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(12) United States Patent (10) Patent No.: US 7,960,564 B2 Borchardt Et Al

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(12) United States Patent (10) Patent No.: US 7,960,564 B2 Borchardt Et Al USOO796.0564B2 (12) United States Patent (10) Patent No.: US 7,960,564 B2 BOrchardt et al. (45) Date of Patent: Jun. 14, 2011 (54) CRYSTALLINE CHEMOTHERAPEUTC FOREIGN PATENT DOCUMENTS WO WO2004 113304 A1 12/2004 (75) Inventors: Thomas B. Borchardt, Kenosha, WI WO WO2007050574 A1 5/2007 (US); Michael J. Rozema, Kenosha, WI (US) OTHER PUBLICATIONS U.S. Pharmacopoeia, pp. 1843-1884 (1995). (73) Assignee: Abbott Laboratories, Abbott Park, IL Dai, et al., “Discover of N-(4-(3-Amino-1H-indazol-4-yl)phenyl)-N'- (US) (2-fluoro-5-methylphenyl)urea (ABT-869), a 3-Aminoindazole Based Orally Active Multitargeted Receptor Tyrosine Kinase Inhibi (*) Notice: Subject to any disclaimer, the term of this tor”. J. Med. Chem, 50, 1584-1597 (2007). patent is extended or adjusted under 35 International Search Report, Jan. 19, 2009. U.S.C. 154(b) by 419 days. Aulton M.E., ed., Pharmaceutics: The Science of Dosage Form Design, 2nd Edition, Churchill Livingstone, 2004, Table of Contents. (21) Appl. No.: 12/251,893 Hilfiker R., ed., Polymorphism in the Pharmaceutical Industry, Wiley-VCH Verlag GmbH & Co. KGaA. Weinheim, Germany, (22) Filed: Oct. 15, 2008 2006, Table of Contents. Morris K.M., "Structural Aspects of Hydrate and Solvates.” (65) Prior Publication Data Polymorphism in Pharmaceutical Solids, 1999, pp. 125-181. Spanish Minerals: X-rays and the Diffraction by Crystals, http:// US 2009/O1248.15A1 May 14, 2009 translate.googleusercontent.com/translate c?hl=en&sl=es &u=http://wwww.spanishmi. Related U.S. Application Data (60) Provisional application No. 60/981.253, filed on Oct. * cited by examiner 19, 2007. Primary Examiner — Kamal A Saeed (51) Int. C. (74) Attorney, Agent, or Firm — Glen J. Gesicki CO7D 23L/56 (2006.01) (52) U.S. Cl. .................................................... 548/362.1 (58) Field of Classification Search ........................ None (57) ABSTRACT See application file for complete search history. N-4-(3-Amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5- methylphenyl)urea Crystalline Form 1, ways to make it, for (56) References Cited mulations comprising it and made with it and methods of U.S. PATENT DOCUMENTS treating patients having disease using it are disclosed. 7,297,709 B2 11/2007 Dai et al. 2005.0020603 A1* 1/2005 Dai et al. ................. 514,252.06 1 Claim, 1 Drawing Sheet U.S. Patent Jun. 14, 2011 US 7,960,564 B2 0990|| 0976 0998 099|| US 7,960,564 B2 1. 2 CRYSTALLINE CHEMOTHERAPEUTIC providing a mixture comprising N-4-(3-amino-1H-inda Zol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea Tolu CROSS REFERENCE TO RELATED eneate Crystalline Form 1 and acetonitrile; APPLICATION causing N-4-(3-Amino-1H-indazol-4-yl)phenyl-N'-(2- fluoro-5-methylphenyl)urea Crystalline Form 1 to exist in the This application claims priority to U.S. Provisional Appli mixture, which N-4-(3-Amino-1H-indazol-4-yl)phenyl-N'- cation No. 60/981,253, filed Oct. 19, 2007, and herein incor (2-fluoro-5-methylphenyl)urea Crystalline Form 1, when porated by reference in its entirety. measured at about 25° C. with radiation at 1.54178 A, is characterized by a powder diffraction pattern having respec FIELD OF THE INVENTION 10 tive 20 values of about 7.8, 9.1°, 11.0°, 11.8°, and 12.1; and This invention pertains to N-4-(3-Amino-1H-indazol-4- isolating the N-4-(3-Amino-1H-indazol-4-yl)phenyl-N'- yl)phenyl-N'-(2-fluoro-5-methylphenyl)urea Crystalline (2-fluoro-5-methylphenyl)urea Crystalline Form 1. Form 1, ways to make it, formulations comprising it and made Still another embodiment comprises N-4-(3-Amino-1H with it and methods of treating patients having disease using 15 indazol-4-yl)phenyl-N'-(2-fluoro-5-methylphenyl)urea it. Crystalline Form 1 prepared by the process of the preceding embodiment. Still another embodiment comprises ABT-869 Tolueneate BACKGROUND OF THE INVENTION for use in preparing N-4-(3-Amino-1H-indazol-4-yl)phe N-4-(3-Amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5- nyl-N'-(2-fluoro-5-methylphenyl)urea Crystalline Form 1. Still another embodiment comprises a salt of ABT-869 for methylphenyl)urea (ABT-869) belongs to a family of protein use in preparing N-4-(3-Amino-1H-indazol-4-yl)phenyl tyrosine kinases (PTKs) which catalyze the phosphorylation N'-(2-fluoro-5-methylphenyl)urea Crystalline Form 1. of specific tyrosine residues in cellular proteins. Aberrant or Still another embodiment comprises the hydrochloride salt excessive PTK activity has been observed in many disease 25 of ABT-869 for use in preparing N-4-(3-Amino-1H-indazol states including benign and malignant proliferative disorders 4-yl)phenyl-N'-(2-fluoro-5-methylphenyl)urea Crystalline and diseases resulting from inappropriate activation of the Form 1. immune system. Crystallinity of ABT-869 may effect, among other physical BRIEF DESCRIPTION OF THE FIGURES and mechanical properties, their stability, Solubility, dissolu 30 tion rate, hardness, compressibility and melting point. FIG. 1 is a powder X-ray diffraction pattern of N-4-(3- Because ease of manufacture and formulation of ABT-869 is amino-1H-indazol-4-yl)phenyl-N'-(2-fluoro-5-methylphe dependent on some, if not all, of these properties, there is an nyl)urea Crystalline Form 1. existing need in the chemical and therapeutic arts for identi fication of crystalline forms of ABT-869 and ways to repro 35 DETAILED DESCRIPTION OF THE INVENTION ducibly make them. This invention pertains to discovery of N-4-(3-amino-1H SUMMARY OF THE INVENTION indazol-4-yl)phenyl-N'-(2-fluoro-5-methylphenyl)urea Crystalline Form 1, ways to make it, ways to characterize it, 40 formulations containing it and made with it, and methods of One embodiment of this invention, therefore, pertains to treating cancer using it. The terms "N-4-(3-amino-1H-inda N-4-(3-Amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5- Zol-4-yl)phenyl)-N'-(2-fluoro-5-methylphenyl)urea” and methylphenyl)urea Crystalline Form 1 which, when mea “ABT-869 are meant to be used interchangeably. sured at about 25°C. with radiation at 1.54178 A, is charac The terms “ABT-869” and “an ABT-869” without any indi terized by a powder diffraction pattern having respective 20 45 cia of crystallinity or non-crystallinity associated with it, as values of about 7.8, 9.1°, 11.0°, 11.8°, and 12.1°. used herein, mean amorphous ABT-869, a crystalline ABT Another embodiment pertains to formulations comprising 869, microcrystalline ABT-869, ABT-869 in solution, a semi an excipient and N-4-(3-Amino-1H-indazol-4-yl)phenyl solid, wax or oil form of ABT-869, mixtures thereof and the N'-(2-fluoro-5-methylphenyl)urea Crystalline Form 1 which, like. when measured at about 25°C. with radiation at 1.54178 A. 50 The terms “crystalline and “microcrystalline,” as used is characterized by a powder diffraction pattern having herein, mean having a regularly repeating arrangement of respective 20 values of about 7.8°, 9.1°, 11.0°, 11.8°, and molecules which is maintained over a long range or external 12.1o. face planes. Still another embodiment pertains to methods of treating Unless stated otherwise, percentages herein are weight/ cancer in a mammal comprising administering thereto, with 55 weight (W/w) percentages. or without one or more than one additional anticancer drugs, The term “hydrochloride salt, as used herein, means hav a therapeutically effective amount of N-4-(3-Amino-1H-in ing associated therewith one or more than one hydrochloride dazol-4-yl)phenyl-N'-(2-fluoro-5-methylphenyl)urea Crys equivalent. talline Form 1 which, when measured at about 25°C. with The term “solvent, as used herein, means a liquid in which radiation at 1.54178 A, is characterized by a powder diffrac 60 a compound is soluble or partially soluble enough at a given tion pattern having respective 20 values of about 7.8, 9.1°. concentration to dissolve or partially dissolve the compound. 11.0°, 11.8°, and 12.1°. The term “anti-solvent, as used herein, means a liquid in Still another embodiment pertains to a process for making which a compound is insoluble enough at a given concentra N-4-(3-Amino-1H-indazol-4-yl)phenyl)-N'-(2-fluoro-5- tion to be effective for precipitating that compound from a methylphenyl)urea Crystalline Form 1 comprising: 65 Solution. making N-4-(3-amino-1H-indazol-4-yl)phenyl-N'-(2- Solvents and anti-solvents may be mixed with or without fluoro-5-methylphenyl)urea; separation of phases. US 7,960,564 B2 3 4 It is meant to be understood that, because many solvents ophthalmically or orally in liquid dosage forms include, for and anti-solvents contain impurities, the level of impurities in example, 1,3-butylene glycol, castor oil, corn oil, cottonseed solvents and anti-solvents for the practice of this invention, if oil, ethanol, fatty acid esters of Sorbitan, germ oil, groundnut present, are at a low enough concentration that they do not oil, glycerol, isopropanol, olive oil, polyethylene glycols, interfere with the intended use of the solvent in which they are propylene glycol, Sesame oil, water, mixtures thereof and the present. like. The term “acid, as used herein, means a compound having Excipients for preparation of formulations comprising or at least one acidic proton. Examples of acids for the practice made with ABT-869 Crystalline Form 1 to be administered of this invention include, but are not limited to, hydrochloric osmotically include, for example, chlorofluorohydrocarbons, acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic 10 ethanol, water, mixtures thereof and the like.
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