Metabolic pathways of the anti-hypertensive agent, N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride. II: Studies in the dog.

The metabolic fate of a new anti-hypertensive, 1-pyrrolyl-pyridazinamine, was studied in male Beagle dogs given both p.o. and i.v. doses of the 14C-labelled drug (1 mg/kg). The compound given as a single i.v. injection disappeared from the central compartment with a half-life of about 0.9 h. Plasma levels of total 14C were represented mostly by metabolites. Eight urinary metabolites designated as metabolites I, II and XI-XVI were purified and their structures assigned by means of u.v., i.r., n.m.r. and mass spectrometry. Quantitatively the primary metabolic attack involved the morpholine moiety of the molecule which undergoes oxidative opening. A minor pathway afforded the cleavage of the pyrrole followed by chemical rearrangements to form six-membered sidnone-like products or a triazole derivative. The major (XIII) and three minor metabolites were studied for their antihypertensive activity in rats and were shown to be inactive.