Antihypertensives. N-1H-Pyrrol-1-yl-3-pyridazinamines

The hypothesis that the side effects of hydralazine, such as mutagenicity and lupus erythematosus like syndrome, might be due to the NHNH2 group prompted us to incorporate part of this moiety into a pyrrole ring. Therefore, we prepared a series of N-1H-pyrrol-1-yl-3-pyridazinamines and a limited number of N-1H-pyrrol-1-yl-1-phthalazinamines by reaction of 3-hydrazinopyridazines and 1-hydrazinophthalazines with gamma-diketones. Most of these compounds, especially in the pyridazine series, showed moderate to strong antihypertensive activity in spontaneously hypertensive rats. The decrease in blood pressure generally had a slow onset after either oral or intravenous administration. N-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (30) (MDL 899) showed no mutagenic activity in several tests and is now in clinical trials in patients.