Cytochrome P-450 (designated as P-450) is a family of heme-containing metallo-enzymes named after the absorption band at 450 nm of their carbon monoxide form. P-450 metabolizes various kinds of xenobiotics, including drugs, oxidatively or reductively, playing an important role in drug metabolism.1) Many chemical models for P-450 have been developed to elucidate and/or mimic the function of the enzymes. Several models function as efficient oxidation systems for simple substrates, but there have been only a few reports on the application of these models to the in vitro metabolic study of heterocycles, which are often used as an important structural backbone for drugs and candidate drugs. For example, in the case of the oxidation of 3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine (Ibudilast; IBPP), which has been developed as an antiasthma drug and cerebral vasodilator, ring hydroxylation of the pyrazolo[1,5-a]pyridine nucleus occurred smoothly to give the monoepoxide derivative along with the diepoxide derivative.2) Those compounds are unstable precursors of the final metabolites of IBPP.2-Methylimidazole is an important pharmacophore, e.g., in thromboxane A 2 synthase inhibitors, aromatase inhibitors, 5-hydroxytryptamine (5HT) inhibitors, muscarinic acetylcholine receptor antagonists, and so on.3) In general, the imidazole ring is rather metabolically labile, affording ring polyoxygenated and related metabolites. 4) However, there has been no report on the isolation and structural determination of imidazole ring mono-oxygenated metabolites (designated as imidazolones), which are thought to be precursors of the final metabolites of various drugs and candidate drugs.It has been reported for several imidazole-containing drugs that trace amounts of drug equivalents are retained in connective tissue after administration to laboratory animals.5-7) Although the mechanism(s) of the retention in connective tissue is not yet known, it may involve the reaction of a reactive intermediate (such as imidazolone), formed by metabolism of the imidazole moiety, with tissue macromolecules.8) Therefore, it is important to develop an efficient method for the preparation of imidazolone derivatives under biomimetic reaction conditions. Direct transformation of 2-methylimidazole to 2-methylimidazolone using a cuproascorbate system (cupric chloride and L-ascorbic acid) was reported, but the yield was very poor.9) We retested this system, but found that reproducibility was poor (data not shown).In this paper, we present a novel mono-oxidation of 2-methylimidazole by using metalloporphyrin-iodosylbenzene as a chemical model system for cytochrome P-450.10-12) Application of this system to a 2-methylimidazole-containing candidate drug is also described.
ExperimentalGeneral Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected. 1 H-NMR spectra were measured in CDCl 3 with tetramethylsilane (TMS) and the solvent peak as internal standards, on a JEOL JMN-A400 spectrometer. Mass spectra (MS) were obtain...
