Synthesis and antiinflammatory activity of 5-(1,2-dihydropyridyl)-tetrazol-2-acetic acids, esters and amides

Abstract

A series of 5-[4-(1,2-dihydropyridyl)]-2 H-tetrazol-2-acetic acids 13–19, esters 4–12 and amides 20–22 were synthesized in order to investigate the effect of 1,2-dihydropyridyl substituents (R 1 = aryl, alkyl; R 2 = phenoxycarbonyl, 4-chlorobenzoyl, hydrogen) on antiinflammatory activity in the carrageenan-induced rat paw edema assay. Compounds possessing a dihydropyridyl C-2 phenyl or n-butyl substituent exhibited, in most cases, more potent activity. The dihydropyridyl N-1 substituent was a determinant of activity in both the acetic acid ester and acetic acid classes of compounds where the relative potency order was 4-chlorobenzoyl > phenoxycarbonyl. The difference in activity between acetic acid esters (R 3 = OMe) and the corresponding acetic acids (R 3 = OH) was usually small. A dihydropyridyl N-1 substituent is essential for activity since the N-unsubstituted compound 20 was inactive. 2-Methyl-2-[5-[4-(1-phenoxycarbonyl-2-phenyl-1,2-dihydropyridyl)]-2 H-tetrazol-2-yl} acetic acid 14 was the most potent antiinflammatory agent in the group, reducing inflammation 75% (75 mg/kg po dose) relative to ibuprofen's 52% inhibition (100 mg/kg po dose) at 5 h.