Pyridazino[3,4,5-de]phthalazines. II. Synthesis of nitrogen-substituted derivatives

The synthesis of a wide variety of 9-substituted-3-oxo-3H-2,9-dihydropyridazino[3,4,5-de]phthalazines ( 11 ) was achieved by treatment of 3-substituted-3,4-dihydro-4-oxophthalazine-5-carboxylic esters ( 10 ) with hydrazine hydrate. These esters were prepared from 3-hydroxyphthalide-7-carboxylic acid ( 7 ) by two different routes. Under basic conditions, alkylation of 3-oxo-3H-2,9-dihydropyridazino[3,4,5-de]phthalazine ( 1 ) gave 9-substituted products. These undergo further alkylation at the 2-position. Some of them were converted to 3-chloro, 3-thiono, and 3-hydrazino compounds by standard methods. Dehalogenation of selected 3-chloro compounds or desulphurization of 3-thiono derivatives gave 1-substituted-1H-pyridazino[3,4,5-de]phthalazines ( 22 ), some of which were also prepared by direct alkylation of the parent heterocycle 2 under basic conditions. However, treatment of 2 or its 1 -methyl homologue with methyl iodide resulted in products in which nitrogen attached to carbon had been attacked rather than the 1- or 9-position. Treatment of the acid chloride of 3,4-dihydro-4-oxophthalazine-5-carboxylic acid with methyl hydrazine led to 2-methyl-3-oxo-3H-2,9-dihydropyridazino[3,4,5-de]phfhalazine ( 21 a) which was purified by cyanoethylation at the 9-position, recrystallization, and hydrazinolysis of the cyanoethyl group. Biological testing revealed that many of the compounds lowered blood pressure in animal models but none had a sufficient therapeutic ratio of activity vs. side effects to warrant clinical trial.