SYNTHESIS AND ANTIINFLAMMATORY ACTIVITY OF 5-(1,2-DIHYDROPYRIDYL)-TETRAZOL-2-ACETIC ACIDS, ESTERS AND AMIDES

A series of 5-[4-(1,2-dihydropyridyl)]-2H-tetrazol-2-acetic acids 13-1 9, esters 4-12 and amides 20-22 were synthesized in order to investiga te the effect of 1,2-dihydropyridyl substituents (R1 = aryl, alkyl; R2 = phenoxycarbonyl, 4-chlorobenzoyl, hydrogen) on antiinflammatory act ivity in the carrageenan-induced rat paw edema assay. Compounds posses sing a dihydropyridyl C-2 phenyl or n-butyl substituent exhibited, in most cases, more potent activity. The dihydropyridyl N-1 substituent w as a determinant of activity in both the acetic acid ester and acetic acid classes of compounds where the relative potency order was 4-chlor obenzoyl > phenoxycarbonyl. The difference in activity between acetic acid esters (R3 = OMe) and the corresponding acetic acids (R3 = OH) wa s usually small. A dihydropyridyl N-1 substituent is essential for act ivity since the N-unsubstituted compound 20 was inactive. henyl-1,2-di hydropyridyl)]-2H-tetrazol-2-yl)acetic acid 14 was the most potent ant iinflammatory 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.