New Indole and Pyridazinoindole Analogs — Synthesis and Study as Inhibitors of Phosphodiesterases and as Inhibitors of Blood Platelet Aggregation

This paper presents the synthesis of new indole, pyridazino[4,5‐ b ]indole, and pyridazino[4,5‐ a ]indole analogs as well as a study of their “ in vitro ” activity as inhibitors of different phosphodiesterases isolated from dog cardiac tissue, dog aorta, and bovine platelets; the study of their activity as inhibitors of platelet aggregation in guinea pig whole blood, with ADP and arachidonic acid (AA) as pro‐aggregants, is also included. The selected compounds 8‐benzyloxy‐3,4‐dihydro‐1‐(3,4,5‐trimethoxy)benzylideneaminopyridazino[4,5‐ b ]indole 14g , and 8‐benzyloxy‐4‐[(3,5‐dimethyl)pyrazolyl]pyridazino[4,5‐ b ]indole 20 present an interesting profile as potential inodilators, with a complementary, beneficial activity as inhibitors of the aggregation, activities which could possibly be related to the inhibition of the PDE's. Among the other compounds studied, 8‐benzyloxy‐3,4‐dihydro‐1‐[4‐(methyl)piperazino]acetamidopyridazino[4,5‐ b ]indol‐4‐one 16c and 8‐benzyloxy‐3,4‐dihydro‐1‐[4‐(2‐methoxyphenyl)piperazino]acetamidopyridazino[4,5‐ b ]indol‐4‐one 16f stood out as inhibitors of platelet aggregation, with a mechanism that could possibly be related to the AA cascade.