- NOVEL CRYSTAL FORM OF 3,4-DIFLUORO-2-(2-FLUORO-4-IODO-PHENYL AMINO)-N-(2-HYDROXY-ETHOXY)-5-(3-OXO-[1,2]OXAZINAN-2-YLMETHYL)-BENZAMIDE
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PROBLEM TO BE SOLVED: To provide an active pharmaceutical ingredient that is useful as MEK inhibitors and is stable physicochemically. SOLUTION: The present invention provides an educt I-type crystal of 3,4-difluoro-2-(2-fluoro-4-iodo-phenyl amino)-n-(2-hydroxy-ethoxy)-5-(3-oxo-[1,2]oxazinan-2-ylmethyl)-benzamide, having peaks with diffraction angles expressed by 2θ of 14.9, 16.9 and 23.1° (±0.2°) in a powder X-ray diffraction pattern measured using Cu Kα(1.54060?) as an X-ray source. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0039; 0043; 0044; 0045
(2016/10/09)
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- Design and synthesis of novel allosteric MEK inhibitor CH4987655 as an orally available anticancer agent
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The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.
- Isshiki, Yoshiaki,Kohchi, Yasunori,Iikura, Hitoshi,Matsubara, Yasuaki,Asoh, Kohsuke,Murata, Takeshi,Kohchi, Masami,Mizuguchi, Eisaku,Tsujii, Shinji,Hattori, Kazuo,Miura, Takaaki,Yoshimura, Yasushi,Aida, Satoshi,Miwa, Masanori,Saitoh, Ryoichi,Murao, Naoaki,Okabe, Hisafumi,Belunis, Charles,Janson, Cheryl,Lukacs, Christine,Schück, Verena,Shimma, Nobuo
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scheme or table
p. 1795 - 1801
(2011/05/11)
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- Beyond the MEK-pocket: Can current MEK kinase inhibitors be utilized to synthesize novel type III NCKIs? Does the MEK-pocket exist in kinases other than MEK?
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An approach and preliminary results for utilizing legacy MEK inhibitors as templates for a reiterative structural based design and synthesis of novel, type III NCKIs (non-classical kinase inhibitors) is described. Evidence is provided that the MEK-pocket
- Tecle, Haile,Shao, Jianxing,Li, Yanhong,Kothe, Michael,Kazmirski, Steven,Penzotti, Julie,Ding, Yuan-Hua,Ohren, Jeffrey,Moshinsky, Deb,Coli, Rocco,Jhawar, Nidhi,Bora, Emilia,Jacques-O'Hagan, Suzanne,Wu, Joe
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scheme or table
p. 226 - 229
(2009/05/26)
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- 5-SUBSTITUTED-2-PHENYLAMINO-BENZAMIDE AS MEK INHIBITOR
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An objective of the present invention is to provide compounds that exhibit strong MEK-inhibiting activity and are stable in vivo and soluble in water, which can be used as preventive or therapeutic agents for proliferative diseases. The compounds of the present invention and pharmaceutically acceptable salts thereof are represented by the following formula (1): [where R1, R2, R3, R4, and X are the same as defined in the present patent application].
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Page/Page column 73-74
(2008/06/13)
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