Novel 1-trifluoromethyl-4-quinolone derivatives (8a,b) were synthesized, and the antibacterial activity of each was evaluated. An oxidative desulfurization-fluorination reaction was employed to introduce a trifluoromethyl group at the N-1 position as a key step. Among the derivatives, 8a was found to exhibit antibacterial activity comparable to that of norfloxacin (1) against Staphylococcus aureus Smith, Streptococcus pneumoniae IID1210, and Escherichia coli NIHJ JC-2.

The tachykinin neuropeptides, substance P (SP), neurokinin A (NKA), and neurokinin B (NKB), are neurotransmitters or neuromodulatory agents. Each of these structurally related neuropeptides has a preferred receptor: the NK 1 receptor for SP, the NK 2 receptor for NKA, and the NK 3 receptor for NKB. The NK 1 and NK 2 receptors are widely distributed in the central nervous system (CNS) and peripheral tissue; NK 3 may be more localized in the CNS.1) Of these peptides, SP 2) is known to exhibit a wide variety of biological responses, both centrally and peripherally. Through binding to the NK 1 receptor, SP has been implicated in the transmission of pain and stress signals, inflammation, and the contraction of smooth muscle. Therefore, NK 1 antagonists may be efficacious for the clinical treatment of a wide range of diseases. In particular, we were interested in the relationship between tachykinin and the activation of the micturition-related refluxes, 3,4) with a view to possible application in the treatment of pollakiuria and urinary incontinence. Recently, the Kyorin Discovery Chemistry group reported the design, synthesis, and evaluation of novel 2-substituted-4-aryl-6,7,8,9-tetrahydro-5H-pyrimido [4,5-b]]oxazocin-5-one (1, KRP-103) was identified as an effective NK 1 antagonist, and was promoted for development as a drug candidate for the treatment of pollakiuria and urinary incontinence.5-7) As a continuation of this research, a large quantity of 1 was required to support the preclinical and clinical development work. Furthermore, the reduced production cost of 1 was a requested requirement in the early stage. The first synthesis of 1 by the Discovery Chemistry group is shown in Chart 1.Condensation of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (2) 8) with 3-[3,5-bis(trifluoromethyl)phenylmethylamino]-1-propanol (3), 9) via acid chloride produced a condensation product (4), which was subjected to nucleophilic intramolecular cyclization to afford pyrimido[4,5-b][1,5]oxazocine (5). Suzuki coupling reaction of 5 with otolylboronic acid provided the coupled product (6), which was subjected to oxidation to afford a sulfone (7). Finally, nucleophilic displacement of 7 with 1-acetylpiperazine provided KRP-103 (1).5-7) However, this method was impractical for the preparation of large quantities of material for preclinical development, because it required multiple chromatographic purifications and was not cost competitive. The formation of compound (6) by way of Suzuki coupling process of 5 with o-tolylboronic acid might be substituted for Knoevenagel condensation reaction between o-tolualdehyde and malonate followed by construction of 4-aryl-6-oxo-1,6-dihydropyrimidine skeleton. Herein, we describe a new practical process for the synthesis of 1, which requires no chromatographic purification and is cost-effective to large-scale production of KRP-103 (1). obtain 2-(4-acetylpiperadin-1-yl)-6-[3,5-bis(trifluoromethyl)-phenylmethyl]-4-(2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-

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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...