WO2011071821A1 - Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof. - Google Patents

Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof. Download PDF

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WO2011071821A1
WO2011071821A1 PCT/US2010/059108 US2010059108W WO2011071821A1 WO 2011071821 A1 WO2011071821 A1 WO 2011071821A1 US 2010059108 W US2010059108 W US 2010059108W WO 2011071821 A1 WO2011071821 A1 WO 2011071821A1
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crystalline
peaks
diffraction pattern
powder diffraction
ray powder
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PCT/US2010/059108
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English (en)
French (fr)
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Joerg Berghausen
Prasad Koteswara Kapa
Joseph Mckenna
Joel Slade
Raeann Wu
Zhengming Du
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Novartis Ag
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Priority to NZ600070A priority Critical patent/NZ600070A/en
Priority to DK10788479.3T priority patent/DK2509963T3/en
Priority to SI201031119A priority patent/SI2509963T1/sl
Priority to BR112012013784-0A priority patent/BR112012013784B1/pt
Priority to KR1020127017618A priority patent/KR101787784B1/ko
Priority to CN2010800550783A priority patent/CN102639510A/zh
Priority to JP2012543183A priority patent/JP5714024B2/ja
Priority to MX2012006562A priority patent/MX2012006562A/es
Priority to CA2781431A priority patent/CA2781431C/en
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to RU2012128351/04A priority patent/RU2572848C2/ru
Priority to ES10788479.3T priority patent/ES2562462T3/es
Priority to PL10788479T priority patent/PL2509963T3/pl
Priority to PH12014502593A priority patent/PH12014502593A1/en
Priority to EP10788479.3A priority patent/EP2509963B1/en
Priority to US13/514,308 priority patent/US9067896B2/en
Priority to AU2010328391A priority patent/AU2010328391B2/en
Publication of WO2011071821A1 publication Critical patent/WO2011071821A1/en
Priority to ZA2012/03612A priority patent/ZA201203612B/en
Priority to IL220012A priority patent/IL220012B/en
Priority to TNP2012000263A priority patent/TN2012000263A1/en
Priority to MA35005A priority patent/MA33849B1/fr
Priority to HK12111776.3A priority patent/HK1171016A1/zh
Priority to HRP20160126T priority patent/HRP20160126T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present technology relates to anhydrous polymorphs, hydrated polymorphs and amorphous forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-l- ⁇ 6-[4-(4-ethyl-piperazin-l-yl)- phenylamino]-pyrimidin-4-yl ⁇ -l -methyl-urea, its salts, methods for preparing them, compositions containing them, and methods of treatment employing them.
  • the compound of Formula I is a protein kinase inhibitor and is useful in the treatment of proliferative diseases mediated by protein kinases.
  • the compound of Formula I inhibits FGFR1, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret kinases. It is therefore useful in the treatment of cancers including AML, melanocyte neoplasia, breast cancer, colon cancer, lung cancer (especially small-cell lung cancer), cancer of the prostate or Kaposi's sarcoma.
  • the crystalline form of the active pharmaceutical ingredient (API) of a particular drug is often an important determinant of the drug's ease of preparation, hygroscopicity, stability, solubility, storage stability, ease of formulation, rate of dissolution in gastrointestinal fluids and in vivo bioavailability. Crystalline forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular crystalline form.
  • Crystalline forms may also include different hydrates or solvates of the same compound.
  • the numerous properties of the forms are compared and the preferred form chosen based on the many physical property variables. It is entirely possible that one form can be preferable in some circumstances where certain aspects such as ease of preparation, stability, etc. are deemed to be critical. In other situations, a different form may be preferred for greater dissolution rate and/or superior bioavailability. It is not yet possible to predict whether a particular compound or salt of a compound will form polymorphs, whether any such polymorphs will be suitable for commercial use in a therapeutic composition, or which polymorphs will display such desirable properties.
  • crystal and amorphous forms of the compound of Formula I compositions including the crystal and amorphous forms, and methods of preparing the crystal and amorphous forms and compositions.
  • the present technology further provides methods of using the crystal or amorphous forms of compounds of Formula I and compositions thereof to treat various diseases, including but not limited to, those that can be prevented, inhibited or ameliorated by inhibition of kinase activity selected from FGFR1, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret kinases.
  • Figures 1A-E XRPD of free base (Figure 1A) of the compound of Formula I and its phosphate salts: form A ( Figure IB); and form B ( Figure 1C), the free base monohydrate (Figure ID), and the hydrochloride dihydrate ( Figure IE).
  • FIGs 2A and 2B DSC thermograms for the compound of Formula I as the anhydrous free base ( Figure 2A and as the phosphate salt (form A, Figure 2B).
  • Figures 3 A - 3C TGA thermograms for the compound of Formula I as the anhydrous free base ( Figure 3A), as the phosphate salt (form A, Figure 3B), and as the hydrochloride salt (dihydrate, Figure 3C).
  • Figures 4A-4C Sorption-desorption isotherms for the compound of Formula I as the anhydrous free base ( Figure 4A), as the phosphate salt (form A, Figure 4B) and as the monohydrate free base (Figure 4C) collected by DVS at 25°C.
  • Figures 5A and 5B SEM micrographs of the compound of Formula I as the crystalline free base ( Figure 5A) and as the phosphate salt (form A, Figure 5B).
  • Figure 8 A and 8B Raman spectra of the compound of Formula I as the anhydrous free base (Figure 8A) and as the monohydrate of the free base ( Figure 8B).
  • the present technology provides anhydrous and hydrated crystalline forms of the compound of Formula I (the free base):
  • the present technology provides an anhydrous crystalline form of the free base having an X-ray powder diffraction pattern comprising a characteristic peak, in terms of 2 ⁇ , at about 12°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 10.5°, about 15.2°, about 19.5°, and about 21.0°.
  • the X-ray powder diffraction pattern for an anhydrous form of the free base may comprise one, two, three, four, or five characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 10.5°, about 12.0°, about 15.2°, about 19.5°, and about 21.0°.
  • the X-ray powder diffraction pattern may further include one, two or three additional characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 11.9°, about 21.3°, and about 22.6°.
  • the anhydrous crystalline form of the free base has an X-ray powder diffraction pattern substantially as shown in Figure 1 A.
  • the terms "about” and “substantially” indicate, with respect to values of 2 ⁇ , that such values for individual peaks can vary by ⁇ 0.4°. In some embodiments, the values of 2 ⁇ for individual peaks can vary by ⁇ 0.2°.
  • the anhydrous crystalline form of the free base may be characterized thermally.
  • the anhydrous crystalline form of the free base has a differential scanning calorimetry (DSC) thermogram showing an onset of an endotherm at about 217° C.
  • the anhydrous crystalline form of the free base has a differential scanning calorimetry thermogram substantially as shown in Figure 2A.
  • the terms "about” and “substantially” indicate with respect to features such as endotherms, exotherms, baseline shifts, etc., that their values can vary ⁇ 2° C.
  • variation in the temperatures observed will depend upon the rate of temperature change as well as sample preparation technique and the particular instrument employed. Thus, the values reported herein relating to DSC thermograms can vary ⁇ 4° C.
  • the anhydrous crystalline form of the free base may also be characterized by Raman spectroscopy.
  • the anhydrous crystalline form of the free base exhibits characteristic Raman peaks at about 2950, about 1619, about 1539, about 1297, about 1233, about 1191, and about 998 cm “1 .
  • the anhydrous crystalline form of the free base exhibits one or more further characteristic Raman peaks at about 3067, about 2927, about 2828, about 1690, about 1585, about 1458, about 1385, about 1358, about 1098, about 1062, about 819, about 778, about 695, about 668, about 637, about 498, about 468, and about 420 cm "1 .
  • the anhydrous crystalline form of the free base has a Raman spectrum substantially as shown in Figure 8 A.
  • the terms “about” and “substantially” indicate, with respect to wave number values, that such values for individual peaks can vary by ⁇ 2 cm "1 .
  • the present technology provides a crystalline monohydrate of the free base having an X-ray powder diffraction pattern comprising a characteristic peak, in terms of 2 ⁇ , at about 20.3°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 21.2° and 19°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 4.7°, about 9.4°, and about 11.0°.
  • the X-ray powder diffraction pattern for a monohydrate form of the free base may comprise one, two, three, four, five, or six characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 4.7°, about 9.4°, about 1 1.0°, about 18.8°, about 20.3°, and about 21.2°.
  • the X-ray powder diffraction pattern for a monohydrate form of the free base may additionally include one, two, three, four, five, six or seven characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 11.8°, about 15.3°, about 16.2°, about 19.1°, about 22.3°, about 22.8°, and about 25.3°.
  • the crystalline monohydrate form of the free base has an X-ray powder diffraction pattern substantially as shown in Figure ID.
  • the crystalline monohydrate form of the free base may be characterized thermally.
  • the crystalline monohydrate form of the free base has a DSC
  • thermogram showing an onset of an endotherm at about 211° C.
  • the crystalline monohydrate form of the free base has a DSC thermogram and/or a TGA thermogram substantially as shown in Figure 7.
  • the monohydrate crystalline form of the free base may also be characterized by Raman spectroscopy.
  • the anhydrous crystalline form of the free base exhibits characteristic Raman peaks at about 2957, about 2831, about 1618, about 1511, about 1465, about 1361, about 1229, about 1186, and about 994 cm “1 .
  • the anhydrous crystalline form of the free base exhibits further characteristic Raman peaks at about 1580, about 1415, about 1312, about 1284, about 1184, about 1057, about 854, about 721, about 661, and about 624 cm “1 .
  • the monohydrate crystalline form of the free base has a Raman spectrum substantially as shown in Figure 8B.
  • the present technology provides an anhydrous crystalline monophosphoric acid salt (or phosphate) of the compound of Formula I:
  • the anhydrous crystalline monophosphoric acid salt is of form A which has an X-ray powder diffraction pattern comprising a characteristic peak, in terms of 2 ⁇ , at about 15°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 13.7°, about 16.8°, about 21.3° and about 22.4°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2°.
  • the anhydrous crystalline form (form A) of a monophosphoric acid salt (or the phosphate salt) of the compound of Formula I has an X-ray powder diffraction pattern comprising at least three characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 13.7°, about 15°, about 16.8°, about 21.3° and about 22.4°.
  • the X-ray powder diffraction pattern for form A of the phosphate salt may comprise one, two, three, four, five, six, seven, eight, nine, ten or eleven characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 9.2°, about 9.6°, about 13.7°, about 15°, about 16.8°, about 18.7°, about 20.0°, about 21.3° and about 22.4°, about 22.9°, and about 27.2°.
  • the anhydrous crystalline form (form A) of the phosphate salt has an X- ray powder diffraction pattern substantially as shown in Figure IB.
  • the anhydrous crystalline form of the phosphate salt (form A) may be characterized thermally.
  • the anhydrous crystalline form of the phosphate salt (form A) has a differential scanning calorimetry thermogram showing an onset of an endotherm at about 184°C.
  • the anhydrous crystalline form of the phosphate salt (form A) has a differential scanning calorimetry thermogram substantially as shown in Figure 2B.
  • the present technology provides an anhydrous crystalline monophosphoric acid salt of form B which has an X-ray powder diffraction pattern comprising one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 9.3°, about 12.5°, about 13.4°, about 15.8°, and about 17°.
  • the form B of the phosphate salt has an X-ray powder diffraction pattern substantially as shown in Figure 1C.
  • the present technology provides the amorphous form of the monophosphoric acid salt of the compound of Formula I:
  • the present technology provides the hydrochloric acid salt (or the hydrochloride) of the compound of Formula I:
  • the hydrochloride salt is the crystalline dihydrate.
  • the dihydrate may have an X-ray powder diffraction pattern comprising one or more
  • the hydrochloride salt has an X-ray powder diffraction pattern substantially as shown in Figure IE.
  • Figure IE X-ray powder diffraction pattern
  • the present technology provides a method of making the anhydrous crystalline form of the phosphate salt of form A, comprising contacting a suspension of a compound of Formula I (the free base):
  • the suspension of the compound of Formula I comprises isopropanol.
  • the method further comprises crystallizing the anhydrous crystalline form of the phosphate salt of form A from the suspension.
  • the method further comprises isolating the crystallized anhydrous crystalline form A.
  • the phosphoric acid contacted is present in an amount from about 1 equivalent to about 10 equivalents, from about 2 equivalents to about 9 equivalents, from about 3 equivalents to about 8 equivalents, or from about 4 equivalents to about 7 equivalents, with respect to the molar amount of the free base contacted. In other embodiments, the phosphoric acid contacted is present in an amount from about 2 equivalents to about 4 equivalents or at about 3 equivalents with respect to the molar amount of the free base contacted. In certain embodiments, the suspension of the free base and the phosphoric acid are reacted or contacted from about 2 h to about 40 h, from about 4 h to about 20 h, or from about 8 h to about 10 h.
  • the free base and the phosphoric acid are reacted at a temperature in the range of about 25° C to about 100° C, about 40° C to about 85° C, or about 55° C to about 70° C. In certain embodiments, the free base and the phosphoric acid are reacted at a temperature at which a solvent employed in the reaction refluxes. In certain embodiments, the reaction is performed using reactants and one or more solvents that are substantially free of water (i.e., almost completely free of water).
  • the anhydrous crystalline form of the phosphate salt of form A obtained by the methods of the present technology may be further subjected to steps such as, e.g., drying, purification, etc.
  • the isolated crystals may be subjected to drying at a suitable temperature.
  • the crystals are dried at a temperature in the range of about 20° C to about 80° C.
  • the crystals are dried at a temperature in the range of about 30° C to about 70° C.
  • the crystals are dried at a temperature in the range of about 40° C to about 60° C.
  • the crystals are dried under reduced pressure in the range, for example, of about 10 mbar - about 40 mbar.
  • the drying step may be conducted for a suitable period of time.
  • the crystals are dried for a period of about 1 to about 72 hours, from about 2 to about 36 hours or from about 4 to about 18 hours. In some embodiments, the crystals are dried for about 48 h.
  • the phosphate salt of the compound of Formula I may be used to prepare the monohydrate of the free base.
  • the phosphate salt may be dissolved in an aqueous solution of an inorganic base, such as aqueous ammonium hydroxide. Over time, the free base precipitates out as a crystalline monohydrate.
  • additional steps such as filtration, washing and drying may be used to isolate the crystalline free base monohydrate, just as the phosphate salt was isolated as described above.
  • Crystalline forms of the present technology may be isolated in substantially pure form.
  • substantially pure it is meant that more than 50% by weight of 3-(2,6-dichloro- 3 ,5 -dimethoxy-phenyl)- 1 - ⁇ 6- [4-(4-ethyl-piperazin- 1 -yl)-phenylamino] -pyrimidin-4-yl ⁇ - 1 - methyl-urea is present in one of the crystalline forms disclosed herein.
  • 3-(2,6- dichloro-3 ,5 -dimethoxy-phenyl)- 1 - ⁇ 6- [4-(4-ethyl-piperazin- 1 -yl)-phenylamino] -pyrimidin-4- yl ⁇ -l -methyl-urea is present at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99%) by weight of the indicated form.
  • the present technology provides phosphate salts of the free base wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total phosphate salt of the free base is present as form A, form B or the amorphous form.
  • the present technology provides the free base such that at least about 50%, at least about 70%, at least about 80%), at least about 90%o, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total of the free base is present as the crystalline anhydrous free base, the crystalline monohydrate of the free base, or the amorphous form of the free base.
  • the present technology provides hydrochloride salts of the free base wherein at least about 50%, at least about 70%, at least about 80%>, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total is the amorphous or the crystalline dihydrate form of the hydrochloride salt.
  • compositions and medicaments which may be prepared by mixing one or more anhydrous or hydrated crystalline or amorphous forms (of, e.g., the free base, the phosphate salts or the
  • hydrochloride salts thereof) of the present technology with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat certain diseases as described herein.
  • the present technology provides compositions comprising an anhydrous or hydrated crystalline form or an amorphous form of the present technology and a pharmaceutically acceptable carrier, excipient, and/or diluent.
  • the anhydrous crystal form is of the compound of Formula I as the free base.
  • the hydrated crystal form is the monohydrate of the compound of Formula I as the free base.
  • the anhydrous crystalline form is of the
  • the anhydrous crystalline form of the monophosphoric acid salt is of form A.
  • the anhydrous crystalline form of the monophosphoric acid salt is of form B.
  • the monophosphoric acid salt of the compound of Formula I is amorphous.
  • the form is of the hydrochloride salt of the compound of Formula I.
  • the hydrochloride salt is the crystalline dihydrate or the amorphous form.
  • compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the composition is substantially free of water.
  • the instant compositions can be formulated for various routes of administration, for example, by oral and parenteral administration.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections.
  • the following dosage forms are given by way of example and should not be construed as limiting the instant technology.
  • Injectable dosage forms generally include oil suspensions or aqueous suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. In certain embodiments, such aqueous injectable forms are prepared (or reconstituted) immediately before administration to the subject. Alternatively, sterile oils may be employed as solvents or suspending agents.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the pharmaceutical compositions and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the pharmaceutical compositions may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more anhydrous crystalline form of the present technology, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides.
  • a starch or other additive are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, ge
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
  • Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • compositions and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • a sterile liquid such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents may be added for oral or parenteral administration.
  • the liquid dosage forms, particularly of the crystalline forms of the free base monophosphate salt are substantially free of water.
  • suspensions may include oils.
  • oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspensions of pharmaceutical compositions may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to,
  • poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension pharmaceutical compositions.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present technology. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
  • compositions of the present technology may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below.
  • the pharmaceutical compositions may also be prepared for controlled release or for slow release.
  • compositions may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical compositions and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.
  • Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing therapeutically effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the present technology.
  • the present technology provides compositions comprising the free base of the compound of Formula I, wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total free base in the composition is present as the anhydrous form, or as the monohydrate form.
  • the compositions of the present technology consist essentially of the free base, where at least about 95%, at least about 97%, at least about 98%, or at least about 99% of the free base is present in the composition as the anhydrous form, or as the monohydrate form.
  • the present technology provides compositions comprising the phosphate salt of the free base wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total phosphate salt of the free base in the composition is present as form A, as form B, or as the amorphous form.
  • compositions of the present technology consist essentially of a phosphate salt of the free base, where at least about 95%, at least about 97%, at least about 98%, or at least about 99% of the phosphate salt of the free base is present in the composition as form A, as form B, or as the amorphous form.
  • the present technology provides compositions comprising the hydrochloride salt of the free base wherein at least about 50%, at least about 70%, at least about 80%), at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total hydrochloride salt of the free base in the
  • composition is present as the dihydrate, or as the amorphous form.
  • compositions of the present technology consist essentially of a hydrochloride salt of the free base, where at least about 95%, at least about 97%, at least about 98%, or at least about 99% of the phosphate salt of the free base is present in the composition as the dihydrate, or as the amorphous form.
  • the present technology provides a method of treatment comprising administering a therapeutically effective amount of an anhydrous or hydrated crystalline form or an amorphous form or a composition comprising an anhydrous or hydrated crystalline form or amorphous form of the present technology to a subject suffering from a disease, the pathology and/or symptoms of which disease can be prevented, inhibited or ameliorated by inhibition of a kinase activity wherein the kinase is selected from the group consisting of FGFRl, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret.
  • the present technology provides the use of the anhydrous or hydrated crystalline forms, the amorphous forms or the compositions including the anhydrous or hydrated crystalline forms or amorphous forms of the present technology in the manufacture of a medicament for treating a disease in a subject wherein the kinase activity of FGFRl, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret contributes to the pathology and/or symptoms of the disease.
  • the kinase is selected from the group consisting of FGFRl , FGFR2, FGFR3, FGFR4.
  • Treatment within the context of the instant technology means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing or halting of further progression or worsening of those symptoms, or tending to prevent or ward off the disease or disorder in a subject at risk for developing the disease or disorder.
  • diseases or disorders include, but are not limited to carcinoma of the kidneys, liver, adrenal glands, bladder, breast, stomach, ovaries, colon, rectum, prostate, pancreas, lungs, vagina or thyroid; sarcoma; glioblastoma; leukemia; tumors of the neck or head; psoriasis; prostate hyperplasia; or neoplasia.
  • a successful treatment may include an alleviation of symptoms or slowing or halting the progression of the disease, as measured by a reduction in levels or activity of one or more corresponding kinases.
  • a "therapeutically effective amount” refers to an amount of the anhydrous or hydrated crystalline form or amorphous form of the compound of Formula I (including the free base), or the anhydrous crystalline form or amorphous form of the phosphate salt of the compound of Formula I, they hydrochloride salt of the compound of Formula I (including the dihydrate or amorphous form) or compositions including them, that alleviates, in whole or in part, symptoms associated with the disorder or disease treated, or slows or halts of further progression or worsening of its symptoms, or prevents or provides prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder.
  • a subject is any animal that can benefit from the administration of any of the forms of the compound of Formula I or a composition including it, as disclosed herein.
  • the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse.
  • the mammal is a human.
  • a therapeutically effective amount of an anhydrous or hydrated crystalline form, or an amorphous form, or a composition comprising any such form of the present technology may vary depending upon the route of administration and dosage form.
  • Effective amounts of the anhydrous or hydrated crystalline forms or amorphous forms of the compounds of Formula I typically fall in the range of about 0.01 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 25 mg/kg/day.
  • the anhydrous or hydrated crystalline form, the amorphous form and the composition comprising such forms of the present technology are selected to provide pharmaceutical compositions that exhibit high therapeutic indices.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50.
  • the LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population.
  • the LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
  • the pH of a solution was determined as exemplified: approximately 10 mg of the free base or its salt was transferred to a 20 ml vial and 10 ml of the corresponding buffer or water added to it. The solution was stirred continuously as the pH was measured. pH measurement can be carried out by a variety of methods, such as, by using micro pH electrodes.
  • the intrinsic dissolution rate measurements were carried out in 0.5 cm 2 VanKel punch and die assemblies at a pellet pressure of 2000 pounds.
  • the dissolution was measured using fiber optics dissolution system (C technologies Inc.) and a Cary UV/VIS
  • Hygroscopicity was measured from sorption/desorption isotherms using Surface Measurement System DVS-1 at 25 ⁇ 0.5°C. Samples were evaluated at various humidities including 75%, 85%, and 95%.
  • Instrument TA instrument Q500; temperature range: room temperature to 300°C; scan rate: 10°C/min; nitrogen flow: 60 ml/min.
  • Mettler TGA 850 temperature range: room temperature to 300°C; scan rate: 20°C/min; nitrogen flow: 40 ml/min.
  • Instrument TA instrument Ql 000; temperature range: room temperature to 210°C; scan rate: 10°C/min; nitrogen flow: 60 mL/min.
  • Instrument Bruker D8 Advance; irradiation: Cu Ka, (30 kV, 40 niA); variable slit V12 mm; scan range 2 - 40° (2 theta value); scan rate 0.3 s per step.
  • XDS2000 by Scintag, Inc. was used; irradiation: Cu Ka (45 kV, 40 mA); divergence slice: 3 mm and 2 mm; measuring slice: 0.3 mm and 0.2 mm; chopper 0.02 grd; scan time: 6 minutes (3 minutes per frame); scan range: 2° - 35° or 40° (2 theta value); scan rate 0.5°/min (2 theta value).
  • Instrument Thermo Magna 560; mode: transmission; scan range: 4000 cm “1 - 600 cm “1 .
  • Example 1 Screening Acid Salts of the Free Base of Formula I.
  • a salt screening experiment was performed with the free base of Formula I (prepared as described in Example 2 below) and a variety of different acids: acetic acid, benzoic acid, citric acid, fumaric acid, hippuric acid, hydrobromic acid, hydrochloric acid, lactic acid (D,L), maleic acid, malic acid (L), malonic acid, methanesulfonic acid, phosphoric acid, naphthalene- 1, 5 -disulfonic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid (D), and tartaric acid (L).
  • the free base (30 mg) was dissolved in 12 mL THF.
  • the phosphate salt was found to be highly crystalline. Hygroscopicity as assessed by DVS sorption/desorption isotherms indicated that even at 95% RH, less than a 2% weight gain due to water absorption was observed. At 75% and 85% RH, less than a 1% weight gain was observed.
  • hydrochloride salt For the hydrochloride salt, several XRPD patterns were observed indicating the presence of more than one polymorph. Most of these salts had low crystallinity. The dihydrate was identified as the most crystalline. The hydrochloride salt was more hygroscopic than the phosphate salt. In one form of the hydrochloride salt, a weight gain of about 4.1% (75% RH) to about 16.9% (95% RH) was observed by DVS. [0074] For the malonate salts, four forms were identified based on their observed XRPD patterns. The one evaluated further, demonstrated a fragile crystal, was only made once, had a wet pattern, and was hygroscopic (about 10% weight gain at all humidities tested).
  • methane sulfonic acid (or mesylate) salt For the methane sulfonic acid (or mesylate) salt, several XRPD patterns were observed of which only one could be made consistently but it was hygroscopic (exhibiting about 2.6% to 10% weight gain by DVS). Similarly, the succinate salt was also hygroscopic (exhibiting about a 4.1% to 10% weight gain by DVS).
  • Results of an initial solubility test in pH 3 buffer and in water are shown below in Table 1.
  • the phosphate salt was more soluble than the methanesulfonate, malonate, and succinate salts in pH 3 buffer and in water.
  • the phosphate salt was also more soluble in water than the free base.
  • This material was prepared by a modified procedure published in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of commercially available 4,6- dichloropyrimidine (20 g, 131.6 mmol, 1.0 eq.) in isopropanol (60 ml) is added 33% methylamine in ethanol (40.1 ml, 328.9 mmol, 2.5 eq.) at such a rate that the internal temperature does not rise above 50°C. After completion of the addition the reaction mixture was stirred for lh at room temperature. Then, water (50 ml) is added and the suspension formed is chilled in an ice bath to 5°C.
  • the title compound was prepared by adding 2,6-dichloro-3,5-dimethoxyphenyl- isocyanate (1.25 eq.) to a solution of N-[4-(4-ethyl-piperazin-l-yl)-phenyl]-N'-methyl- pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 eq.) in toluene and stirring the reaction mixture for 1.5h at reflux.
  • Example 4 Manufacture of the Free Base Monohydrate Form of the Compound of Formula I.
  • the solid was filtered through a 3 L coarse frit sintered glass funnel with a coarse frit (40-60 ASTM). The filter cake was rinsed with deionized water (2 L). The solid was dried at 60° C under vacuum (5 torr) for 16 hours to give the free base as a monohydrate (559 g, 96.7% of theory for a monohydrate).
  • Example 5 Physicochemical Properties of the Free Base, the Phosphate Salt (Form A), and the Hydrochloride.
  • the anhydrous free base showed good crystallinity (for XRPD spectrum, see Figure 1 A). It was slightly hygroscopic, and upon heating at 10°C /min, melted at 217°C (onset) with subsequent decomposition (for DSC thermogram, see Figure 2A).
  • the TGA for the anhydrous base is shown in Figure 3A, and the observed weight loss is consistent with the anhydrous form. It was not soluble in aqueous media at high pH (ca. 0.00004 mg/mL in pH 6.8 buffer and ca 0.00009 mg/mL with pH 6.67 in water), and sparingly to slightly soluble in common organic solvents.
  • anhydrous free base changes into another form (likely a form of hydrochloride).
  • the monohydrate form of the free base also showed good crystallinity (for XRPD spectrum, see Figure ID).
  • An SEM micrograph of the anhydrous free base is shown in Figure 5A.
  • the phosphate salt showed good crystallinity (for XRPD spectrum, see Figure IB (phosphate salt (form A)). It was slightly hygroscopic, and upon heating at 10°C/min, melted at 184.0 °C (onset) with subsequent decomposition (See Figure 2B (phosphate salt (form A)). The TGA of the phosphate salt is shown in Figure 3B, and the observed weight loss is consistent with the anhydrous form. It was not soluble in pH 6.8 buffer (ca. 0.00009 mg mL), but, unlike the free base, was soluble in water (1.3 mg mL). It was sparingly soluble in common organic solvents. Additional solubility studies are presented below.
  • the hydrochloride salt showed moderate crystallinity (for XRPD spectrum, see Figure IE) in the dihydrate form.
  • the TGA is shown in Figure 3C, and the observed weight loss is consistent with the dihydrate form.
  • the hydrochloride is hygroscopic and the present form is a dihydrate. Solubility studies are presented in Example 8, Table 3D.
  • Example 6 Amorphous Form of the Phosphate Salt of the Free Base.
  • the measurements were carried out on a VanKel instrument using a Cary UV/VIS
  • Solubility of the monohydrate of the anhydrous and monohydrate free base was measured in various aqueous media (e.g., pH 6.8 buffer, pH 4.5 buffer, pH 1 buffer), including simulated and actual human fluids.
  • aqueous media e.g., pH 6.8 buffer, pH 4.5 buffer, pH 1 buffer
  • the simulated fluid compositions are shown in table 3A-3C below.
  • Peaks in Figure 8B include 2957, 2831, 1618, 1580, 1511, 1465, 1415, 1361, 1312, 1284, 1229, 1186, 1148, 1057, 994, 854, 721, 661, 624 cm "1 .
  • Example 10 Single Crystal X-ray Crystallographic Analysis of the Crystalline
  • the free base was stable, but the phosphate salt showed about 45% degradation. This does not impact the administration of the phosphate salt orally; in fact, as demonstrated below, the phosphate salt has about a 2-fold higher bioavailability than the free base.
  • the stability difference between the free base and phosphate salt may be due to the higher aqueous solubility of the phosphate salt compared to the free base, as well as the tendency of the phosphate salt to cause the pH of water to decrease, which may increase the rate of degradation.
  • Both the free base and phosphate salt showed the highest degradation in 1 :1 acetonitrile/water (about 8% and 70%, respectively).
  • a solvent water or ethanol was added drop wise to the phosphate salt (form A) placed in a mortar until the solid in the mortar was sufficiently wet, and ground using a pestle until a paste-like consistency was obtained.
  • the paste was dried at around 40°C and under reduced pressure for > 8 hours.
  • the solids were evaluated by XRPD, and no changes in the XRPD spectra were observed. These results demonstrated the stability of the crystalline form of the phosphate salt (form A).
  • the maximum water uptake for the monohydrate was less than 1.4% at 25°C up to 95% RH.
  • the monohydrate with an approximate water content of 3% could not be completely dried during the experiment but the water that could be removed was reversibly reabsorbed.
  • the plateau of existence of the monohydrate form is found to be within 10% and 95% RH with a slight hysteresis at the second desorption cycle.
  • the phosphate salt was prepared as follows. In a glass vial, 10.7 mg of the free base was dissolved in 4 ml THF. Phosphoric acid (1.76 ml) in acetone (0.01 M) was added. The mixture was warmed to 50°C for about 2 minutes. The vial was left open for partial evaporation at room temperature. Overnight, a suspension was formed, which was filtered yielding about 5.5 mg of an off-white powder.
  • the bioavailabilities, in rats, of the active agents (the free base and its phosphate salt), formulated variously, are tabulated below (Table 10).

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PCT/US2010/059108 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof. WO2011071821A1 (en)

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RU2012128351/04A RU2572848C2 (ru) 2009-12-07 2010-12-06 Кристаллические формы 3-(2,6-дихлор-3,5-диметоксифенил)-1-{ 6-[4-(4-этилпиперазин-1-ил)-фениламино]-пиримидин-4-ил} -1-метилмочевины и ее долей
AU2010328391A AU2010328391B2 (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl) -1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino] -pyrimidin-4-yl}-1-methyl-urea and salts thereof.
SI201031119A SI2509963T1 (sl) 2009-12-07 2010-12-06 Kristalinične oblike 3-(2,6-dikloro-3,5-dimetoksi-fenil)-1-(6-(4-4-etil-piperazin-1-il)- fenilamino)-pirimidin-4-il)-1-metil-uree in njenih soli
BR112012013784-0A BR112012013784B1 (pt) 2009-12-07 2010-12-06 Formas cristalinas de 3-(2,6-dicloro-3,5-dimetoxi fenil)-1-{6-[4-(4-etil piperazin-1-il) fenil amino] pirimidin-4-il}-1-metil uréia, seus sais, seu uso e seu método de preparação, e composição
KR1020127017618A KR101787784B1 (ko) 2009-12-07 2010-12-06 3－（2,6―디클로로―3,5―디메톡시―페닐）－1－｛6－［4－（4－에틸－피페라진－1－일）－페닐아미노］－피리미딘－4－일｝－1－메틸－우레아의 결정질 형태 및 그의 염
CN2010800550783A CN102639510A (zh) 2009-12-07 2010-12-06 3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-脲及其盐的晶型
JP2012543183A JP5714024B2 (ja) 2009-12-07 2010-12-06 ３−（２，６−ジクロロ−３，５−ジメトキシ−フェニル）−１−｛６−［４−（４−エチル−ピペラジン−１−イル）−フェニルアミノ］−ピリミジン−４−イル｝−１−メチル−尿素の結晶形態およびその塩
MX2012006562A MX2012006562A (es) 2009-12-07 2010-12-06 Formas cristalinas de 3-(2,6-dicloro-3,5-dimetoxi-fenil)-1-{6-[4-( 4-etil-piperazin-1-il)-fenil-amino]-pirimidin-4-il}-1-metil-urea y sales de las mismas.
CA2781431A CA2781431C (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof
DK10788479.3T DK2509963T3 (en) 2009-12-07 2010-12-06 Crystalline Forms of 3- (2,6-DICHLOR-3,5-DIMETHOXY-PHENYL) -1- {6- [4- (4-ETHYLPIPERAZIN-1-YL) -PHENYLAMINO] -PYRIMIDIN-4-YL} -1 -METHYL-UREA AND SALTS THEREOF
ES10788479.3T ES2562462T3 (es) 2009-12-07 2010-12-06 Formas cristalinas de 3-(2,6-dicloro-3,5-dimetoxifenil)-1-{6-[4-(4-etilpiperazin-1-il)-fenilamino]-pirimidin-4-il}-1-metilurea y sus sales
NZ600070A NZ600070A (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl} -1-methyl-urea and salts thereof
EP10788479.3A EP2509963B1 (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof.
PH12014502593A PH12014502593A1 (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl]-1-methyl-urea and salts thereof
PL10788479T PL2509963T3 (pl) 2009-12-07 2010-12-06 Krystaliczne postaci 3-(2,6-dichloro-3,5-dimetoksyfenylo)-1-{6-[4-(4-etylopiperazyno-1-ylo)-fenylamino]-pirymidyno-4-ylo}-1-metylomocznika i jego soli
US13/514,308 US9067896B2 (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof
ZA2012/03612A ZA201203612B (en) 2009-12-07 2012-05-17 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4[(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof
IL220012A IL220012B (en) 2009-12-07 2012-05-24 Crystal forms of 3-(6,2-dichloro-5,3-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl} -1-methyl-urea and its salts
TNP2012000263A TN2012000263A1 (en) 2009-12-07 2012-05-25 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof.
MA35005A MA33849B1 (fr) 2009-12-07 2012-06-26 Formes cristallines de la 3-(2,6-dichloro-3,5-diméthoxy-phényl)-1- {6-[4-(4-éthyl-pipérazin-1-yl) -phénylamino] -pyrimidin-4-yl} -1-méthyl-urée et de ses sels
HK12111776.3A HK1171016A1 (zh) 2009-12-07 2012-11-19 -{ }- -二氯- -二甲氧基-苯基 -{ -乙基-哌嗪- -基 -苯基氨基 -嘧啶- -基}- -甲基-脲及其鹽的晶型
HRP20160126T HRP20160126T1 (hr) 2009-12-07 2016-02-04 Kristalinični oblici 3-(2,6-diklor-3,5-dimetoksi-fenil)-1-{6-[4-(4-etilpiperazin-1-il)-fenilamino]-pirimidin-4-il}-1-metil-ureje i njihove soli

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