Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a potential substrate for new aldose reductase inhibitors

The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open d erivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substrates for the synthesis of new aldose reduc tase inhibitors with respect to the previously reported 5,6-dihydrobenzo[h] cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few derivatives lacking t he 5-acetyl group were prepared. Several compounds derived from 2 displayed inhibitory properties comparable to those of Sorbinil. In this class the p resence at position 6 of a phenyl carrying an electron-withdrawing substitu ent proved to be beneficial, independently from its position on the ring (5 g,j-l). Acetic acid derivatives were more effective than propionic and buty ric analogues. On the contrary, all the monocyclic compounds (6-8) were eit her inactive or only weakly active. The 3-methyl-4-(p-chlorophenyl)isoxazol o-[3,4-d]-pyridazin-7-(6H)-one acetic acid (5g), which proved to be the mos t potent derivative, was also investigated in molecular modeling studies, t o assess possible similarities in its interaction with the enzyme, with res pect to the model 1.