and ibuprofen, respectively. These structure-activity correlations indicate the 1,4-dihydropyridyl ring system present in 6 is a suitable bioisostere for the aryl (heteroaryl) ring present in aryl(heteroaryl)acetic acid non-steroidal antiinflammatory drugs.