Synthesis and biotransformation of 3-hydrazinopyridazine drugs

Several derivatives of 3-hydrazinopyridazine are reported to possess interesting biological properties as chemotherapeutics, anti-inflammatory agents, CNS depressants and stimulants and anti-hypertensives. In particular, variously substituted 3-hydrazinopyridazines raised considerable interest as peripheral vasodilators with improved potency and safety compared to hydralazine and dihydralazine. More recently, some compounds bearing substituents which may also account for beta-adrenoceptor blocking properties were prepared and studied in approaches aimed at combining in single molecules both the vasodilating and the beta-adrenoceptor blocking activity in an appropriate balance. When substituents are alkylic or arylic, the pyridazine nucleus is synthesized through the appropriate 4-oxoacid, otherwise 3,6-dichloropyridazine is generally used as starting compound. In the latter case, while the nucleophilic substitution of the first chlorine atom is easily obtained, the reactivity of the second chlorine is considerably reduced when the first group introduced has electro-donating properties (alkoxy or alkylamino groups) and an excess of hydrazine is required under forcing conditions. Since 3-chloro-6-hydrazinopyridazine is practically unreactive, it was found to be convenient to convert it to 3-chloro-6-(triphenylmethylazo)pyridazine, whose halogen atom is activated towards nucleophiles, and to restore the hydrazino group after the substitution. 3-Hydrazinopyridazines are extensively metabolized, mainly by acetylation of the free hydrazino group, followed by cyclization, or by reaction with endogenous carbonyl compounds and, to a lower extent, by hydrolysis or oxidation. When the hydrazino group is protected, biotransformation is generally less extensive, giving rise to an active metabolite which in turn follows the metabolic pathways outlined above. Interestingly, pharmacokinetic studies on cadralazine (a 3-hydrazinopyridazine protected as ethoxycarbonyl derivative) support the attractive hypothesis that the pro-drug is biotransformed topically to the active metabolite in the endothelium of arterial vessels, close to the site at which smooth muscle relaxation is required.