Metabolic oxidation of the pyrrole ring: structure and origin of some urinary metabolites of the anti-hypertensive pyrrolylpyridazinamine, mopidralazine.: III: Studies with the ¹³C-labelled drug

Abstract

1. The metabolism of the anti-hypertensive drug, mopidralazine, N-(2′,5′ -dimethyl-1H-pyrrol-1-yl)-6-(4″-morpholinyl)-3-pyridazinamine, was reinvestigated in rats using the [2′(5′)-CH₃]-labelled drug to determine the significance of the pharmacologically active intermediate 3-hydrazino-6-(4-morpholinyl)pyridazine.

2. The previously proposed mesonic structure of the major metabolite I, i.e., 5′-hydroxy-3′,6′-dimethyl-1′-[6-(4″-morpholinyl)-3-pyridazinyl]pyridazinium hydroxide inner salt, was confirmed by chemical synthesis, X-ray diffraction analysis and ¹H n.m.r. of the [3′,6′-¹³CH₃]-labelled metabolite I.

3. Metabolite II, 3-methyl-6-(4-morpholinyl)-triazolo [4,3–6b]pyridazine and metabolite VII, 3-methyl-7-(4-morpholinyl)-3H-pyridazino[1,6-c]pyridazine, were shown to retain the ¹³CH₃ labelling of mopidralazine, whereas metabolite X, 3-acetyl-hydrazino-6-(4-morpholinyl)-pyridazine, loses the labelling, indicating that their formation involves two different pathways.

4. It is hypothesized that the oxidation of the pyrrole leads to ring opening followed by a chemical rearrangement giving rise directly to metabolites II and VII or, with the intermediacy of the pharmacologically active 3-hydrazino-6-(4-morpholinyl) derivative and an enzymic acetylation or conjugation with pyruvic acid, to metabolites X, II and VII.