Pyridazino[3,4,5-de]phthalazines. II. Synthesis of nitrogen-substituted derivatives
| Autor: | Francis John E, Paula M. Schutte, Robert E. Detlefsen, Doebel Karl J, Ernst F. Bachmann |
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| Rok vydání: | 1982 |
| Předmět: | |
| Zdroj: | Canadian Journal of Chemistry. 60:1214-1232 |
| ISSN: | 1480-3291 0008-4042 |
| DOI: | 10.1139/v82-180 |
| Popis: | 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 (21a) 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. |
| Databáze: | OpenAIRE |
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