Chem. Pharm. Bull. 55(7) 1039—1043 (2007)

4-(imidazoyl-1-yl)butanamide derivatives as antimuscarinic activity agents were reported by the Kyorin Discovery Research group. Among them, 4-(2-methyl-1H-imidazol1-yl)-2,2-diphenylbutanamide [KRP-197/ONO-8025, 1] is under clinical evaluation as a new type of treatment for urinary incontinence with highly subtype receptor selective antimuscarinic activity. During the course of the metabolite studies of 1, using high performance liquid chromatography (HPLC)-mass spectrometry (LC-MS/MS) suggested degradation from the imidazole structure for four of the six metabolites of 1, the imidazolidine dione structure and Nglucuronide (Chart 1). Especially, N-glucuronide was proposed to be the presence of quarter ammonium containing unique chemical structure 2 as a major metabolite in only humans. Thus, our efforts have been focused on the synthesis of the above metabolites, which were synthesized in order to confirm their pharmacological efficacy. Synthesis of Ammonium N-Glucronide (2) The synthetic route to quaternary N-glucuronide 2 from methyl 2,3,4-tri-O-benzoyl-1-methanesulfonyl-a -D-glucopyranuronate 9 as a glycosyl donor is shown in Chart 2. 1,2,3,4tetra-O-benzoyl-b-D-glucopyranouronate 8, as a starting material, was synthesized from D-( )-glucurono-3,6-lacton by applying the reported method. 8 was treated with methansulfonic acid in CH2Cl2 to afford a-methansulfonate 9 in 49% yield. The glycosidation reaction between 1 and 9 was carried out in CHCl3 to provide 10 in 41% yield, and also stereoselectivity was only obtained for the single b-isomer. Deprotection and hydrolysis of the methyl ester afforded ammonium N-glucuronaide 2 as inner salt after HP-20SS resin treatment. Synthesis of Imidazolidine Dion 3 The synthesis of the metabolite 3 is outlined in Chart 3. N-(1-Aminoethyl)benzamide hydrochloride 11, prepared according to Carotti’s method, was transformed to 12 on treatment with chloroacethyl chloride followed by cyclization and protection by the Boc group in 30% yield (3 steps). The ring oxidation reSynthesis of the Metabolites of 4-(2-Methyl-1H-imidazol-1-yl)-2,2diphenylbutanamide (KRP-197/ONO-8025)