NONACIDIC ANTIINFLAMMATORY COMPOUNDS .2. SYNTHESIS AND ACTIVITY OF 6-AMINO-2,4-LUTIDINE DERIVATIVES

Benzamides I, phenylalkanamides II and cinnamamides III are structural ly related to the antiinflammatory N-(4,6-dimethylpyridin-2-yl)benzami de 1. These were synthesized and the transformation of the 2-aminopyri dine nucleus of benzamides I into a 2-imino-1,2-dihydropyridine struct ure (compounds IV) was also carried out. Of the 49 new derivatives, th e 3-fluorobenzamide 9 was the most potent in the oral treatment of car rageenen-induced peripheral edema; IC50 = 12.2 mg.kg(-1). It was 3 tim es as active as benzamide 1, but the latter nevertheless had a better therapeutic index (LD(50)/IC50) of 52 against 23. Benzamide 1, a non-a cidic antiinflammatory compound devoid of any blocking activity on cyc looxygenase, markedly reduces the production of reactive oxygen specie s in rat peritoneal macrophages. This compound probably acts at the me mbrane, perhaps by interference with transmembrane events.