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. acid, Sulfuric acid, phosphoric acid and the like. Excipients for preparation of formulations comprising or The term “base, as used herein, means a compound made with ABT-869 Crystalline Form 1 to be administered capable of accepting a proton. Examples of bases for the parenterally include, for example, 1,3-butanediol, castor oil, practice of this invention include, but are not limited to, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, Sodium carbonate, Sodium bicarbonate, potassium carbonate, 15 liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, potassium bicarbonate, dibasic sodium phosphate (i.e. safflower oil, sesame oil, soybean oil, U.S.P. or isotonic NaHPO, KHPO and the like), triethylamine, diisopropy sodium chloride solution, water, mixtures thereof and the lethylamine and the like. like. The term "isolating as used herein, means separating Excipients for preparation of formulations comprising or ABT-869 Crystalline Form 1 from solvent, anti-solvent, or a made with ABT-869 Crystalline Form 1 to be administered mixture of Solvent anti-solvent. This is typically accom rectally or vaginally include, but are not limited to, cocoa plished by means such as centrifugation, filtration with or butter, polyethylene glycol, wax, mixtures thereof and the without vacuum, filtration with positive pressure, distillation, like. evaporation or a combination thereof. ABT-869 Crystalline Form 1 is also useful when adminis Therapeutically acceptable amounts of ABT-869 Crystal 25 tered with anticancer drugs such as alkylating agents, angio line Form 1 depend on recipient of treatment, disorder being genesis inhibitors, antibodies, , antimitotics, treated and severity thereof, composition containing it, time antiproliferatives, aurora kinase inhibitors, Bcr-Abl kinase of administration, route of administration, duration of treat inhibitors, biologic response modifiers, cyclin-dependent ment, its potency, its rate of clearance and whether or not kinase inhibitors, inhibitors, cyclooxygenase-2 another drug is co-administered. The amount of ABT-869 30 inhibitors, leukemia viral oncogene homolog (ErbB2) recep Crystalline Form 1 used to make a formulation to be admin tor inhibitors, growth factor inhibitors, heat shock protein istered daily to a patient in a single dose or individed doses is (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, from about 0.03 to about 200 mg/kg body weight. Single dose hormonal therapies, immunologicals, intercalating antibiot formulations contain these amounts or a combination of Sub ics, other kinase inhibitors, including other PTKS, mamma multiples thereof. 35 lian target of rapamycin inhibitors, mitogen-activated extra ABT-869 Crystalline Form 1 may be administered with or cellular signal-regulated kinase inhibitors, non-steroidal anti without an excipient, typically with an excipient. Excipients inflammatory drugs (NSAIDs), platinum chemotherapeutics, include but are not limited to, for example, encapsulating polo-like kinase inhibitors, proteasome inhibitors, purine materials and additives such as absorption accelerators, anti analogs, pyrimidine analogs, receptor tyrosine kinase inhibi oxidants, binders, buffers, carriers, coating agents, coloring 40 tors, /deltoids plant alkaloids, topoisomerase inhibi agents, diluents, disintegrating agents, emulsifiers, extenders, tors and the like. fillers, flavoring agents, glidants, humectants, lubricants, per Alkylating agents include , AMD-473, fumes, preservatives, propellants, releasing agents, steriliz AP-5280, apaziquone, , brostallicin, , ing agents, Sweeteners, solubilizers, wetting agents, mixtures , (BCNU), , Clore thereof and the like. 45 tazineTM (VNP 401.01M), , decarbazine, Excipients for preparation of formulations comprising or estramustine, , , , made with ABT-869 Crystalline Form 1 to be administered KW-2170, (CCNU), , , orally in Solid dosage form include, for example, agar, alginic , mitolactol, , N-ox acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, ide, , , , , trofos 1,3-butylene glycol, carbomers, castor oil, cellulose, cellu 50 famide and the like. lose acetate, cocoa butter, copovidone, corn starch, corn oil, Angiogenesis inhibitors include endothelial-specific cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gela factor receptor (EGFR) inhibitors, insulin growth factor-2 tin, germ oil, glucose, glycerol, groundnut oil, hydroxypro receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 pylmethyl cellulose, isopropanol, isotonic saline, lactose, 55 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) magnesium hydroxide, magnesium Stearate, malt, , inhibitors, platelet-derived growth factor receptor (PDGFR) monoglycerides, olive oil, povidone, peanut oil, potassium inhibitors, thrombospondin analogs vascular endothelial phosphate salts, potato starch, povidone, propylene glycol, growth factor receptor tyrosine kinase (VEGFR) inhibitors Ringer's Solution, safflower oil, Sesame oil, silicon dioxide, and the like. Sodium carboxymethyl cellulose, sodium phosphate salts, 60 Aurora kinase inhibitors include AZD-1152, MLN-8054, Sodium lauryl Sulfate, Sodium Sorbitol, Sodium Stearylfuma VX-680 and the like. rate, soybean oil, Stearic acids, Stearyl fumarate. Sucrose, Bcr-Abl kinase inhibitors include DASATINIB(R) (BMS Surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, trig 354825), GLEEVECR) (imatinib) and the like. lycerides, vitamin E and derivatives thereof, water, mixtures CDK inhibitors include AZD-5438, BMI-1040, BMS-032, thereof and the like. 65 BMS-387, CVT 2584, flavopyridol, GPC-286199, MCS-5A, Excipients for preparation of formulations comprising or PD0332991, PHA-690509, (CYC-202, R-rosco made with ABT-869 Crystalline Form 1 to be administered vitine), ZK-304709 and the like. US 7,960,564 B2 5 6 COX-2 inhibitors include ABT-963, ARCOXIAR (etori nolatrexed, ocfosfate, pelitrexol, , , Rib coxib), BEXTRAR (valdecoxib), BMS347070, CELE avirin, triapine, trimetrexate, S-1, , , TS-1, BREXTM (), COX-189 (lumiracoxib), CT-3, Vidarabine, UFT and the like. DERAMAXX(R) (deracoxib), JTE-522, 4-methyl-2-(3,4- Antibiotics include intercalating antibiotics , dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), actinomycin D, , annamycin, adriamycin, BLE MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, NOXANER) (), , CAELYX(R) or SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXXOR) MYOCETR) (), , epirbucin, glarbui (rofecoxib) and the like. cin, ZAVEDOS(R) (), , memorubicin, EGFR inhibitors include ABX-EGF, anti-EGFR immuno neocarzinostatin, peplomycin, , rebeccamycin, liposomes, EGF-vaccine, EMD-7200, ERBITUX(R) (cetux 10 stimalamer, streptozocin, VALSTARR) (), Zinosta imab), HR3, IgA antibodies, IRESSAR) (gefitinib), tin and the like. TARCEVAR) (erlotinib or OSI-774), TP-38, EGFR fusion Topoisomerase inhibitors include aclarubicin, 9-ami protein, TYKERB(R) (lapatinib) and the like. nocamptothecin, amonafide, , becatecarin, belote ErbB2 receptor inhibitors include CP-724-714, CI-1033 15 can, BN-80915, CAMPTOSAR(R) ( hydrochlo (canertinib), HERCEPTINR) (trastuzumab), TYKERB(R) (la ride), , CARDIOXANER) (dexrazoxine), patinib), OMNITARG(R) (2C4, petuzumab), TAK-165, diflomotecan, edotecarin, ELLENCE(R) or PHARMORUBI GW-572016 (ionafamib), GW-282974, EKB-569, PI-166, CINR (), , , 10-hydroxycamp dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti tothecin, gimatecan, , , orathecin, HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 tri pirarubicin, , , sobuzoxane, SN-38, taf functional bispecific antibodies, maB AR-209, maB 2B-1 luposide, and the like. and the like. Antibodies include AVASTIN (bevacizumab), CD40-spe Histone deacetylase inhibitors include depsipeptide, LAQ cific antibodies, chTNT-1/B, denosumab, ERBITUX(R) 824, MS-275, trapoxin, suberoylanilide hydroxamic acid (cetuximab), HUMAX-CD4 (Zanolimumab), IGF1R-spe (SAHA), TSA, valproic acid and the like. 25 cific antibodies, lintuzumab, PANOREXR (edrecolomab), HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF RENCAREXR (WXG250), RITUXANR) (rituximab), ticili 101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI mumab, trastuzimab and the like. 504, KOS-953, MYCOGRABR), NCS-683664, PU24FC1, Hormonal therapies include ARIMIDEXOR (anastrozole), PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the AROMASINR) (exemestane), arzoxifene, CASODEX(R) (bi like. 30 calutamide), CETROTIDE(R) (cetrorelix), degarelix, deslore MEK inhibitors include ARRY-142886, ARRY-438.162 lin, DESOPANR) (trilostane), dexamethasone, DROGE PD-325901, PD-98.059 and the like. NIL(R), (flutamide), EVISTAR (raloxifene), fadrozole, mTOR inhibitors include AP-23573, CCI-779, everolimus, FARESTONR) (toremifene), FASLODEX(R) (fulvestrant), RAD-001, rapamycin, temsirolimus and the like. FEMARAR), (letrozole), formestane, glucocorticoids, HEC Non-steroidal anti-inflammatory drugs include AMIGE 35 TOROL(R) or RENAGEL(R) (doxercalciferol), lasofoxifene, SICR (salsalate), DOLOBIDR) (diflunisal), MOTRINR) (ibu leuprolide acetate, MEGACE(R) (megesterol), MIFEPREX(R) profen), ORUDIS(R) (ketoprofen), RELAFENR) (nabume (mifepristone), NILANDRONTM (nilutamide), NOLVA tone), FELDENE(R) (piroxicam) ibuprofen cream, ALEVER) DEX(R) (tamoxifen citrate), PLENAXISTM (abarelix), pred and NAPROSYNR) (naproxen), VOLTARENR) (diclofenac), nisone, PROPECIAR (finasteride), rillostane, SUPREF INDOCINR) (indomethacin), CLINORIL(R) (sulindac), 40 ACTR) (buserelin), TRELSTAR(R) (luteinizing hormone TOLECTINR) (tolimetin), LODINE(R) (etodolac), TORA releasing hormone (LHRH)), VANTAS(R) (histrelin implant), DOL(R) (ketorolac), DAYPROR (oxaprozin) and the like. VETORYL(R), (trilostane or modrastane), ZOLADEX(R) (fos PDGFR inhibitors include C-451, CP-673, CP-868596 and relin, goserelin) and the like. the like. Deltoids and retinoids include seocalcitol (EB1089, Platinum chemotherapeutics include , ELOXA 45 CB1093), lexacalcitrol (KH1060), fenretinide, PANRETINR) TINR () eptaplatin, lobaplatin, , PARA (aliretinoin), ATRAGENR) (liposomal ), TARGRE PLATINR) (), and the like. TINR) (), LGD-1550 and the like. Polo-like kinase inhibitors include BI-2536 and the like. Plant alkaloids include, but are not limited to, , Thrombospondin analogs include ABT-510, ABT-567, , , and the like. ABT-898, TSP-1 and the like. 50 Proteasome inhibitors include VELCADE(R) (), VEGFR inhibitors include AVASTIN (bevacizumab), MG132, NPI-0052, PR-171 and the like. ABT-869, AEE-788, ANGIOZYMETM, axitinib (AG-13736), Examples of immunologicals include interferons and other AZD-2171, CP-547,632, IM-862, Macugen (pegaptamib), immune-enhancing agents. Interferons include interferon NEXAVAR(R) (sorafenib, BAY43-9006), pazopanib (GW alpha, interferon alpha-2a, interferon alpha-2b, interferon 786034), (PTK-787, ZK-222584), SUTENTR) (sunitinib, 55 beta, interferon gamma-1a, ACTIMMUNER) (interferon SU-11248), VEGF trap, , ZACTIMATM (vandet gamma-1b), or interferon gamma-nl, combinations thereof anib, ZD-6474) and the like. and the like. Other agents include ALFAFERONE(R), BAM Antimetabolites include ALIMTAR) ( diso 002, BEROMUNR) (tasonermin), BEXXARR) (to situmo dium, LY231514, MTA), 5-, XELODAR (capecit mab), CamPath (alemtuzumab), CTLA4 (cytotoxic lympho abine), , LEUSTATR) (), , cyt 60 cyte antigen 4), decarbazine, denileukin, epratuZumab, arabine, ocfosfate, cytosine arabinoside, GRANOCYTER (lenograstim), lentinan, leukocyte alpha , deferoxamine, , eflornithine, interferon, imiquimod, MDX-010, melanoma vaccine, mitu EICAR, enocitabine, ethnylcytidine, , hydrox momab, molgramostim, MYLOTARGTM (gemtuzumab ozo yurea, 5- (5-FU) alone or in combination with gamicin), NEUPOGENR (filgrastim), OncoVAC-CL, leucovorin, GEMZAR(R) (), hydroxyurea, 65 OvaRexR (oregovomab), pemtumomab (Y-muHMFG1), ALKERANR) (melphalan), , 6-mercaptopu PROVENGER), sargaramostim, sizofilan, teceleukin, Thera rine riboside, , mycophenolic acid, , Cys(R), ubenimex, VIRULIZINR), Z-100, WF-10, PROLEU US 7,960,564 B2 7 8 KINR) (aldesleukin), ZADAXINR) (thymalfasin), ZENA REVLIMIDR (lenalidomide), RSR13 (), PAX(R) (daclizumab), ZEVALINR) (90Y-Ibritumomab SOMATULINE(R) LA (lanreotide), SORIATANE(R) (acitre tiuxetan) and the like. tin), staurosporine (Streptomyces staurospores), tallabostat Biological response modifiers are agents that modify (PT100), TARGRETINR) (bexarotene), Taxoprexin(R) (DHA defense mechanisms of living organisms or biological ), TELCYTATM (TLK286), temilifene, TEMO responses. Such as Survival, growth, or differentiation of tis DAR(R) (temozolomide), tesmilifene, thalidomide, THER sue cells to direct them to have anti-tumor activity and include ATOPER (STn-KLH), thymitaq (2-amino-3,4-dihydro-6- krestin, lentinan, sizofuran, picibanil PF-3512676 (CpG methyl-4-oxo-5-(4-pyridylthio)cquinazoline 8954), ubenimex and the like. dihydrochloride), TNFeradeTM (adenovector: DNA carrier Pyrimidine analogs include cytarabine (ara C or Arabino 10 containing the gene for tumor necrosis factor-C), TRA side C), cytosine arabinoside, doxifluridine, FLUDARAR CLEER(R) or ZAVESCAR (bosentan), tretinoin (Retin-A), (fludarabine), 5-FU (5-fluorouracil), , tetrandrine, TRISENOX(R) (), VIRULIZINR, GEMZAR(R) (gemcitabine), TOMUDEX(R) (ratitrexed), ukrain (derivative of alkaloids from the greater celandine TROXATYLTM (triacetyluridine troxacitabine) and the like. plant), vitaxin (anti-alphavbeta3 antibody), XCYTRINR) Purine analogs include LANVISR) (thioguanine) and 15 (motexafin gadolinium), XINLAYTM (), XYO PURI-NETHOLR(mercaptopurine). TAXTM (paclitaxel, poliglumex), YONDELISTM (trabect Antimitotic agents includebatabulin, D (KOS edin), ZD-6126, ZINECARDR (dexrazoxane), Zometa (Zo 862), N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-meth lendronic acid), and the like. oxybenzenesulfonamide, (BMS 247550), pacli It is also expected that ABT-869 Crystalline Form 1 would taxel, TAXOTERE(R) (), PNU100940 (109881), inhibit growth of cells derived from a pediatric cancer or patupilone, XRP-9881, , ZK-EPO and the like. neoplasm including embryonal rhabdomyosarcoma, pediat Compounds of the present invention are also intended to be ric acute lymphoblastic leukemia, pediatric acute myelog used as a radiosensitizer that enhances the efficacy of radio enous leukemia, pediatric alveolar rhabdomyosarcoma, pedi therapy. Examples of radiotherapy include, but are not limited atric anaplastic ependymoma, pediatric anaplastic large cell to, external beam radiotherapy, teletherapy, brachytherapy 25 lymphoma, pediatric anaplastic medulloblastoma, pediatric and sealed and unsealed source radiotherapy. atypical teratoid/rhabdoid tumor of the central nervous sys Additionally, ABT-869 Crystalline Form 1 may be com tem, pediatric biphenotypic acute leukemia, pediatric Bur bined with other chemotherapeutic agents such as ABRAX kitts lymphoma, pediatric cancers of Ewing's family of ANETM (ABI-007), ABT-100 (farnesyltransferase inhibitor), tumors such as primitive neuroectodermal rumors, pediatric ADVEXINR, ALTOCORR) or MEVACORR (lovastatin), 30 diffuse anaplastic Wilm's tumor, pediatric favorable histol AMPLIGENR (poly I: poly C12U, a synthetic RNA), APTO ogy Wilm's tumor, pediatric glioblastoma, pediatric medullo SYNTM (), AREDIAR (pamidronic acid), arglabin, blastoma, pediatric neuroblastoma, pediatric neuroblastoma L-, atamestane (1-methyl-3,17-dione-androsta derived myelocytomatosis, pediatric pre-B-cell cancers (such 1,4-diene), AVAGE(R) (tazarotene), AVE-8062, BEC2 (mitu as leukemia), pediatric psteosarcoma, pediatric rhabdoid kid momab), cachectin or cachexin (tumor necrosis factor), can 35 ney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell vaxin (vaccine), CeaVacTM (cancer vaccine), CELEUKOR) cancers such as lymphoma and skin cancer and the like. (celmoleukin), CEPLENER) (histamine dihydrochloride), Preparation of ABT-869 and its utility as a PTK inhibitoris CERVARIXTM (human papillomavirus vaccine), CHOPR (C: described in commonly-owned U.S. Pat. No. 7.297,709. CYTOXANR) (cyclophosphamide); H: ADRIAMYCINR) The following examples are presented to provide what is (hydroxydoxorubicin); O: Vincristine (ONCOVINR); P: 40 believed to be the most useful and readily understood descrip prednisone), CyPatTM, combrestatin A4P, DAB(389)EGF or tion of procedures and conceptual aspects of this invention. TransMID-107RTM (diphtheria toxins), , dactino mycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), EXAMPLE 1. eniluracil, EVIZONTM (squalamine lactate), DIMERI CINE(R) (T4N5 liposome lotion), discodermolide, DX-8951f 45 Preparation of ABT-869 Tolueneate Crystalline Form (exatecan mesylate), enzastaurin, EPO906, GARDASILR (quadrivalent human papillomavirus (Types 6, 11, 16, 18) This example was prepared by recrystallizing ABT-869 recombinant vaccine), GASTRIMMUNETM (gastrin-dipith from toluene at about 110° C. and filtering. eria conjugate), GENASENSETM ( sodium), GMK (ganglioside conjugate vaccine), GVAX(R) (prostate 50 EXAMPLE 2 cancer vaccine), halofuginone, histerelin, hydroxycarbam ide, ibandronic acid, IGN-101, IL-13-PE38, IL-13 Preparation of ABT-869 Crystalline Form 1 PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon-C, interferon-Y, JUNOVANTM or A mixture of EXAMPLE 1 and acetonitrile was stirred at MEPACTTM (mi?amurtide), lonafamib, 5,10-methylenetet 55 reflux until ABT-869 Crystalline Form 1 formed, and was rahydrofolate, miltefosine (hexadecylphosphocholine), then cooled and filtered. NEOVASTATR (AE-941), NEUTREXINR (trimetrexate Powder X-ray diffraction was performed using an XDS glucuronate), NIPENTR) (pentostatin), ONCONASE(R) (a 2000/X-ray diffractometer equipped with a 2 kW normal ribonuclease enzyme), ONCOPHAGER) (melanoma vaccine focus X-ray tube and a Peltier cooled germanium solid-state treatment). OncoVAX (IL-2 Vaccine), ORATHECINTM (ru 60 detector (Scintag Inc., Sunnyvale, Calif.). The data were pro bitecan), OSIDEMR (antibody-based cell drug), OvaRexR) cessed using DMSNT software (version 1.37). The X-ray MAb (murine monoclonal antibody), paclitaxel, PAN source was a copper filament (Cu-KC, at 1.54178 A) oper DIMEXTM (aglycone saponins from ginseng comprising ated at 45 kV and 40 mA. The alignment of the goniometer 20OS)protopanaxadiol (aPPD) and 20(S)protopanaxatriol was checked daily using a Corundum standard. The sample (aPPT)), panitumumab, PANVAC(R)-VF (investigational can 65 was placed in a thin layer (with no prior grinding) onto a Zero cer vaccine), , PEG Interferon A, phenoXodiol. background plate and continuously scanned at a rate of 220 , rebimastat, REMOVAB(R) (catumaxomab), per minute over a range of 2°–40° 20. US 7,960,564 B2 10 FIG. 1 is a powder X-ray diffraction pattern for the crystal a peak from one pattern is determined to have a position of line form 1, showing the respective 2 theta values. 11.0°, for comparison purposes the allowable variability It is meant to be understood that relative intensities of peak allows the peak to be assigned a position in the range of heights in a PXRD pattern may vary and will be dependent on 10.9.0-11.19. variables such as the temperature, size of crystal size or mor Accordingly, for example, the phrase “about 7.8, 9.1°. phology, sample preparation, or sample height in the analysis 11.0°, 11.8°, and 12.1°, as used herein, means about 7.8°, well of the X-ray diffractometer. about 9.1°, about 11.0°, about 11.8°, and about 12.1°, which, It is also meant to be understood that peak positions may in turn, means 7.8°+0.1°, 9.1+0.1°, 11.0+0.1°, 11.8°+0.1°, vary when measured with different radiation sources. For and 12.1-0.1°. 10 The term “about preceding a temperature means the given example, Cu-KC, Mo—KC. Co-KC, and Fe—KC. radia temperature +2° C. For example, about 25° C. means 25° tion, having wavelengths of 1.54060 A, 0.7107 A, 1.7902 A C29 C. Or 23 C-279 C. and 1.9373 A, respectively, may provide peak positions The foregoing is meant to be illustrative of the invention which differ from those measured with Cu—KO. radiation, and not intended to limit it to the disclosed embodiments. which has a wavelength of 1.5478 A. 15 Variations and changes obvious to one skilled in the art are The term “about preceding a series of peak positions intended to be within the scope and nature of the invention as means that all of the peaks of the group which it precedes are defined in the claims. reported in terms of angular positions (two theta) with an We claim: allowable variability of +0.1° as specified by the U.S. Phar 1. N-4-(3-Amino-1H-indazol-4-yl)phenyl-N'-(2-fluoro macopeia, pages 1843-1884 (1995). The variability of +0.1 5-methylphenyl)urea Crystalline Form 1 which, when mea is intended to be used when comparing two powder X-ray sured at about 25° C. with radiation at a wavelength of diffraction patterns. In practice, if a diffraction pattern peak 1.54178 A, is characterized by a powder diffraction pattern from one pattern is assigned a range of angular positions (two having respective 20 values of about 7.8°, 9.1°, 11.0°, 11.8°, theta) which is the measured peak position +0.1° and if those and 12.1°. ranges of peak positions overlap, then the two peaks are considered to have the same angular position. For example, if