Synthesis of the Metabolites of 4-(2-Methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide (KRP-197/ONO-8025)

Abstract

The synthesis and structure-activity relationships of novel 4-(imidazoyl-1-yl)butanamide derivatives as antimuscarinic activity agents were reported by the Kyorin Discovery Research group.1-3) Among them, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide , 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. 1,2,3,4-tetra-O-benzoyl-b-D-glucopyranouronate 8, as a starting material, was synthesized from D-(ϩ)-glucurono-3,6-lacton by applying the reported method. 4) 8 was treated with methansulfonic acid in CH 2 Cl 2 to afford a-methansulfonate 9 in 49% yield. The glycosidation reaction between 1 and 9 was carried out in CHCl 3 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 3The synthesis of the metabolite 3 is outlined in Chart 3. N-(1-Aminoethyl)benzamide hydrochloride 11, prepared according to Carotti's method, 5) 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 re- -1H-imidazol-1-yl) Research Center, Kyorin Pharmaceutical Co., Ltd.; 1848 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan: and b School of Parmaceutical Sciences, Toho University; 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan. Received March 12, 2007; accepted April 28, 2007 We synthesized the six presumed metabolites (2-7) of 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide [KRP-197/ONO-8025, 1], a urinary incontinence therapeutic agent, in order to confirm the structures of the metabolites. Metabolite (2) was synthesized via glucuronidaion of compound (1) and methyl 2,3,4-tri-Obenzoyl-1-methanesulfonyl-a a-D-glucopyranuronate. Metabolite (3) was synthesized via 3-(tert-butoxycarbonyl)-2-methyl-1,3-imidazolidine-4,5-dione. Metabolites (4-7) were synthesized via 4-amino-2-diphenylbutanamide, respectively. The structures of the metabolites (2-7) in humans were identified by means of synthesis of the authentic compounds. Synthesis of the...

Synthesis of Glycosides of Glucuronic, Galacturonic and Mannuronic Acids: An Overview

“…Activation of the anomeric position of the glucuronate donor can also be achieved with a sulfonyl group. N -glucuronide 78, a major metabolite of 4-(imidazole-1-yl)butanamide derivative KRP-197/ONO-8025, known for its antimuscarinic activity, was synthesized via glucuronidation of compound 76 using methyl 2,3,4-tri- O- benzoyl-1-methanesulfonyl-α- D -glucopyranuronate ( 75 ) [ 29 ] ( Scheme 19 ). The latter showed β-selectivity and the glucuronide 77 was obtained in moderate yield (41%).…”