Vasorelaxant Activity of a New Phthalazinone. Synthesis and Studies on the Mechanism of Action

Hypertension is one of the most common cardiovascular diseases, leading to the development of stroke, coronary heart disease, cardiac failure or renal insufficiency [1]. Consequently, much work is ongoing with the aim of developing novel and more efficacious antihypertensive drugs. Drugs which increase vascular relaxation through different mechanisms are a major focus of such work. Many studies have shown that phthalazinone derivatives can display important antihypertensive and anti-asthmatic effects, and such drugs have also been demonstrated to exert inhibitory activity on phosphodiesterases and on platelet aggregation [2]. We have synthesized a new family of phthalazinones displaying vasorelaxant activity. Among them, compound F-16061 exerted the greatest vasorelaxant effect on rat aortic rings previously stimulated with phenylephrine (PE). Additionally, when pre-incubated with rat aorta, this compound reduced the subsequent vasoconstrictive effect of PE. The phthalazinone was prepared, as shown in the scheme below, through condensation of trimellitic anhydride with p-chlorophenylacetic acid to give an intermediate benzalphthalide, which was properly reduced to the corresponding alcohol, further treated with methylhydrazine to provide phthalazinone 1, whose Swern oxidation led to the corresponding aldehyde, F-16061.