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

Abstract

1. 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).

2. The compound given as a single i.v. injection disappeared from the central compartment wirh a half-life of about 0.9h. Plasma levels of total ¹⁴C were represented mostly by metabolites.

3. 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.

4. 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.

5. The major (XIII) and three minor metabolites were studied for their anti-hypertensive activity in rats and were shown to be inactive.