Non-acidic antiinfiammatory compounds II. Synthesis and activity of 6-amino-2,4-lutidine derivatives

Article abstract of DOI:10.1016/0223-5234(94)90107-4

Benzamides I, phenylalkanamides II and cinnamamides III are structurally related to the antiinflammatory N-(4,6-dimethylpyridin-2-yl)benzamide I. These were synthesized and the transformation of the 2-aminopyridine nucleus of benzamides I into a 2-imino-1,2-dihydropyridine structure (compounds IV) was also carried out. Of the 49 new derivatives, the 3-fluorobenzamide 9 was the most patent in the oral treatment of carrageenen-induced peripheral edema; IC₅₀ = 12.2 mg·kg^-1. It was 3 times as active as benzamide 1, but the latter nevertheless had a better therapeutic index (LD₅(/)IC₅₀) of 52 against 23. Benzamide 1, a non-acidic antiinflammatory compound devoid of any blocking activity on cyclooxygenase, markedly reduces the production of reactive oxygen species in rat peritoneal macrophages. This compound probably acts at the membrane, perhaps by interference with transmembrane events.