Pyridazino[3,4,5-de]phthalazines. I. Synthesis of the heterocyclic system and key intermediates

Abstract

1H-Pyridazino[3,4,5-de]phthalazine (4) and 3-hydrazino-1(or 9) H-pyridazino[3,4,5-de]-phthalazine (6) represent intramolecular hydrazones of the drugs hydralazine and dihydralazine, respectively. These novel heterocycles were synthesized by several different routes starting from 2,6-dimethylbenzoic acid, 3-methylphthalic anhydride, or hemimellitic acid. Tetrabromination of 2,6-dimethylbenzoic acid with bromine and carbon tetrachloride under free radical conditions followed by treatment with dilute aqueous hydrazine hydrate produced pure 4 in yields up to 58%. Treatment of 3-methylphthalic anhydride with 2 mol of N-bromosuccinimide under radical conditions followed by reaction of the dibromo compound with hydrazine hydrate in methyl Cellosolve produced 3-oxo-3H-2,9(or 1,2)-dihydropyridazino[3,4,5-de]phthalazine in 60% yield. This intermediate was converted to the 3-thiono compound or 3-chloro-1(or 9)H-pyridazino[3,4,5-de]phthalazine from which the hydrazine 6 was generated by hydrazine hydrate treatment. This hydrazine was further characterized by conversion with acid chlorides to novel tetracyclic condensed triazoles or by nitrous acid to a tetracyclic condensed tetrazole. The unsubstituted heterocycle 4 was uninteresting in pharmacological screens but the hydrazine 6 resembled hydralazine by lowering blood pressure in several animal test models and in limited clinical trials.