US008883780B2 (12) United States Patent (10) Patent No.: US 8,883,780 B2 Aret (45) Date of Patent: Nov. 11, 2014 (54) CRYSTAL OF A BENZOXAZINONE (56) References Cited COMPOUND U.S. PATENT DOCUMENTS (75) Inventor: Edwin Aret, Amsterdam (NL) 6,624,161 B2 * 9/2003 Hodson et al. ............. 514,230.5 6,656,934 B2 * 12/2003 Hodson et al. ............. 514,230.5 (73) Assignee: Norgine B.V., Amsterdam (NL) 7,396,952 B2 7/2008 Holzer et al. 2003/0027821 A1 2/2003 Hodson et al. 2003/0195206 A1 10, 2003 Hodson et al. *) Notice: Subject to anyy disclaimer, the term of this 2007/0232825 A1 10, 2007 Holzer et al. patent is extended or adjusted under 35 2008. O161301 A1 7/2008 Hodson et al. U.S.C. 154(b) by 241 days. 2008.0171891 A1 7/2008 Holzer et al. (21) Appl. No.: 13/265,599 FOREIGN PATENT DOCUMENTS JP 2006169244 A 6, 2006 (22) PCT Filed: Apr. 22, 2010 WO WO-00, 40247 A1 T 2000 WO WOOO4O247 A1 * T 2000 (86). PCT No.: PCT/UP2010/0571 10 WO WOOO40569 A1 * T 2000 S371 (c)(1), OTHER PUBLICATIONS (2), (4) Date: Dec. 22, 2011 English Translation of the International Preliminary Report on Pat entability for PCT/JP2010/0571 10 mailed Dec. 1, 2011. (87) PCT Pub. No.: WO2010/123047 Extended European Search Report for 10767104.2, 6 pages (Sep. 27. 2012). PCT Pub. Date: Oct. 28, 2010 International Search Report of PCT/JP2010/0571 10 mailed Jun. 22, 2010. (65) Prior Publication Data * cited by examiner US 2012/0101090 A1 Apr. 26, 2012 Primary Examiner — Kahsay Habte (30) Foreign Application Priority Data (74) Attorney, Agent, or Firm — Choate, Hall & Stewart, LLP; Charles E. Lyon; John P. Rearick Apr. 24, 2009 (JP) ................................. 2009-106.606 (57) ABSTRACT Disclosed is a crystal of 2-(hexadecyloxy)-6-methyl-4H-3, 1 (51) Int. Cl. benzoxazin-4-one useful as a preventive or therapeutic agent CO7D 265/26 (2006.01) for obesity and the like. Specifically disclosed is a crystal of A6 IK3I/536 (2006.01) 2-(hexadecyloxy)-6-methyl-4H-3,1-benzoxazin-4-one hav (52) U.S. Cl. ing a powder X-ray diffraction pattern in which characteristic USPC .......................................... 514/230.5:544/93 peaks appearat powder X-ray diffraction interplanar spacings (58) Field of Classification Search (d) of around 16.54+0.2, 13.26+0.2, 4.70+0.2, 4.38+0.2, and USPC .......................................... 514/230.5:544/93 3.67.0.2. See application file for complete search history. 3 Claims, 1 Drawing Sheet U.S. Patent Nov. 11, 2014 US 8,883,780 B2 ig, &Yo-YYYYYYYYYYYYYYYxxxxtreexYs Y*.xxxxwywww.www.x.................... SS s s s s |R. S. s s S. S: was versm xxxii. & Sssssssssssssssssssssss8.- S Stfeast ps: *''x''xs'-xxx-xx-xx-xx-x-xx-asssssssssssssssssssss------------------------- assaxoss-ex a-sasssssssssssssssssssssss | s&Syss $$$$.&swaxx's s $$$. $8,88 US 8,883,780 B2 1. 2 CRYSTAL OF A BENZOXAZNONE aZinone compound) of the present invention can be a solvate COMPOUND Such as a hydrate, etc., or a non-Solvate. The aforementioned hydrate, for example, can be between RELATED APPLICATIONS 0.5 hydrate and 5.0 hydrate. Preferable among these area 0.5 hydrate, 1.0 hydrate, 1.5 hydrate, 2.0 hydrate and 2.5 hydrate. This application is a national phase application under 35 The 0.5 hydrate, 1.0 hydrate and 1.5 hydrate are particularly U.S.C. 371 of PCT International Application No. PCT/ advantageous. JP2010/0571 10 (published PCT application no. WO 2010/ The benzoxazinone compound of the present invention or 123047), filed Apr. 22, 2010, which claims priority to Japa hydrate thereof may also be a deuterium converter. nese Application No. 2009-106606, filed Apr. 24, 2009, the 10 The benzoxazinone compound crystal of the present inven contents of which are hereby incorporated by reference in tion can also be a solvate other than a hydrate. their entirety for all purposes. Examples of Solvate crystal of benzoxazinone compound TECHNICAL FIELD include alcohol Solvate crystals such as methanol Solvate crystal and ethanol solvate crystal (preferably C alcohol The present invention relates to a crystal of benzoxazinone 15 Solvate crystal) and organic solvent hydrate crystal with compound that is useful in the prevention and treatment of added water and organic solvent (e.g., alcohol hydrate crystal obesity. Such as methanol hydrate crystal and ethanol hydrate crystal; preferably Calcohol hydrate crystal). BACKGROUND ART The crystal of the present invention can be manufactured by crystal transition using either a non-crystal benzoxazinone The use of 2-(Hexadecyloxy)-6-methyl-4H-3,1-benzox compound or other crystal benzoxazinone compound. azin-4-one having the action of lipase inhibition has been In crystal transition, the crystal structure undergoes a reported as useful in the prevention and treatment of obesity, change above a certain temperature or pressure. etc., in the specification of U.S. Pat. No. 6,624,161. Examples of the Crystal Transition Method include those 25 known in the art, Such as crystallization from liquid (e.g., the OUTLINE OF THE INVENTION concentration method, slow-cooling method, reaction An agent is needed that is highly effective and safe in the method diffusion method, electrolysis method, hydrother prevention and treatment of obesity. The present invention mal cultivation method and fusing method, etc.), crystalliza aims to submit a new crystal of 2-(Hexadecyloxy)-6-methyl tion from vapor (vaporization method sealed tube method, 4H-3,1-benzoxazin-4-one that is useful as an agent of pre 30 gas flow method, gas phase reaction method, chemical trans vention and treatment of obesity. port method), crystallization from melt normal freezing As a result of intensive research, the present inventor Suc method (pull-up method, temperature gradient method, ceeded in producing a crystal of2-(Hexadecyloxy)-6-methyl Bridgeman method), Zone melting method Zone leveling 4H-31-benzoxazin-4-one (Cetilistat) that is extremely safe; method, float Zone method, special growth method VLS discovered that said crystal is pharmaceutically acceptable, 35 method, liquid phase epitaxy method), steam fog method and based on this knowledge, completed the present inven dissolving crystal in a solvent, and after filtration evaporat tion. ing the solvent under atmospheric conditions, slurry method That is, the present invention relates to: adding crystal to solvent to form a liquid Suspension of (1) A crystal of 2-(Hexadecyloxy)-6-methyl-4H-3,1-ben excess Solid, and after agitation at atmospheric temperature or Zoxazin-4-one with lattice spacing (d) of the powder 40 under heating or cooling conditions, filtering of the Solid. X-ray diffraction pattern characteristically peaking in reduced-pressure drying, grinding, pulverization and pressur the vicinity of 16.54+0.2, 13.26+0.2, 4.70+0.2, 4.38+0.2 ization. and 3.67+0.2, angstroms, Among the aforementioned methods, the slurry method is (2) A pharmaceutical containing the crystal of aforemen particularly favorable for obtaining the crystal of the present tioned (1), 45 invention. Particularly advantageous is the method whereby a (3) Pharmaceuticals, etc., of aforementioned (2) which are crystal of benzoxazinone compound is added to a Suspension agents for prevention and treatment of obesity. of excess Solid in a solvent and, after agitation, the Solid is filtered off. Examples of the solvent to use include aromatic EFFECTIVENESS OF THE INVENTION hydrocarbons (e.g., benzene, toluene and Xylene), hydrocar 50 bon halides (e.g., dichloromethane, chloroform, etc.), satu The crystal of the present invention (e.g., hereinafter rated hydrocarbons (e.g., hexane, heptane, cyclohexane, referred to as A-type crystal and B-type crystal) is useful as a etc.), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydro pharmaceutical having exceptional lipase inhibiting action foran, dioxane etc.), nitryls (e.g., acetonitryl, etc.), ketones and lipid absorption controlling action, as well as low toxic (e.g., acetone, etc.), Sulfoxides (e.g., dimethyl Sulfoxide, 1ty. 55 etc.), acid amides (e.g., N,N-dimethylformamide, etc.), esters (e.g., acetic ether, etc.), alcohols (e.g., methanol, ethanol, SIMPLE EXPLANATION OF DIAGRAMS isopropyl alcohol, etc.), and water. These solvents can be used alone or two or more can be used in a mixture of suitable ratio FIG. 1 shows a powder X-ray diffraction pattern of the (e.g., 1:1 or 1:100). It is advantageous to use aromatic hydro B-type crystal of preferred embodiment 1. 60 carbons (e.g., Xylene), ethers (e.g., tetrahydrofuran, etc.), and FIG. 2 shows a powder X-ray diffraction pattern of the preferably ethers (e.g., tetrahydrofuran, etc.). A-type crystal of reference embodiment 1. The volume of solvent to use is normally approx. 2.5 ml-approx. 10 ml per 1 g of benzoxazinone compound crys DETAILED DESCRIPTION OF THE INVENTION tal, and preferably approx. 2.5 ml-approx. 3 ml. 65 After agitating the liquid Suspension at atmospheric tem The crystal 2-(Hexadecyloxy)-6-methyl-4H-3,1-benzox perature, it is advisable to cool and agitate again. In the azin-4-one (or otherwise abbreviated hereinafter to benzox specification of the present invention, room temperature and US 8,883,780 B2 3 4 atmospheric temperature mean approx. 15° C.-approx. 30° postprandial hyperlipidemia), hyperglycemia (type II diabe C. The period for agitation at atmospheric temperature is tes, impaired glucose tolerance), high blood pressure, cardio normally approx. 2 hours-approx. 24 hours; preferably vascular disease, cerebral stroke, gastrointestinal disease, approx. 15 hours-approx. 24 hours. The period of agitation etc., or complications thereof (e.g., complications of type II under cooling is normally approx. 4 hours-approx 24 hours; diabetes, complications of hyperlipidemia and metabolic preferably approx.