WO2007082946A1 - Formes solides d’un derive pyrrolopyrimidine et leur utilisation antitumorale - Google Patents

Formes solides d’un derive pyrrolopyrimidine et leur utilisation antitumorale Download PDF

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WO2007082946A1
WO2007082946A1 PCT/EP2007/050567 EP2007050567W WO2007082946A1 WO 2007082946 A1 WO2007082946 A1 WO 2007082946A1 EP 2007050567 W EP2007050567 W EP 2007050567W WO 2007082946 A1 WO2007082946 A1 WO 2007082946A1
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phenyl
ethyl
pyrrolo
amine
piperazin
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PCT/EP2007/050567
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English (en)
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Michael Mutz
Reto Fischer
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Novartis Ag
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Application filed by Novartis Ag filed Critical Novartis Ag
Priority to JP2008550775A priority Critical patent/JP2009523768A/ja
Priority to CA002636954A priority patent/CA2636954A1/fr
Priority to BRPI0706729-1A priority patent/BRPI0706729A2/pt
Priority to AU2007206925A priority patent/AU2007206925A1/en
Priority to EP07704035A priority patent/EP1979357A1/fr
Publication of WO2007082946A1 publication Critical patent/WO2007082946A1/fr
Priority to TNP2008000312A priority patent/TNSN08312A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to new crystalline forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-etriyl)-amine, the process for preparation of these crystalline forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/- pyrrolo[2,3-tf]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine, compositions containing these crystalline forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4- yl ⁇ - ⁇ (R)-1-phenyl-ethyl)-amine, and the use of these crystalline forms of ⁇ 6-[
  • the invention relates to the amorphous form of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine, the process for preparation of the amorphous form of ⁇ 6-[4-(4-ethyl-piperazin-1-yimethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((/?)-1-phenyl-ethyl)-amine, compositions containing the amorphous form of ⁇ 6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4- yl ⁇ -((R)-1-phenyl-ethyl)-amine, and the use of amorphous form of
  • the drug ⁇ 6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7tf-pyrro!o[2,3-c/]pyrimidin-4-yl ⁇ - ((R)-I -phenyl-ethyl)-amine is a dual EGF/VEGF inhibitor and exhibits anti-tumour behaviour.
  • the preparation of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyi)-phe ⁇ yl]-7H-pyrrolo[2,3- cf]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine is known in the art.
  • the invention provides a crystalline form A of ⁇ 6-[4-(4- ethyl-piperazin-1-y!methyl)-phenyl]-7H-pyrrolo[2,3-cy]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)- ami ⁇ e.
  • the crystalfine form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7tf- pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine has an X-ray diffraction pattern with a peak at an angle of diffraction 2 theta ( ⁇ ) of 4.4°, 8.8°, 9.1 °, 13.2°, 14.2°, 17.2°, 18.2°, 19.4° ⁇ 0.2° as depicted in FIG. 1.
  • the invention provides a composition that contains ⁇ 6-[4- ⁇ 4-ethyl-pipera2in-1-ylmethyl)-phenyl]-7/-/-pyrrolo[2,3-rfIpyrimidin-4-yl ⁇ -((R)-1- phenyl-ethyl)-amine in a solid form, wherein at least 80% by weight of the solid ⁇ 6-[4-(4-ethyl- piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ -((R)-1 -phenyl-ethyl)-amine is its crystalline form A having an X-ray diffraction pattern with a peak at an angle of diffraction 2 ⁇ of 4.4°, 8.8°, 9.1 °, 13.2°, 14.2°, 17.2°, 18.2°, 19.4° ⁇ 0.2° as depicted in FIG. 1.
  • the invention provides a pharmaceutical composition that includes crystalline form A of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition is for oral administration.
  • the invention provides a process for preparing the crystalline form A of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7tf-pyrrolo[2,3- cflpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine, the process including:
  • the invention provides a process for preparing the crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- cflpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine from crystalline form C of ⁇ 6-[4-(4-ethyl- piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -( ⁇ R)-1 -phenyl-ethyl)-amine by melting crystalline form C of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethy!)-phenyl]-7H-pyrrolo[2,3- cflpyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine in an inert gas or solvent, which
  • the invention provides a crystalline form B of ⁇ 6-[4-(4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)- amine.
  • the crystalline form B of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/- pyrrolo[2,3-cflpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine has an X-ray diffraction pattern with a peak at an angle of diffraction 2 ⁇ of 5.7°, 6.9°, 7.7°, 11.7°, 15.6°, 18.5° ⁇ 0.2° as depicted in FIG. 5.
  • the invention provides a composition that contains ⁇ 6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrroio[2,3-d]pyrimidin-4-yl ⁇ -((R)-1 - phenyl-ethyl)-amine in a solid form, wherein at least 80% by weight of the solid ⁇ 6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-rf
  • Various embodiments and variants are provided.
  • the invention provides a pharmaceutical composition that includes crystalline form B of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-cflpyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-ami ⁇ e and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition is for oral administration.
  • the invention provides a process for preparing the crystalline form B of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- c/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine, the process including:
  • the invention provides a crystalline form C of ⁇ 6-[4-(4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-o(]pyrimidm-4-yl ⁇ -((f?)-1-phenyl-ethyl)- amine.
  • the crystalline form C of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-of]pyrimtdin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine has an X-ray diffraction pattern with a peak at an angle of diffraction 2 ⁇ of 5.7°, 6.8°, 7,5°, 10.2°, 11.6°, 13.3°, 15.2°, 18.4°, 20.8° ⁇ 0.2° as depicted in FlG. 7.
  • the invention provides a composition that contains ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrro!o[2,3-c(]pyrimidin-4-yl ⁇ -((f?)-1- pheny!-ethyl)-amine in a solid form, wherein at least 80% by weight of the solid ⁇ 6-[4-(4-ethyl- piperazin-1 -ylmethyl)-phenyl]-7tf-pyrrolo[2,3-c(]pyrirnidin-4-yl ⁇ -((R)-1 -phenyl-ethyl)-amine is its crystalline form C having an X-ray diffraction pattern with a peak at an angle of diffraction 2 ⁇ of 5.7°, 6.8°, 7.5°, 10.2°, 11.6°, 13.3°, 15.2°, 18.4°, 20.8° ⁇ 0.2°
  • the invention provides a pharmaceutical composition that includes crystalline form C of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-d]py ⁇ midin-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)-amine and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition is for oral administration.
  • the invention provides a process for preparing the crystalline form C of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- c(]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethy!)-amine, the process including:
  • the invention provides a process for the preparation of an amorphous form of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-cf]pyrimidin-4-yl ⁇ - ⁇ (f?)-1-phenyl-ethyl)-amine involving spray drying a solution . containing ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-o(]pyrimidin-4-yl ⁇ -( ⁇ R)-1- phenyl-ethyl)-amine.
  • compositions that include a prophylactically or therapeutically effective amount of the amorphous form of ⁇ 6-[4-(4-ethyi-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine produced by the process described, and one or more pharmaceutically acceptable excipients are also provided.
  • FIG. 1 shows the X-ray powder diffraction diagram of crystalline form A of ⁇ 6-[4-(4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)- amine.
  • FIG. 2 is a characteristic infrared spectrum of crystalline form A of ⁇ 6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ - ⁇ (R)-1-pheny!-ethyl)-amine.
  • FIG. 3 shows the DSC of crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-y! ⁇ -((R)-1-phenyl-ethyl)-amine.
  • FIG. 4 shows the Raman spectrum of crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine.
  • FIG. 5 shows the X-ray powder diffraction diagram of crystalline form B of ⁇ 6-[4-(4- ethyl-piperazin-i-ylmethyO-phenyll ⁇ H-pyrrolo ⁇ .S-cdpyrimidin ⁇ -yO-ftRJ-i-phenyl-ethyl)- amine.
  • FIG. 6 shows the DSC of crystalline form B of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7W-pyrrolo[2,3-c/]py ⁇ midin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine.
  • FIG. 7 shows the X-ray powder diffraction diagram of crystalline form C of ⁇ 6-[4- ⁇ 4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)- amine.
  • FIG. 8 is a characteristic infrared spectrum of crystalline form C of ⁇ 6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-t/]pyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine.
  • FIG. 9 shows the DSC of crystalline form C of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine.
  • FIG. 10 shows the Raman spectrum of crystalline form C of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyi-ethyl)-amine.
  • FIG. 11 shows the X-ray powder diffraction diagram of amorphous form of ⁇ 6-[4-(4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]py ⁇ midin-4-yl ⁇ -((R)-1-phenyl-ethyl)- amine.
  • crystalline form A The crystalline compound, designated herein as "crystalline form A" and referred to hereinafter as crystalline form A of ⁇ 6-[4-(4-ethyl-piperaz ⁇ n-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-c/]pyrim ⁇ din-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)-am ⁇ ne, is a new crystalline form of ⁇ 6-[4-(4- ethyl-p ⁇ perazin-1-ylmethyl)-pheny!]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)- amine. It is characterized via X-ray powder diffraction, DSC, Raman Spectrum and/or infrared spectroscopy. It is further described below.
  • crystalline form B The crystalline compound, designated herein as "crystalline form B" and referred to hereinafter as crystalline form B of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-cf]pyrimid ⁇ n-4-yl ⁇ -((f?)-1-phenyl-ethyl)-amine, is a new crystalline form of ⁇ 6-[4-(4- ethyl-p ⁇ peraz ⁇ n-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-rf]pyrimidin-4-yl ⁇ -((/?)-1-phenyl-ethyl)- amine. It is characterized via X-ray powder diffraction and/or DSC. It is further described below.
  • crystalline form C The crystalline compound, designated herein as "crystalline form C" and referred to hereinafter as crystalline form C of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyr ⁇ mtd ⁇ n-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine, is a new crystalline form of ⁇ 6-[4-(4- ethyl-piperazin-i-ylmethyO-phenyn ⁇ H-pyrrolo ⁇ .S-cdpyrimidin ⁇ -ylJ- ⁇ RJ-i-phenyl-ethyl)- amine.
  • “Pharmaceutically acceptable” means being useful for preparing a pharmaceutical composition that is generally non-toxic and is not biologically undesirable and includes that which is acceptable for veterinary use and/or human pharmaceutical use.
  • an "anti-solvent” is a solvent which when added to an existing solution of a substance reduced the solubility of the substance.
  • composition includes, but is not limited to, a powder, a solution, a suspension, a gel, an ointment, an emulsion and/or mixtures thereof.
  • composition is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts.
  • a “composition” may contain a single crystalline form or a mixture of crystalline forms of the active ingredient.
  • a “compound” is a chemical substance that includes molecules of the same chemical structure.
  • composition is intended to encompass a product comprising the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s) and pharmaceutically acceptable excipients.
  • excipient means a component of a pharmaceutical product that is not the active ingredient, such as filler, diluent and carrier.
  • the excipients that are useful in preparing a pharmaceutical composition are preferably generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use, as well as human pharmaceutical use.
  • a pharmaceutically acceptable excipient as used in the specifications and claims, includes both one and more than one such excipient.
  • “Therapeutically effective amount” means the amount of a compound that, when administered for treating or preventing a disease, is sufficient to effect such treatment or prevention for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • the terms “treating”, “contacting” and “reacting” are used interchangeably herein and refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product.
  • reaction which produces the indicated and/or desired product may not necessarily result directly from the combination of two reagents which were initially added, i.e., there may be one or more intermediates which are produced in the mixture which ultimately leads to the formation of the indicated and/or desired product.
  • essentially pure is understood in the context of the present invention to mean especially that at least 90%, preferably at least 95% by weight of the crystals of an acid addition salt of formula (I) are present in the crystal form according to the invention.
  • the invention relates especially to particular crystalline forms, preferably to those, which are referred to hereinafter as crystalline form A of a ⁇ 6-[4-(4-ethyi-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -( ⁇ R)-1 -phenyl-ethyl)-amine of the compound of formula (I), described above; to the crystalline form B of ⁇ 6-[4-(4-ethyl- piperazin-1 -ylmethy!)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1 -phenyl-ethyl)-amine and to the crystalline form C of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- c/]pyrimidin-4-yl ⁇ - ⁇ (f?)
  • Different solid forms of the same drug substance may exhibit different properties, including characteristics, that have functional implications with respect to their use as drug substance and may have substantial differences in such pharmaceutically important properties as dissolution rates and bioavailability.
  • different crystalline forms may have different processing properties, such as hygroscopicity, flowability and the like, which could affect their suitability as active pharmaceuticals for commercial production.
  • the assigned margin of error in a preferred variant, is approximately ⁇ 0.2° for each of the peak assignments.
  • the crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7W-pyrrolo[2,3- cflpyrimidin-4-yl ⁇ -( ⁇ f?)-1-pheny!-ethy!-amine may be also characterized by infrared spectroscopy.
  • the crystalline form A exhibits a characteristic absorption pattern in infrared (IR) spectroscopic analysis as depicted in FIG. 2. IR spectroscopic analysis was measured on a Bruker IFS-55.
  • the crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-cf]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine has characteristic absorptions, which can be distinguished from that of other polymorphs, at about 695, 802, 836, 923, 934, 1013, 1095, 1146, 1165, 1207, 1229, 1292, 1300, 1310, 1348, 1358, 1507, 1546, 1595 and 3269 cm "1 in IR spectroscopic analysis. Some margin of error is present in each of the characteristic absorptions reported herein. The assigned margin of error in the characteristic absorptions is approximately 2 cm "1 in the range of 1900-800 cm "1 .
  • the crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- cdpyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine may be also characterized by Differential Scanning Calorimeter (DSC).
  • DSC Differential Scanning Calorimeter
  • the crystalline form A exhibits a characteristic pattern in DSC analysis as depicted in FIG. 3. DSC analysis was measured on a Perkin Elmer Pyris 1.
  • the crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/-pyrrolo[2,3-cr]pyrimidin-4- yl ⁇ -((f?)-1-phenyl-ethyl)-amine has a characteristic melting peak with an onset temperature above 240 0 C, preferably above 250 0 C. Melting is associated with decomposition. The onset temperature, therefore, varies with the heating rate and instrumental conditions used for analysis.
  • the crystalline form A of ⁇ 6-[4-(4-ethy[-piperazin-1-ylmethyl)-pheny ⁇ ]-7H-pyrrolo[2,3- o0pyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)-amine may be also characterized by Raman Spectrum.
  • the crystalline form A exhibits a characteristic pattern in Raman Spectrum as depicted in FIG. 4. Raman Spectrum analysis was measured on a Bruker RFS 100 instrument.
  • the crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7W-pyrrolo[2,3-d]pyrimtdin-4- y! ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine has characteristic absorptions, which can be distinguished from that of other polymorphs, at about 158, 183, 920, 935, 1002, 1159, 1178, 1308, 1405, 1422, 1446, 1496, 1544, 1618 and 3060 cm "1 in Raman Spectrum analysis. Some margin of error of ⁇ 3 cm "1 in the range 2000-500 cm "1 is present in each of the characteristic absorptions reported herein.
  • One or more of physical properties and/or spectroscopic properties can be the basis for characterizing the crystal or polymorphic forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-cf]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine.
  • the invention also provides a composition containing solid ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyi]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)-amine, which is at least 80%, by total weight of the solid ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine in the composition, its crystalline form A.
  • composition ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-cflpyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine powder suitable for use as active ingredient in formulating pharmaceutical products.
  • the remainder of the solid ⁇ 6-[4-(4-ethyl- piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-cflpyrimidin-4-yl ⁇ -((f?)-1 -phenyl-ethyl)-amine in the composition i.e., 20% or less of the total weight of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-cflpyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyi)-arnine may be, e.g., other crystalline forms of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-cf]pyrirnidin-4- yl ⁇ -((R)-1-phenyl-ethyl)-amine.
  • the composition contains at least 90% of the crystalline form A of ⁇ 6-[4-(4-ethyi-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- cdpyrirnidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine with respect to the total weight of the solid ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl- ethyl)-amine in the composition.
  • the composition contains at least 95% of the crystalline form A with respect to the total weight of the solid ⁇ 6-[4-(4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -( ⁇ /?)-1-phenyl-ethyl)- amine in the composition.
  • a process for the preparation of crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyi)-phe ⁇ yl]-7/-/-pyrrolo[2,3-of]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine involves:
  • ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- cflpyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)-amine is contacted with methanol at an elevated temperature so no remaining crystals are visible.
  • the solution is placed in an ice bath and agitated. The precipitate is collected on a filter.
  • the precipitate is subsequently re-suspended with isopropanol at an elevated temperature before the solution is filtered and dried to produce crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-of]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine.
  • the above conditions for the selective preparation of the individual crystal forms are not conclusive. In general, e.g., it is possible to vary parameters such as the weight ratio of the compound of formula (I) to the solvent and anti-solvent.
  • the assigned margin of error in a preferred variant, is approximately ⁇ 0.02 for each of the peak assignments.
  • the crystalline form B of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- cHpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine mav De also characterized by DSC.
  • the crystalline form B exhibits a characteristic peak in DSC analysis as depicted in FIG. 6. DSC analysis was measured on a Perkin Elmer Pyris 1.
  • the crystalline form B of ⁇ 6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine shows a characteristic endothermic transition at about 94°C followed by an exothermic event at about 138 0 C and an endothermic peak at about 255°C.
  • One or more of physical properties and/or spectroscopic properties can be the basis for characterizing the crystal forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethy!)-phenyl]-7/-/- pyrrolo[2,3-d]pyrimidin-4-yi ⁇ -((R)-1-phenyl-ethyl)-amine.
  • the invention also provides a composition containing solid ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-cy]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine, which is at least 80%, by total weight of the solid ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine in the composition, its crystalline form B.
  • composition ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-cfl ⁇ yrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine powder suitable for use as active ingredient in formulating pharmaceutical products.
  • the remainder of the solid ⁇ 6-[4- ⁇ 4-ethyl- piperazin-1 -ylmethyl)-phenyl]-7tf-pyrrolo[2,3-c(]pyrirnidin-4-yl ⁇ -((R)-1 -phenyl-ethyl)-amine in the composition i.e., 20% or less of the total weight of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine may be, e.g., other crystalline forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4- Y 1 H( ⁇ )-I -phenyl-ethyl)-amine.
  • the composition contains at least 90% of the crystalline form B of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethy!)-phenyl]-7H-pyrrolo[2,3- Gdpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine with respect to the total weight of the solid ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyl- ethyl)-amine in the composition.
  • the composition contains at least 95% of the crystalline form B with respect to total weight of the solid ⁇ 6-[4-(4-ethyl- piperazin-i-ylmethylJ-phenyll ⁇ H-pyrrolo ⁇ .S-oOpyrimidin ⁇ -ylJ-ffRJ-i-phenyl-ethylJ-amine in the composition.
  • a process for the preparation of crystalline form B of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1- yl methyl )-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine involves:
  • ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl ⁇ - ⁇ (f?)-1-phenyl-ethyl)-arnine is contacted with methanol at an elevated temperature, so no remaining crystals are visible.
  • the solution is placed in an ice bath and agitated.
  • the precipitate is collected on a filter dried to produce crystalline form B of ⁇ 6-[4-(4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(3pyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)- amine.
  • ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- rf]pyrimidin-4-yl ⁇ -((f?)-1-phenyl-ethyl)-amine is contacted with ethanol at an elevated temperature so no remaining crystals are visible.
  • the solution is placed in an ice bath and agitated.
  • the precipitate is collected on a filter dried to produce crystalline form B of ⁇ 6-[4-(4- ethyl-piperazin-i-yimethylJ-phenylJ-ZH-pyrrolo ⁇ .S-oOpyrimidin ⁇ -yll-ttRJ-i-phenyl-ethyl)- amine.
  • the X-ray diffraction pattern depicted in FIG. 7 for crystalline form C of ⁇ 6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -((f?)-1-phenyl-ethyl)-amine is summarized in Table 5.
  • the crystalline form C of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- cflpyrimidin-4-yl ⁇ -( ⁇ f?)-1-phenyl-ethyl)-amine may be also characterized by infrared spectroscopy.
  • the crystalline form C exhibits a characteristic absorption pattern in IR spectroscopic analysis as depicted in FIG. 7. IR spectroscopic analysis was measured on a Bruker IFS-55.
  • the crystalline form C of ⁇ 6-[4-(4-ethy!-piperazin-1-yimethyl)-phenyl]-7H- pyrrolo[2,3-cdpyrimidin-4-yl ⁇ -((ff)-1-phenyl-ethyl)-amine has characteristic absorptions, which can be distinguished from those of other crystalline forms, at about 701 , 764, 842, 932, 1013, 1110, 1127, 1147, 1164, 1121 , 1300, 1312, 1347, 1544, 1597, 3130 and 3429 cm "1 in IR spectroscopic analysis. Some margin of error is present in each of the characteristic absorptions reported herein. The assigned margin of error in the characteristic absorptions is approximately 2 cm "1 in the range of 1900-800 cm "1 .
  • the crystalline form C of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- of]pyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)-amine may be also characterized by DSC.
  • the crystalline form C exhibits a characteristic peak in DSC analysis as depicted in FIG. 9. DSC analysis was measured on a Perkin Elmer Pyris 1.
  • the crystalline form C of ⁇ 6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- ⁇ f]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine shows a characteristic endothermic transition at about 99 D C followed by an exothermic event at about 139 0 C and an endothermic peak at about 253°C.
  • the crystalline form C of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrirnidin-4-yl ⁇ -((/?)-1-phenyl-ethyl)-amine may be also characterized by Raman Spectrum.
  • the crystalline form C exhibits a characteristic pattern in Raman Spectrum as depicted in FIG. 4. Raman Spectrum analysis was measured on a Bruker RFS 100 instrument.
  • the crystalline form C of ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-tf]pyrimidin-4- yl ⁇ -((R)-1-phenyl-ethyl)-amine has characteristic absorptions, which can be distinguished from that of other polymorphs, at about 179, 254, 776, 803, 844, 933, 1000, 1024, 1166, 1309, 1405, 1450, 1497, 1543, 1570, 1618 and 3059 cm "1 in Raman Spectrum analysis. Some margin of error of ⁇ 3 cm "1 in the range of 200-500 cm "1 is present in each of the characteristic absorptions reported herein.
  • One or more of physical properties and/or spectroscopic properties can be the basis for characterizing the crystalline forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-cdpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-an ⁇ ine.
  • the invention also provides a composition containing solid ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyf)-amine, which is at least 80%, by total weight of the solid ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-riIpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine in the composition, its crystalline form C.
  • composition ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-rf]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine powder suitable for use as active ingredient in formulating pharmaceutical products.
  • the remainder of the solid ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1 -phenyl- ethyl)-amine in the composition i.e., 20% or less of the total weight of ⁇ 6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ - ⁇ (/?)-1-phenyl-ethyl)-amine may be, e.g., other crystalline forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethy!-phenyl]-7tf-pyrrolo[2,3- cf]pyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine.
  • the composition contains at least 90% of the crystalline form C of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((f?)-1-phenyt-ethyl)-amine with respect to the total weight of the solid ⁇ 6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ -((R)-1 - phenyl-ethyl)-amine in the composition.
  • the composition contains at least 95% of the crystalline form C with respect to total weight of the solid ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ -((R)-1-phenyl- ethyl)-amine in the composition.
  • a process for the preparation of crystalline form C of ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7/-/-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine involves:
  • ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/-pyrrolo[2,3- cdpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine is dissolved in methanol at an elevated temperature; the solution is cooled to about 0°C; and crystalline form C of ⁇ 6-[4-(4-ethyl- piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ - ⁇ (R)-1 -phenyl-ethyl)-amine is obtained.
  • This process is highly-reproducible and the resulting crystalline product has good filtration properties.
  • the powder obtained by the inventors is amorphous.
  • the invention also provides a composition containing solid ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yi ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine, which is at least 80%, by total weight of the solid ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine in the composition, its amorphous form.
  • composition solid ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl ⁇ - phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl ⁇ - ⁇ (R)-1-phenyl-ethyl)-amine powder suitable for use as active ingredient in formulating pharmaceutical products.
  • the remainder of the solid ⁇ 6-[4- (4-ethyl-piperazin-1-ylmethyl)-phenyI]-7H-pyrrolo[2,3-o(]pyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)- amine in the composition i.e., 20% or less of the total weight of ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrro!o[2,3-cf]pyrimidin-4-yi ⁇ -((R)-1-phenyl-ethyl)-amine may be, e.g., crystalline forms of ⁇ 6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(jpyrimidin-4- yl ⁇ -((R)-1-phenyJ-ethyl)-amine.
  • the composition contains at least 90% of the amorphous form of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/-pyrro!o[2,3- ⁇ yrimidin-4-yl ⁇ -((f?)-1-phenyl-ethyl)-amine with respect to the total weight of the solid ⁇ 6-[4- (4-ethyl-piperazin-1-ylmethyl)-pheny!]-7H-pyrrolo[2,3-of]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)- amine in the composition.
  • the composition contains at least 95% of the amorphous form with respect to total weight of the solid ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine in the composition.
  • the composition is substantially free of any forms of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-pheny!]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl- ethyl)-amine other than its amorphous form.
  • compositions containing one of the crystalline forms A, B, C or the amorphous form of ⁇ 6-[4-(4-ethy!-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine of the present invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition include one or more pharmaceutically acceptable carriers, also known as excipients, which ordinarily lack pharmaceutical activity, but have various useful properties which may, e.g., enhance the stability, sterility, bioavailability and ease of formulation of a pharmaceutical composition.
  • the carriers are pharmaceutically acceptable, meaning that they are not harmful to humans or animals when taken appropriately and are compatible with other ingredients in a given formulation.
  • the carriers may be solid, semi-solid or liquid, and may be formulated with the compound in bulk, but ultimately in the form of a unit-dose formulation, i.e., a physically discrete until containing a specific amount of active ingredient, such as a tablet or capsule.
  • the pharmaceutical compositions may include, in addition to a compound of this invention, one or more active pharmaceutical compounds.
  • compositions of the present invention comprising the crystalline forms of the present invention may be in the form of suspensions, solutions, elixirs, aerosols or solid dosage forms.
  • compositions are contemplated in various formulations suitable for various modes of administration including, but not limited to, inhalation, oral, rectal, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), implantable and transdermal administration.
  • parenteral including subcutaneous, intradermal, intramuscular and intravenous
  • implantable and transdermal administration The most suitable route of administration in an given case depends on the duration of the subject's condition, the length of treatment desired, the nature and severity of the condition being treated, and the particular formulation that is being used.
  • the formulations may be in bulk or in unit dosage form, and may be prepared by methods well-known in the art for a given formulation.
  • a pharmaceutical composition will generally contain about 0.1% by weight to about 99% by weight of the active ingredient, preferably about 1 % by weight to 50% by weight for oral administration and about 0.2% by weight to about 20% by weight for parenteral administration.
  • Formulations suitable for oral administration include capsules (hard and soft), cachets, lozenges, syrups, suppositories and tablets, each containing a predetermined amount of the active compound; as a powder or granules, as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such formulations may be prepared by any suitable method of pharmacy that includes the step of bringing into association the active compound and a suitable carrier or carriers.
  • the amount of active ingredient per unit dosage of solid formulations may be as described in prior art for preparations of ⁇ 6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ - ( ⁇ /?)-1 -phenyl-ethyl)-amine.
  • the invention also provides methods of treatment using the compounds and the pharmaceutical compositions of this invention.
  • subject is meant a human or an animal, preferably human.
  • Animals contemplated by this invention include any animal safely treatable by compounds of this invention.
  • the crystalline forms A, B, C or the amorphous form of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- cflpyrimidin-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-amine of the present invention show high antiproliferative and anti-tumor activity, as a result of dual EGF and VEGF inhibition, which may be extremely useful for cancer treatment.
  • dual EGF and VEGF inhibitor may lead to superior clinical outcomes for the patient, i.e., delay or suppress disease progression, with equally tolerable regimens.
  • Potential applications include a variety of solid tumors and more specifically for example breast cancer, colon cancer, ovarian cancer and leukemia.
  • various other indications that may be affected by dual EGF and VEGF activity may be effectively treated by these compositions, including multi-drug resistance (MDR), one of the major problems in currently employed cancer chemotherapy and inflammatory diseases in general.
  • MDR multi-drug resistance
  • the present invention relates especially to crystalline forms A, B, C or the amorphous form of ⁇ 6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-Gf]pyrimidin-4-yl ⁇ -( ⁇ R)-1 - phenyl-ethyl)-amine disclosed herein for the treatment of one of the said diseases or in the preparation of a pharmacological agent for the treatment thereof.
  • the invention relates also to a process for the treatment of warm-blooded animals suffering from said diseases, especially a tumor disease, wherein a quantity of the crystalline forms A, B, C or the amorphous form of ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-t/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine, which is effective against the disease concerned, especially a quantity with anti-proliferative and especially tumor-inhibiting efficacy, is administered to warm-blooded animals in need of such treatment.
  • the invention relates moreover to the use of crystalline forms A, B, C or the amorphous form of ⁇ 6-[4- ⁇ 4- ethyl-piperazin-1-yl methyl )-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)- amine for the inhibition of the above-mentioned, or for the preparation of pharmaceutical compositions for use in treating the human or animal body, especially for the treatment of a variety of solid tumors and more specifically, e.g., breast cancer, colon cancer, ovarian cancer and leukemia.
  • effective doses e.g., daily doses of about 1-2500 mg, preferably 1-1000 mg, especially 5-500 mg, are administered to warm-blooded animals of about 70 kg body weight.
  • the invention relates also to pharmaceutical preparations which contain an effective amount, especially an effective amount for prevention or treatment of one of the said diseases, of the crystalline forms A, B, C or the amorphous form of ⁇ 6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine of formula (I) 1 together with pharmaceutically acceptable carriers which are suitable for topical; enteral, e.g., oral or rectal; or parenteral administration and may be inorganic or organic and solid or liquid.
  • diluents e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerin
  • lubricants e.g., silica, talc, stearic acid or salts thereof, typically magnesium or calcium stearate; and/or PEG, are used for oral administration.
  • Tablets may likewise contain binders, e.g., magnesium aluminum silicate, starches, typically corn, wheat or rice starch, gelatin, methylceflulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and, if so desired, disintegrants, e.g., starches, agar, alginic acid or a salt thereof, typically sodium alginate; and/or effervescent mixtures, or adsorbents, coloring agents, flavors and sweetening agents.
  • binders e.g., magnesium aluminum silicate, starches, typically corn, wheat or rice starch, gelatin, methylceflulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone
  • disintegrants e.g., starches, agar, alginic acid or a salt thereof, typically sodium alginate
  • effervescent mixtures e.g., effervescent mixtures, or adsorbents, coloring agents, flavors and
  • Such solutions are preferably isotonic aqueous solutions or suspensions, these possibly being prepared before use, e.g., in the case of lyophilised preparations containing the active substance either alone or together with a carrier, e.g., mannitol.
  • the pharmaceutical substances may be sterilised and/or may contain excipients, e.g., preservatives, stabilisers, wetting agents and/or emulsifiers; solubilizers; salts for the regulation of osmotic pressure; and/or buffers.
  • the present pharmaceutical preparations which, if so desired, may contain further pharmacologically active substances, such as antibiotics, are prepared in a manner known per se, e.g., by means of conventional mixing, granulating, coating, dissolving or lyophilising processes, and contain from about 1-100%, especially from about 1 % to about 20%, of the active substance or substances.
  • Example 1 Preparation of crystalline form A of ⁇ 6-[4-(4-ethyl-piperazin-1 -ylmethyl)- phenyl]-7W-pyrrolo[2,3-cr]pyrimidin-4-yl ⁇ -((/?)-1-phenyl-ethyl)-amine using methanol and isopropanol
  • a reactor is charged with crude ⁇ 6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7tf- pyrrolo[2,3-cf]pyrimidin-4-yl ⁇ -((f?)-1-phenyl-ethyl)-amine and methanol.
  • the solution is aged at about 50-60 0 C.
  • the solution is cooled to about 0 0 C before the precipitate is isolated by filtration.
  • the precipitate is re-suspended in isopropanol for at least 24 hours before being placed in a water bath at about 25 0 C.
  • a reactor is charged with crude ⁇ 6-[4- ⁇ 4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/- pyrrolo[2,3-cflpyrimidin-4-yl ⁇ -((R)-1-phenyl-ethyl)-amine and methanol.
  • the suspension is aged to about 50-60°C, then cooled to about O 0 C before crystalline form B of ⁇ 6-[4-(4-ethyl- piperazin-1 -ylmethyl)-phenyl]-7tf-pyrrolo[2,3-d]pyrimidin-4-yl ⁇ -( ⁇ R)-1 -phenyl-ethyl)-amine is isolated by filtration.
  • a reactor is charged with crude ⁇ 6-[4-(4-ethyl-p ⁇ peraz ⁇ n-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-c(]pyr ⁇ m ⁇ d ⁇ n-4-yl ⁇ -((R)-1-phenyl-ethyl)-am ⁇ ne and ethanol
  • the suspension is aged to about 50-60°C ( then cooled to about O 0 C before crystalline form B of ⁇ 6-[4-(4-ethyl- p ⁇ perazin-1-y!methyl)-phenyl]-7H-pyrrolo[2,3-dJpy ⁇ m ⁇ d ⁇ n-4-yl ⁇ -((R)-1-phenyl-ethyl)-am ⁇ ne is isolated by filtration.
  • a reactor is charged with crude ⁇ 6-[4-(4-ethyl-piperaz ⁇ n-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-(flpyr ⁇ mid ⁇ n-4-yl ⁇ -( ⁇ R)-1-phenyl-ethyl)-am ⁇ ne and methanol
  • the suspension is aged to about 50-60 0 C, then cooled to about 0 0 C before crystalline form C of ⁇ 6-[4-(4-ethyl- piperaz ⁇ n-1 -ylmethyl)-phenyl]-7H-pyrrolo[2 J 3-c/]pyr ⁇ m ⁇ din-4-yl ⁇ -( ⁇ R)-1 -phenyl-ethyl)-amme is isolated by filtration.
  • the clear solution is allowed to evaporate under vacuum for about 15-20 minutes
  • the X-ray powder pattern is shown in Figure 11 and characterized by a broad halo effect.

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Abstract

La présente invention concerne de nouvelles formes cristallines de la {6-[4-{4-éthyl-pipérazin-1-ylméthyl)phényl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1-phényléthyl)amine. L’invention concerne également un procédé de préparation desdites formes cristallines et des compositions les contenant, ainsi que l’utilisation desdites formes cristallines dans la cadre de méthodes diagnostiques ou du traitement thérapeutique d’animaux à sang chaud, en particulier des êtres humains.
PCT/EP2007/050567 2006-01-23 2007-01-19 Formes solides d’un derive pyrrolopyrimidine et leur utilisation antitumorale WO2007082946A1 (fr)

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CA002636954A CA2636954A1 (fr) 2006-01-23 2007-01-19 Formes solides d'un derive pyrrolopyrimidine et leur utilisation antitumorale
BRPI0706729-1A BRPI0706729A2 (pt) 2006-01-23 2007-01-19 formas sólidas de um derivado de pirrolopirimidina e seu uso como agente antitumor
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WO2003013541A1 (fr) * 2001-08-07 2003-02-20 Novartis Ag Derives de la 4-amino-6-phenyl-pyrrolo[2,3-d]pyrimidine
WO2003037897A2 (fr) * 2001-10-29 2003-05-08 Novartis Ag Utilisation de derives de 7h-pyrrolo[2,3-d]pyrimidine dans des maladies a tumeur solide
WO2007017468A2 (fr) * 2005-08-05 2007-02-15 Novartis Ag Composes organiques

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CA2636954A1 (fr) 2007-07-26
BRPI0706729A2 (pt) 2011-04-05
KR20080095859A (ko) 2008-10-29
CN101370814A (zh) 2009-02-18
PE20071323A1 (es) 2008-02-15
AR059090A1 (es) 2008-03-12
JP2009523768A (ja) 2009-06-25
TW200738719A (en) 2007-10-16
AU2007206925A1 (en) 2007-07-26
TNSN08312A1 (en) 2009-12-29
EP1979357A1 (fr) 2008-10-15

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