Specification
CRYSTALLINE CHEMOTHERAPEUTIC
FIELD OF THE INVENTION
This invention pertains to N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1, ways to make it, formulations comprising it and made with it and methods of treating patients having disease using it.
BACKGROUND OF THE INVENTION
N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea (ABT-869) belongs to a family of protein tyrosine kinases (PTKs) which catalyze the phosphorylation of specific tyrosine residues in cellular proteins. Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders and diseases resulting from inappropriate activation of the immune system.
Crystallinity of solvates of ABT-869 may effect, among other physical and mechanical properties, their stability, solubility, dissolution rate, hardness, compressibility and melting point. Because case of manufacture and formulation of ABT-869 is dependent on some, if not all, of these properties, there is an existing need in the chemical and therapeutic arts for identification of crystalline forms of ABT-869 and ways to reproducibly make them.
SUMMARY OF THE INVENTION
One embodiment of this invention, therefore, pertains to N-[4-(3-Amino-lH-indazol-4-yl)phcnyl]-N'-(2-fluoro-5-methylphcnyl)urea-¼ Ethanolate Crystalline Form 1 which, when measured at about -100°C in the triclinic crystal system and PI space group with radiation at 0.7107 Å, is characterized by respective lattice parameter values a, b and c of 8.971 Å ± 0.006Å, 11.646 Å + 0.008 Å and 19.26 Å ± 0.0lÅ and respective α, β and γ values of about 87.67° ± 0.1°, 90.21° + 0.1°, and 76.82° + 0.1°.
Another embodiment pertains to N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1 which, when measured at about 25°C with radiation at 1.54178 A, is characterized by a powder diffraction pattern having respective 29 values of about 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° and 18.4°.
Still another embodiment pertains to formulations comprising an excipient and N-[4-(3-Amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1 which, when measured at about -100°C in the triclinic crystal system and P1 space group with radiation at 0.7107 A, is characterized by respective lattice parameter values a, b and c of 8.971 A ± 0.006A, 11.646 Å + 0.008 A and 19.26 A ± 0.01 Å and respective α, β and γ values of about 87.67° ± 0.1°, 90.21° + 0.1°, and 76.82° ±0.1° or, when measured at about 25°C with radiation at 1.54178 A, characterized by a powder diffraction pattern having respective 28 values of about 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° and 18.4°.
Still another embodiment pertains to methods of treating cancer in a mammal comprising administering thereto, with or without one or more than one additional anticancer drugs, a therapeutically effective amount of N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea- lA Ethanolate Crystalline Form 1 which, when measured at about -100°C in the triclinic crystal system and PI space group with radiation at 0.7107 Å, is characterized by respective lattice parameter values a, b and c of 8.971Å ± 0.006Å, 11.646 Å ± 0.008 Å and 19.26 Å ± 0.0lÅ and respective α, β and γ values of about 87.67° ±0.1°, 90.21° ±0.1°, and 76.82° ±0.1° or, when measured at about 25°C with radiation at 1.54178 Å, characterized by a powder diffraction pattern having respective 29 values of about 4.5°, 7.7°, 11.7°, 12.2°, 14.6°, 16.9°, 17.7° and 18.4°.
Still another embodiment pertains to a process for making N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea1/4 Ethanolate Crystalline Form 1 comprising:
making N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea;
providing a mixture comprising N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea and a solvent comprising ethanol, wherein the N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea is completely dissolved in the solvent;
causing N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenytyurea ¼ Ethanolate Crystalline Form 1 to exist in the mixture, which N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼Ethanolate Crystalline Form 1, when isolated and measured at about -100°C in the triclinic crystal system and P1 space group with radiation at 0.7107 A, is characterized by respective lattice parameter values a, b and c of 8.971 A + 0.006A, 11.646 A ± 0.008 A and 19.26 A + 0.01 A and respective α, β and γ values of about 87.67° ±0.1°, 90.21° + 0.1°, and 76.82° +0.1°; and
isolating the N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼. Ethanolate Crystalline Form 1.
Still another embodiment comprises N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1 prepared by the process of the preceeding embodiment.
Still another embodiment pertains to a process for making N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1 comprising:
making N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea;
providing a mixture comprising N-[4-(3-amino-lH-indazol-4-yl)phcnyl]-N'-(2-fluoro-5-methylphenyl)urea and a solvent comprising ethyl acetate and ethanol, wherein the N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea is completely dissolved in the solvent;
causing N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1 to exist in the mixture by concentrating the mixture, with or without adding ethanol, which N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1, when isolated and measured at about -100°C in the triclinic crystal system and PI space group with radiation at 0.7107 A, is characterized by respective lattice parameter values a, b and c of 8.971 A + 0.006A, 11.646 A + 0.008 A and 19.26 A ± O.OlA and respective α, β and γ values of about 87.67° + 0.1°, 90.21° ±0.1°, and 76.82° +0.1°; and
isolating the N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1.
Still another embodiment comprises N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1 prepared by the process of the preceeding embodiment.
In a process for making N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼. Ethanolate Crystalline Form 1 comprising reacting an acid or diacid salt of N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea and a base and crystallization or recrystallization of N-[4-(3-Amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1, still another embodiment of this invention comprises crystallizing or recrystallizing the N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-V4 Ethanolate Crystalline Form 1 from a solid, semisolid, wax or oil form of N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea that is mixed with one or more than one solvent from the deprotonation reaction.
Still another embodiment comprises N-[4-(3-amino-l H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1 prepared by the process of the preceeding embodiment.
In a process for making N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1 comprising reacting a hydrochloride or dihydrochloride salt of N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea and dibasic sodium phosphate and crystallizing or recrystallizing the N-[4-(3-Amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea ¼ Ethanolate Crystalline Form 1, still another embodiment of this invention comprises crystallizing or recrystallizing the N-[4-(3-Amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea ¼ Ethanolate Crystalline Form 1 from a solid, semisolid, wax or oil form of N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea that is mixed with ethyl acetate from the deprotonation reaction.
Still another embodiment comprises N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea ¼ Ethanolate Crystalline Form 1 prepared by the process of the preceeding embodiment.
Still another embodiment comprises ABT-869 for use in preparing N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1.
Still another embodiment comprises a salt of ABT-869 for use in preparing N-[4-(3-amino-1 H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea- ¼ Ethanolate Crystalline Form 1.
Still another embodiment comprises the hydrochloride salt of ABT-869 for use in preparing N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea- ¼ Ethanolate Crystalline Form 1.
Still another embodiment comprises ABT-869H2O Crystalline Form 1 for use in preparing N-[4-(3-amino-l H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea' ¼ Ethanolate Crystalline Form 1.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is a powder x-ray diffraction pattern of N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1. DETAILED DESCRIPTION OF THE INVENTION
This invention pertains to discovery of N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea-¼ Ethanolate Crystalline Form 1, ways to make it, ways to characterize it, formulations containing it and made with it, and methods of treating cancer using it. The terms "N-[4-(3-amino-lH-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea" and "ABT-869" are meant to be used interchangeably.
The terms "ABT-869" and "an ABT-869" without any indicia of crystallinity or non-crystallinity associated with it, as used herein, mean amorphous ABT-869, a crystalline ABT-869, microcrystalline ABT-869, ABT-869 in solution, a semisolid, wax or oil form of ABT-869, mixtures thereof and the like.
The terms "crystalline" and "microcrystalline," as used herein, mean having a regularly repeating arrangement of molecules which is maintained over a long range or external face planes.
Unless stated otherwise, percentages herein are weight/weight (w/w) percentages.
The term "hydrochloride salt," as used herein, means having associated therewith one or more than one hydrochloride equivalent.
The term "solvent," as used herein, means a liquid in which a compound is soluble or partially soluble enough at a given concentration to dissolve or partially dissolve the compound.
The term "anti-solvent," as used herein, means a liquid in which a compound is insoluble enough at a given concentration to be effective for precipitating that compound from a solution.
Solvents and anti-solvents may be mixed with or without separation of phases.
It is meant to be understood that, because many solvents and anti-solvents contain impurities, the level of impurities in solvents and anti-solvents for the practice of this invention, if present, are at a low enough concentration that they do not interfere with the intended use of the solvent in which they are present.
The term "acid," as used herein, means a compound having at least one acidic proton. Examples of acids for the practice of this invention include, but are not limited to, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, trichloroacetic acid, sulfuric acid, phosphoric acid and the like.
The term "base," as used herein, means a compound capable of accepting a proton. Examples of bases for the practice of this invention include, but are not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, dibasic sodium phosphate (i.e. Na2HPO4, K2HPO4 and the like), triethylamine, diisopropylethylamine and the like.
Causing ABT-869 ¼ Ethanolate Crystalline Form 1 to exist in a mixture comprising ABT-869 and solvent, wherein the ABT-869 has completely dissolved, is known as nucleation.
For the practice of this invention, nucleation may be made to occur by means such as solvent removal, temperature change, solvent-miscible anti-solvent addition, solvent-immiscible anti-solvent addition, chafing or scratching the interior of the container, preferably a glass container, in which nucleation is meant to occur with an implement such as a glass rod or a glass bead or beads, or a combination of the foregoing.
For the practice of this invention, nucleation may be followed by crystal growth, accompanied by crystal growth, or followed and accompanied by crystal growth during which, and as a result of which, the percentage of ABT-869 ¼ Ethanolate Crystalline Form 1 increases.
The term "isolating" as used herein, means separating ABT-869 ¼ Ethanolate Crystalline Form 1 from solvent, anti-solvent, or a mixture of solvent anti-solvent. This is typically accomplished by means such as centrifugation, filtration with or without vacuum, filtration with positive pressure, distillation, evaporation or a combination thereof.
Therapeutically acceptable amounts of ABT-869 % Ethanolate Crystalline Form 1 depend on recipient of treatment, disorder being treated and severity thereof, composition containing it, time of administration, route of administration, duration of treatment, its potency, its rate of clearance and whether or not another drug is co-administered. The amount of ABT-869 ¼ Ethanolate Crystalline Form 1 used to make a formulation to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight. Single dose formulations contain these amounts or a combination of submultiples thereof.
ABT-869 ¼ Ethanolate Crystalline Form 1 may be administered with or without an excipient, typically with an excipient. Excipients include but are not limited to, for example, encapsulating materials and additives such as absorption accelerators, antioxidants, binders, buffers, carriers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, glidants, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
Excipients for preparation of formulations comprising or made with ABT-869 ¼ Ethanolate Crystalline Form 1 to be administered orally in solid dosage form include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution,
safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, mixtures thereof and the like.
Excipients for preparation of formulations comprising or made with ABT-869 ¼ Ethanolate Crystalline Form 1 to be administered ophthalmically or orally in liquid dosage forms include, for example, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like.
Excipients for preparation of formulations comprising or made with ABT-869 ¼ Ethanolate Crystalline Form 1 to be administered osmotically include, for example, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like.
Excipients for preparation of formulations comprising or made with ABT-869 ¼ Ethanolate Crystalline Form 1 to be administered parenterally include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like.
Excipients for preparation of formulations comprising or made with ABT-869 ¼ Ethanolate Crystalline Form 1 to be administered rectally or vaginally include, but arc not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.
In a specific example of a formulation made with ABT-869V4 Ethanolate Crystalline Form 1, carrier polymer (copovidone Type K 28), glidant (colloidal silicon dioxide) and ABT-869 ¼ Ethanolate Crystalline Form 1 were per-blended in a tumble blender. The resulting per-blend was sieved to destroy agglomerates. The sieved pre-blend was blended into a final blending step (with propylene glycol Type 1 and Vitamin E TPGS) and fed into an extruder. During extrusion, the powder blend was molten, and the surfactants (mannitol,
sodium stearyl fumarate and colloidal silicon dioxide) were pumped into the extruder by a liquid dosing system. The mixture was further conveyed along a twin-screw extruder to disperse the ABT-869 homogeneously in the polymer surface matrix. The extruder barrel and extruder speed were controlled. Near the end of the extruder, vacuum was applied for degassing of the melt. After cooling and solidification by calendering, extrudate granules were obtained.
ABT-869-% Ethanolate Crystalline Form 1 is also useful when administered with anticancer drugs such as alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, aurora kinase inhibitors, Bcr-Abl kinase inhibitors, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies, immunologicals, intercalating antibiotics, other kinase inhibitors, including other PTKs, mammalian target of rapamycin inhibitors, mitogen-activated extracellular signal-regulated kinase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), platinum chemotherapeutics, polo-like kinase inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoids/dcltoids plant alkaloids, topoisomcrasc inhibitors and the like.
Alkylating agents include altrctaminc, AMD-473, AP-5280, apaziquonc, bcndamustinc, brostallicin, busulfan, carboquonc, carmustinc (BCNU), chlorambucil, Cloretazine™ (VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, treosulfan, trofosfamide and the like.
Angiogenesis inhibitors include endothelial-specific receptor tyrosine kinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)
inhibitors, thrombospondin analogs vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and the like.
Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC® (imatinib) and the like.
CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and the like.
COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA® (valdecoxib), BMS347070, CELEBREX™ (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-l-(4-sulfamoylphenyl-lH-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX® (rofecoxib) and the like.
EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB (lapatinib) and the like.
ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib), HERCEPTIN® (trastuzumab), TYKERB (lapatinib), OMNITARG (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB®, NCS-683664, PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like.
MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like.
mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus and the like.
Non-steroidal anti-inflammatory drugs include AMIGESIC (salsalate), DOLOBID (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen), RELAFEN® (nabumetone),
FELDENE (piroxicam) ibuprofen cream, ALEVE and NAPROSYN (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LOD1NE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.
PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
Platinum chemotherapeutics include cisplatin, ELOXATIN (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN (carboplatin), satraplatin and the like.
Polo-like kinase inhibitors include BI-2536 and the like.
Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like.
VEGFR inhibitors include AVASTIN" (bevacizumab), ABT-869, AEE-788, ANGIOZYME™, axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, Macugen (pegaptamib), NEXAVAR* (sorafenib, BAY43-9006), pazopanib (GW-786034), (PTK-787,
ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, vatalanib, ZACTIMA™ (vandetanib, ZD-6474) and the like.
Antimetabolites include ALIMTA (pemetrexed disodium, LY231514, MTA), 5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT (cladribine), clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR, enocitabine, ethnylcytidine, fludarabine, hydroxyurea, 5-fluorouracil (5-FU) alone or in combination with leucovorin, GEMZAR (gemcitabine), hydroxyurea, ALKERAN (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, trimetrexate, S-l, tiazofurin, tegafur, TS-1, vidarabine, UFT and the like.
Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE (bleomycin), daunorubicin, CAELYX or MYOCET (doxorubicin), elsamitrucin, epirbucin, glarbuicin, ZAVEDOS (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR~ (valrubicin), zinostatin and the like.
Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR (irinotecan hydrochloride),
R)
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1711-DELNP-2010-Form-3-(30-08-2010).pdf |
2010-08-30 |
| 1 |
1711-DELNP-2010_EXAMREPORT.pdf |
2016-06-30 |
| 2 |
1711-DELNP-2010-Correspondence-Others-(30-08-2010).pdf |
2010-08-30 |
| 2 |
1711-delnp-2010-Pre-Grant-Opposition.pdf |
2015-02-25 |
| 3 |
1711-DELNP-2010-Correspondence-Others-(29-09-2010).pdf |
2010-09-29 |
| 3 |
1711-DELNP-2010-Assignment-(14-02-2014).pdf |
2014-02-14 |
| 4 |
1711-DELNP-2010-Correspondence Others-(14-02-2014).pdf |
2014-02-14 |
| 4 |
1711-DELNP-2010-Assignment-(29-09-2010).pdf |
2010-09-29 |
| 5 |
1711-DELNP-2010-Form-18-(30-03-2011).pdf |
2011-03-30 |
| 5 |
1711-delnp-2010-Assignment-(17-12-2013).pdf |
2013-12-17 |
| 6 |
1711-DELNP-2010-Correspondence Others-(30-03-2011).pdf |
2011-03-30 |
| 6 |
1711-delnp-2010-Correspondence Others-(17-12-2013).pdf |
2013-12-17 |
| 7 |
1711-delnp-2010-gpa.pdf |
2011-08-21 |
| 7 |
1711-delnp-2010-Form-2-(17-12-2013).pdf |
2013-12-17 |
| 8 |
1711-delnp-2010-GPA-(17-12-2013).pdf |
2013-12-17 |
| 8 |
1711-delnp-2010-form-5.pdf |
2011-08-21 |
| 9 |
1711-delnp-2010-form-3.pdf |
2011-08-21 |
| 9 |
Form-1-(17-12-2013).pdf |
2013-12-17 |
| 10 |
1711-delnp-2010-abstract.pdf |
2011-08-21 |
| 10 |
1711-delnp-2010-form-2.pdf |
2011-08-21 |
| 11 |
1711-delnp-2010-claims.pdf |
2011-08-21 |
| 11 |
1711-delnp-2010-form-1.pdf |
2011-08-21 |
| 12 |
1711-delnp-2010-correspondence-others.pdf |
2011-08-21 |
| 12 |
1711-delnp-2010-drawings.pdf |
2011-08-21 |
| 13 |
1711-delnp-2010-description (complete).pdf |
2011-08-21 |
| 14 |
1711-delnp-2010-correspondence-others.pdf |
2011-08-21 |
| 14 |
1711-delnp-2010-drawings.pdf |
2011-08-21 |
| 15 |
1711-delnp-2010-claims.pdf |
2011-08-21 |
| 15 |
1711-delnp-2010-form-1.pdf |
2011-08-21 |
| 16 |
1711-delnp-2010-abstract.pdf |
2011-08-21 |
| 16 |
1711-delnp-2010-form-2.pdf |
2011-08-21 |
| 17 |
1711-delnp-2010-form-3.pdf |
2011-08-21 |
| 17 |
Form-1-(17-12-2013).pdf |
2013-12-17 |
| 18 |
1711-delnp-2010-form-5.pdf |
2011-08-21 |
| 18 |
1711-delnp-2010-GPA-(17-12-2013).pdf |
2013-12-17 |
| 19 |
1711-delnp-2010-gpa.pdf |
2011-08-21 |
| 19 |
1711-delnp-2010-Form-2-(17-12-2013).pdf |
2013-12-17 |
| 20 |
1711-DELNP-2010-Correspondence Others-(30-03-2011).pdf |
2011-03-30 |
| 20 |
1711-delnp-2010-Correspondence Others-(17-12-2013).pdf |
2013-12-17 |
| 21 |
1711-delnp-2010-Assignment-(17-12-2013).pdf |
2013-12-17 |
| 22 |
1711-DELNP-2010-Correspondence Others-(14-02-2014).pdf |
2014-02-14 |
| 22 |
1711-DELNP-2010-Assignment-(29-09-2010).pdf |
2010-09-29 |
| 23 |
1711-DELNP-2010-Assignment-(14-02-2014).pdf |
2014-02-14 |
| 24 |
1711-delnp-2010-Pre-Grant-Opposition.pdf |
2015-02-25 |
| 24 |
1711-DELNP-2010-Correspondence-Others-(30-08-2010).pdf |
2010-08-30 |
| 25 |
1711-DELNP-2010_EXAMREPORT.pdf |
2016-06-30 |