Synthesis and antiinflammatory activity of N-substituted-dihydropyridylacetic acids, esters, and amides.

A group of N-substituted-1,4-dihydropyridylacetic acids (13-16), esters (4-12), and amides (17-23) were synthesized in order to investigate the effect of 4-substituents (R2 = Ph, n-Bu or Me) and alpha-substituents (R3 = H, Me) on antiinflammatory activity. In the acetic ester class of compounds, the relative activities (R2-substituents) were Ph greater than n-Bu greater than Me. The presence of an R3 methyl substituent enhanced activity. Increasing the length of the alkyl ester substituent enhanced activity, since the tri-ester (7) was more active than the bis-ester (6), and the bis-ester (11) was more active than the mono-ester (10). The relative order of antiinflammatory potency was generally ester greater than amide greater than acid. Methyl 2-methyl-2-(-1-[4-phenyl-3-(4,4-dimethyloxazolin-2-yl)-1,4-dihy dropyridyl]) acetate (9) was the most active antiinflammatory agent in the series, reducing inflammation 73.9% at 3 hr after a 100 mg/kg po dose.