Metabolism of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone(M73101), a new anti-inflammatory agent. I. Identification of the metabolites in rabbit and their pharmacological studies.

Abstract

The metabolism of 4-ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (M73101) in rabbits and the pharmacological activities of metabolites were investigated. Rabbits orally received the drug in a dose of 100 mg/kg excreted ten metabolites together with unchanged drug in the urine. These metabolites were characterized by their spectrometric data (infrared, mass, ultraviolet, and nuclear magnetic resonance spectra), thin-layer chromatography and gas chromatography. Some of them were unequivocally identified by comparison with synthesized authentic samples. The following compounds were found to be present in the urine : 4-ethoxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (unchanged drug), 4-hydroxy-2-methyl-5-morpholino-3 (2H)-pyridazinone (M-1), 5-bis (2-hydroxyethyl) amino-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-2), 4-ethoxy-5-[2-(β-hydroxyethyloxy) ethylamino]-2-methyl-3 (2H)-pyridazinone (M-3), 4-ethoxy-5-(2-hydroxyethylamino)-2-methyl-3 (2H)-pyridazinone (M-4), 4-ethoxy-5-(2-hydroxy-tetrahydro-1, 4-oxazin-4-yl)-2-methyl-3 (2H)-pyridazinone (M-5), 4-ethoxy-5-morpholino-3 (2H)-pyridazinone (M-6), 4-ethoxy-2-methyl-5-(3-oxotetrahydro-1, 4-oxazin-4-yl)-3 (2H)-pyridazinone (M-7), 5-(N-carboxymethyl-N-2-hydroxyethylamino)-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-8), 5-[2-(carboxymethyloxy)-ethylamino]-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-9), 5-carboxymethylamino-4-ethoxy-2-methyl-3 (2H)-pyridazinone (M-10). From these results, it was concluded that the major metabolic route in rabbits was oxidative cleavage of C-N and C-O of morpholino group followed by further degradation. Deethylation and demethylation were found to be minor reaction. In the pharmacologocal studies of metabolites, no activities were observed, which indicated that the pharmacological activities of M73101 were not due to these urinary metabolites.