EP1979357A1 - Solid forms of a pyrrolopyrimidine derivative and their use as anti-tumor agents - Google Patents

Solid forms of a pyrrolopyrimidine derivative and their use as anti-tumor agents

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Publication number
EP1979357A1
EP1979357A1 EP07704035A EP07704035A EP1979357A1 EP 1979357 A1 EP1979357 A1 EP 1979357A1 EP 07704035 A EP07704035 A EP 07704035A EP 07704035 A EP07704035 A EP 07704035A EP 1979357 A1 EP1979357 A1 EP 1979357A1
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EP
European Patent Office
Prior art keywords
phenyl
ethyl
pyrrolo
amine
piperazin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07704035A
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German (de)
French (fr)
Inventor
Michael Mutz
Reto Fischer
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Novartis AG
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Novartis AG
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Application filed by Novartis AG filed Critical Novartis AG
Publication of EP1979357A1 publication Critical patent/EP1979357A1/en
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Classifications

    • 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

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-ethyl)-amine, the process for the preparation of these crystalline forms of {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-d]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-d ]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine, and the use of these crystalline forms of {6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-{(R)-1-phenyl-ethyl)-amine in diagnostic methods or therapeutic treatment of warm-blooded animals, especially humans.

Description

SOLID FORMS OF A PYRROLOPYRIMIDINE DERIVATIVE AND THEIR USE AS ANTI-TUMOR AGENTS
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-[4-(4-ethyl- piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((R)-1 -phenyl-ethyl)-amine in diagnostic methods or therapeutic treatment of warm-blooded animals, especially humans.
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 {6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-rf]pyrimidin-4-yl}-((R)-1 -phenyl-ethyl)-amine in diagnostic methods or therapeutic treatment of warm-blooded animals, especially humans.
Background of the Invention
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. In general, the preparation of {6-[4-(4-ethyl-piperazin-1-ylmethyi)-pheπyl]-7H-pyrrolo[2,3- cf]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine is known in the art. However, it is also known that different crystalline forms of the same drug may have substantial differences in certain pharmaceutically important properties. Therefore, there is a continuing need for new solid forms of {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-c0pyrimidin-4-yl}-((R)-1 - phenyl-ethyl)-amine and new methods of preparation.
Summary of the Invention
In accordance with one aspect, 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)- amiπe. 'Preferably, 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 (θ) of 4.4°, 8.8°, 9.1 °, 13.2°, 14.2°, 17.2°, 18.2°, 19.4° ± 0.2° as depicted in FIG. 1.
In accordance with yet another aspect, 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 θ of 4.4°, 8.8°, 9.1 °, 13.2°, 14.2°, 17.2°, 18.2°, 19.4° ± 0.2° as depicted in FIG. 1. Various embodiments and variants are provided.
In accordance with yet another aspect, 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. Preferably, the pharmaceutical composition is for oral administration.
In accordance with yet another aspect, 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:
(a) contacting {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin- 4-yl}-((R)-1-phenyl-ethyl)-amine with an alcohol solvent to form a precipitate;
(b) re-suspending the precipitate in a second alcohol solvent; and
(c) isolating crystalline form A of {6-[4-(4-ethyl-piperaziπ-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-cdpyrimidin-4-yl}-((R)-1-pheny[-ethyl)-amine.
Various embodiments and variants are provided.
In accordance with yet another aspect, 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 produces crystalline form D of {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4- yl}-((R)-1-phenyl-ethyl)-amine and/or crystalline form E of {6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-({R)-1-phenyl-ethyl)-amine, and cooling the mixture to produce crystalline form A of {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-c/]pyrimidin-4-yl}-((R)-1-phenyl-etrιyl)-amiπe.
In accordance with one aspect, 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. Preferably, 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 θ of 5.7°, 6.9°, 7.7°, 11.7°, 15.6°, 18.5° ± 0.2° as depicted in FIG. 5.
In accordance with yet another aspect, 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|pyrimidin-4-yl}-{(R)-1-phenyl-ethyl)-amine is its crystalline form B having an X-ray diffraction pattern with a peak at an angle of diffraction 2 θ of 5.7°, 6.9°, 7.7°, 11.7°, 15.6°, 18.5° ± 0.2° as depicted in FIG. 5. Various embodiments and variants are provided.
In accordance with yet another aspect, 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)-amiπe and a pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition is for oral administration.
In accordance with yet another aspect, 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:
(a) contacting {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-rfjpyrimidin- 4-yl}-({R)-1-phenyl-ethyl)-amine with an alcohol solvent to form a precipitate; and
(c) isolating 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.
Various embodiments and variants are provided. In accordance with one aspect, 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. Preferably, 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 θ 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.
In accordance with yet anothefaspect, 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 θ of 5.7°, 6.8°, 7.5°, 10.2°, 11.6°, 13.3°, 15.2°, 18.4°, 20.8° ± 0.2° as depicted in FIG. 7. Various embodiments and variants are provided.
In accordance with yet another aspect, 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]pyπmidin-4-yl}-{(R)-1-phenyl-ethyl)-amine and a pharmaceutically acceptable carrier or diluent. Preferably, the pharmaceutical composition is for oral administration.
In accordance with yet another aspect, 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:
(a) contacting {6-[4-(4-ethyl-piperazin-1 -ylmethy!)-phenyl]-7H-pyrrolo[2,3-cflpyrimidin- 4-y!}-({f?)-1-phenyl-ethyl)-amine with an alcohol solvent to form a precipitate; and
(b) isolating crystalline form C of {e-^-^-ethyl-piperazin-i-ylmethyO-phenylHH- pyrrolo^.S-dlpyrirnidin^-ylHfRJ-i-phenyl-ethyO-amine.
Various embodiments and variants are provided.
In accordance with yet another aspect, 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. Pharmaceutical 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.
Brief Description of the Drawings
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/]pyπmidin-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(]pyπmidin-4-yl}-((R)-1-phenyl-ethyl)- amine.
Detailed Description of the Invention
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
For the purposes of the present invention, the following terms are defined below.
The crystalline compound, designated herein as "crystalline form A" and referred to hereinafter as crystalline form A of {6-[4-(4-ethyl-piperazιn-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-c/]pyrimιdin-4-yl}-{(R)-1-phenyl-ethyl)-amιne, is a new crystalline form of {6-[4-(4- ethyl-pιperazin-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.
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]pyrimidιn-4-yl}-((f?)-1-phenyl-ethyl)-amine, is a new crystalline form of {6-[4-(4- ethyl-pιperazιn-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.
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]pyrιmtdιn-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. It is characterized via X-ray powder diffraction, DSC, Raman Spectrum and/or infrared spectroscopy. It is further described below. "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.
The term "composition" includes, but is not limited to, a powder, a solution, a suspension, a gel, an ointment, an emulsion and/or mixtures thereof. The term 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.
The term "pharmaceutical 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. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing the active ingredient, additional active ingredient(s) and pharmaceutically acceptable excipients.
The term "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. When referring to a chemical reaction, 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. It should be appreciated that the 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.
The term "substantially free of in reference to a composition, as used herein, means that the substance form which the composition is free of cannot be detected by methods known to those skilled in the art.
The term "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.
{6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/-pyrrolo[2,3-of]pyrimidin-4-yl}-((/:?)-1- phenyl-ethyl)-amine has the following chemical structure:
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?)-1-phenyl-ethyl)-amiπe.
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. Likewise, 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 X-ray diffraction pattern depicted in FIG. 1 for crystalline form A of {6-[4-(4-ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrro)o[2,3-c(]pyrimidin-4-yl}-({R)-1-phenyl-ethyl)-amine is summarized in Table 1. X-ray powder diffraction patterns were measured on a Scintag INC X 1 with CuK alpha radiation source (λ = 1.5406 A).
Table 1. Powder X-Ray Diffraction Peaks for the 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 • deg 2 θ d-spaciπgs Relative Intensity
4.4 20.2 strong
8.8 10.0 weak
9.1 9.7 weak
13.2 6.7 weak
14.2 6.3 weak
17.2 5.1 weak
18.2 4.9 weak
19.4 4.6 weak
It should be kept in mind that slight variations in observed 2 θ angles or d-spacing values are expected based on the specific diffractometer employed, the analyst and the sample preparation technique. More variation is expected for the relative peak intensities. Identification of the exact crystalline form of a compound should be based primarily on observed 2 θ angles with lesser importance attributed to relative peak intensities.
Some margin of error is present in each of the 2 θ angle assignments reported herein. The assigned margin of error, in a preferred variant, the crystalline form A of {6-[4-(4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((/?)-1-phenyl-ethyl)- amine 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). 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 2400C, preferably above 2500C. 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)-phenyϊ]-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. The preferred form of this composition is {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. In one specific embodiment, 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. In another specific embodiment, 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)-pheπyl]-7/-/-pyrrolo[2,3-of]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine involves:
(a) contacting {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin- 4-yl}-«R)-1-pheny[-ethyi)-amine with an alcohol solvent to form a precipitate;
(b) re-suspending the precipitate in a second alcohol solvent; and
(c) isolating crystalline form A of {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/- pyrrolo[2,3-rf]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine.
Various embodiments and variants are provided.
In one embodiment, {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 X-ray diffraction pattern depicted in FIG. 5 for crystalline form B of {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-c/]pyrimidtn-4-yl}-((R)-1-phenyl-ethyl)-amine is summarized in Table 4. X-ray powder diffraction patterns were measured on a Scintag INC X1 with CuK alpha radiation source (λ = 1.5406 A).
Table 4. Powder X-Ray Diffraction Peaks for the Crystalline Form B of {6-[4-(4-Ethyl- piperazin-1-ylmethyl)-phenyl]-7W-pyrrolo[2,3-d]pyrimidin-4-yl}-({R)-1-phenyl- ethyl)-amine ° deg 2 θ d-spacings Relative Intensity
5.7 15.6 strong
6.9 12.8 medium
7.7 11.4 medium
11.7 7.5 medium
15.6 5.7 medium
18.5 4.8 medium
24.4 3.7 weak
24.9 3.6 weak
It should be kept in mind that slight variations in observed 2 θ angles or d-spacing values are expected based on the specific diffractometer employed, the analyst and the sample preparation technique. More variation is expected for the relative peak intensities. Identification of the exact crystalline form of a compound should be based primarily on observed 2 θ angles with lesser importance attributed to relative peak intensities.
Some margin of error is present in each of the 2 θ angle assignments reported herein. The assigned margin of error, in a preferred variant, the crystalline form B of {6-[4-(4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-cy]pyrimidin-4-yl}-{(R)-1-phenyl-ethyl)- amine 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 1380C 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. The preferred form of this composition is {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]- 7H-pyrrolo[2,3-cflρyrimidin-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- Y1H(^)-I -phenyl-ethyl)-amine. In one specific embodiment, 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. In another specific embodiment, 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:
(a) contacting {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-pheπyl]-7H-pyrrolo[2,3-rf]pyrirnidin- 4-yl}-((R)-1-phenyl-ethyl)-amine with an alcohol solvent to form a precipitate; and
(c) isolating crystalline form B of {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-cθpyrimidin-4-yl}-<(R)-1-phenyl-ethyl)-amine.
Various embodiments and variants are provided. In one embodiment, {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.
In one embodiment, {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. X-ray powder diffraction patterns were measured on a Scintag INC X1 with CuK alpha radiation source (λ = 1.5406 A).
Table 5. Powder X-Ray Diffraction Peaks for the Crystalline Form C of {6-[4-(4-Ethyl- piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d|pyrimidin-4-yl}-((f?)-1 -phenyl- ethyl)-amine ° deg 2 B d-spacings Relative Intensity (%)
5.7 15.5 strong
6.8 12.5 strong 7.5 11.8 medium
10.2 8.7 medium
11.6 7.7 medium
13.3 6.7 medium 15.2 5.8 medium
18.4 4.8 medium
18.7 4.7 weak 2O8 4J3 strong
It should be kept in mind that slight variations in observed 2 θ angles or d-spacing values are expected based on the specific diffractometer employed, the analyst and the sample preparation technique. More variation is expected for the relative peak intensities. Identification of the exact crystalline form of a compound should be based primarily on observed 2 θ angles with lesser importance attributed to relative peak intensities.
Some margin of error is present in each of the 2 θ angle assignments reported herein. The assigned margin of error, in a preferred variant, the 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 approximately + 0.02 for each of the peak assignments.
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-αf]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine shows a characteristic endothermic transition at about 99DC followed by an exothermic event at about 1390C 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)-anπine.
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. The preferred form of this composition is {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. In one specific embodiment, 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. In another specific embodiment, 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:
(a) contacting {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin- 4-yl}-((R)-1-phenyl-ethyl)-amine with an alcohol solvent to form a precipitate; and
(b) isolating crystalline form C of {6-[4-(4-ethyl-piperazin-1-y!methyl)-phenyl]-7tf- pyrrolo[2,3-c/]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine. In one embodiment, {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 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.
FIG. 11 shows the X-ray powder diffractogram of 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 measured on a Scintag INC X1 with CuK alpha radiation source (λ = 1.5406 A). As evident from FIG. 11 , 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. The preferred form of this composition is 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. In one specific embodiment, the composition contains at least 90% of the amorphous form of {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/-pyrro!o[2,3- φyrimidin-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. In another specific embodiment, 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. In yet another embodiment, 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.
Also provided are pharmaceutical 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. In addition to the active compound, 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. These 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.
The pharmaceutical 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.
The pharmaceutical 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. 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.
The amount of active ingredient included in a unit dosage form depends on the type of formulation in which the active ingredient is presented. 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.
In another aspect, the invention also provides methods of treatment using the compounds and the pharmaceutical compositions of this invention. By 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. Most notably, 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. Moreover, their highly selective and potent inhibition of the 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. In addition, 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.
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. Depending on species, age, individual condition, mode of administration and the clinical picture in question, 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. Especially tablets or gelatin capsules containing the active substance together with diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycerin; and/or 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. The pharmacologically active compounds of the present invention may further be used in the form of preparations for parenteral administration or infusion solutions. 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.
The invention is further defined by reference to the following examples describing in detail the preparation of the compound and the compositions of the present invention, as well as their utility. It will be apparent to those skilled in the art, that many modifications, both to materials, and methods, may be practiced with out departing from the purpose and interest of this invention. The examples that follow are not intended to limit the scope of the invention as defined hereinabove or as claimed below.
EXAMPLES
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 50-600C. The solution is cooled to about 00C 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 250C. The solution is isolated by filtration to produce the 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.
Example 2 Preparation of crystalline form B of {6-[4-(4-ethyl-piperazin-1 -ylmethyl)- phenyl]-7W-pyrrolo[2,3-d]pyrimidin-4-yl}-{(R)-1-phenyl-ethyl)-amine using methanol
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 O0C 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. Example 3 Preparation of crystalline form B of {6-[4-(4-ethyl-piperazin-1 -ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-({/?)-1-phenyl-ethyl)-amine using methanol
A reactor is charged with crude {6-[4-(4-ethyl-pιperazιn-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-c(]pyrιmιdιn-4-yl}-((R)-1-phenyl-ethyl)-amιne and ethanol The suspension is aged to about 50-60°C( then cooled to about O0C before crystalline form B of {6-[4-(4-ethyl- pιperazin-1-y!methyl)-phenyl]-7H-pyrrolo[2,3-dJpyπmιdιn-4-yl}-((R)-1-phenyl-ethyl)-amιne is isolated by filtration.
Example 4 Preparation of crystalline form C of {6-[4-(4-ethyl-piperazin-1 -ylmethyl)- phenyl]-7W-pyrrolo[2,3-c/]pyrimidin-4-yl}-((/?)-1-phenyl-ethyl)-amine using methanol
A reactor is charged with crude {6-[4-(4-ethyl-piperazιn-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-(flpyrιmidιn-4-yl}-({R)-1-phenyl-ethyl)-amιne and methanol The suspension is aged to about 50-600C, then cooled to about 00C before crystalline form C of {6-[4-(4-ethyl- piperazιn-1 -ylmethyl)-phenyl]-7H-pyrrolo[2J3-c/]pyrιmιdin-4-yl}-({R)-1 -phenyl-ethyl)-amme is isolated by filtration.
Example 5 Preparation of amorphous form of {6-[4-(4-ethyl-piperazin-1 -ylmethyl)- phenyl]-7W-pyrro[o[2,3-cflpyrimϊdin-4-yl}-((R)-1-phenyl-ethyi)-amine
About 100 mg of {6-[4-(4-ethyl-piperazm-1-ylmethyl)-phenyl]-7W-pyrrolo[2,3- φyπmιdιn-4-y]H(ft)-1-phenyl-ethyl)-amme is suspended in about 5 mL of a 1 1 mixture of acetone/n-hexane (v/v) The suspension is equilibrated for about 15 minutes in an ultrasonic bath at room temperature and then filtered using a 0 2 μm cellulose filter. The clear solution is allowed to evaporate under vacuum for about 15-20 minutes The solid residue is characterized by X-ray Powder Diffraction using a Bruker D8 Advance Diffractometer with CuKa radiation (λ = 1 5406 A) The X-ray powder pattern is shown in Figure 11 and characterized by a broad halo effect.

Claims

What Is Claimed Is:
1. A compound which is a crystalline form A of {6-[4-(4-ethyl-piperazrn-1 -ylmethyl)- phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-((f?)-1-phenyl-ethyl)-amine.
2. The compound according to Claim 1 , which shows on X-ray diffraction a peak at an angle of diffraction 2 theta (θ), of 4.4° ± 0.2 degrees <°).
3. The compound according to Claim 1 , having an X-ray diffraction pattern, expressed in terms of 2 θ angles, that includes five or more peaks selected from the group consisting of about 4.4°, 8.8°, 9.1 °, 13.2°, 14.2°, 17.2°, 18.2°, 19.4°± 0.2°.
4. The compound according to Claim 1 , having substantially the same X-ray diffraction pattern as shown in FIG. 1.
5. The compound according to Claim 1 , having an infrared absorption spectrum with absorption bands at about 695, 802, 836, 923, 934, 1013, 1095, 1146, 1165, 1207, 1229, 1292, 1300, 1310, 1348, 1358, 1507, 1546, 1595 and 3269 ± 2 cm"1.
6. A composition comprising {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7/-/-pyrrolo[2,3- d]pyrimidin-4-yl}-{(R)-1-phenyl-ethyl)-amine as a solid, wherein at least 80% by weight of said solid {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-y!}-((R)-1- phenyl-ethyl)-amine is the crystalline form A,
7. The composition according to Claim 6, wherein at least 90% by weight of said solid {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl}-((R)-1-phenyl- ethylj-amine is the crystalline form A.
8. The composition according to Claim 6, wherein at least 95% by weight of said solid {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-{(R)-1-phenyl- ethyl)-amine is the crystalline form A.
9. A pharmaceutical composition comprising: {a) the compound of Claim 1 ; and
(b) a pharmaceutically acceptable carrier or diluent.
10. The pharmaceutical composition according to Claim 9, further comprising one or more pharmaceutically acceptable excipients.
11. The pharmaceutical composition according to Claim 9, which is a dosage form suitable for oral administration.
12. The pharmaceutical composition according to Claim 11 , wherein said dosage form is selected from a tablet, capsule or solution.
13. Use 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 according to any one of the Claims 1-5, for the preparation of a pharmacological agent for the treatment of a tumor disease.
14. A process for the preparation of crystalline form A of {6-[4-{4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl}-{(f?)-1-phenyl-ethyl)-amine comprising:
(a) contacting {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin- 4-yl}-((R)-1-phenyl-ethyl)-amine in a solvent to form a precipitate;
(b) re-suspending the precipitate with a second solvent to form a second precipitate; and
(c) isolating the second precipitate.
15. The process according to Claim 14, wherein the solvent is methanol.
16. The process according to Claim 14, wherein the second solvent is isopropanol.
17. The process according to Claim 14, further comprising drying the isolated precipitate.
18. A compound which is the crystalline form A of {6-[4-(4-ethyl-piperazin-1-ylmethy!)- phenyl]-7H-pyrrolo[2,3-dipyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine produced by the process of Claim 14.
19. A compound which is the crystalline form B of {6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-tf]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine.
20. The compound according to Claim 19, which shows on X-ray diffraction a peak at an angle of diffraction 2 θ, of 5.7° ± 0.2°.
21. The compound according to Claim 19, having an X-ray diffraction pattern, expressed in terms of 2 θ angles, that includes three or more peaks selected from the group consisting of about 5.7°, 6.9°, 7.7°, 11.7°, 15.6°, 18.5° ± 0.2°.
22. The compound according to Claim 19, having substantially the same X-ray diffraction pattern as shown in FIG. 5.
23 A composition comprising {6-[4-(4-ethyl-piperazιn-1-ylmethyl)-pheny!]-7tf-pyrrolo[2,3- rf]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amιne as a solid, wherein at least 80% by weight of said solid {6-[4-(4-ethyl-piperazιn-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrιmidin-4-yl}-((R)-1- phenyl-ethyl)-amine is the crystalline form B.
24. The composition according to Claim 23, wherein at least 90% by weight of said solid {6-[4-(4-ethyl-pιperazιn-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-rf|pyrimidιn-4-yl}-{(/?)-1-phenyl- ethyl)-amine is the crystalline form B.
25. The composition according to Claim 23, wherein at least 95% by weight of said solid {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(|pyrimidιn-4-yl}-((R)-1-phenyl- ethyl)-amine is the crystalline form B.
26. A pharmaceutical composition comprising:
(a) the compound of Claim 19; and
(b) a pharmaceutically acceptable carrier or diluent.
27. The pharmaceutical composition according to Claim 26, further comprising one or more pharmaceutically acceptable excipients.
28. The pharmaceutical composition according to Claim 26, which is a dosage form suitable for oral administration.
29. The pharmaceutical composition according to Claim 28, wherein said dosage form is selected from a tablet, capsule or solution.
30. Use of crystalline form B of {6-[4-<4-ethyl-pιperazιn-1 -ylmethyl)-phenyl]-7H- pyrrolo[2,3-rf|pyrιmidin-4-yl}-((f?)-1-phenyl-et.hy!)-amine according to any one of the Claims 19-22, for the preparation of a pharmacological agent for the treatment of a tumor disease.
31. A process for the preparation of crystalline form B of {6-[4-{4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-of]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine comprising:
(a) contacting {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-cf]pyrimidin- 4-yl}-{{R)-1-phenyl-ethyl)-amine in a solvent to form a precipitate; and
(c) isolating the second precipitate.
32. The process according to Claim 31 , wherein the solvent is methanol.
33. The process according to Claim 31 , further comprising drying the isolated precipitate.
34. A compound which is the crystalline form C of {6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-cf]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine.
35. The compound according to Claim 34, which shows on X-ray diffraction a peak at an angle of diffraction 2 θ, of 7.5° ± 0.2°.
36. The compound according to Claim 34, having an X-ray diffraction pattern, expressed in terms of 2 θ angles, that includes five or more peaks selected from the group consisting of about 5.7°, 6.8°, 7.5°, 10.2°, 11.6°, 13.3°, 15.2°, 18.4°, 20.8° ± 0.2°.
37. The compound according to Claim 34, having substantially the same X-ray diffraction pattern as shown in FIG. 7.
38. The compound according to Claim 34, having an infrared absorption spectrum with absorption bands at about 701 , 764, 842, 932, 1013, 1110, 1127, 1147, 1164, 1121 , 1300, 1312, 1347, 1544, 1597, 3130 and 3429 cm"1 ± 2 cm"1.
39. A composition comprising {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3- o0pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine as a solid, wherein at least 80% by weight of said solid {6-[4-(4-ethy!-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3-φyrimidin-4-yl}-((R)-1 - phenyl-ethyl)-amine is the crystalline form C.
40. The composition according to Claim 39, wherein at least 90% by weight of said solid {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-cf]pyrimidin-4-yl}-((R)-1-phenyl- ethyl)-amine is the crystalline form C.
41. The composition according to Claim 40, wherein at least 95% by weight of said solid {e-^-f^ethyl-piperazin-i-ylmethyO-phenyn-TH-pyrrolo^.S-tflpyrirnidin^-yiy-ft^-i-phenyl- ethyl)-amine is the crystalline form C.
42. A pharmaceutical composition comprising:
(a) the compound of Claim 34; and
(b) a pharmaceutically acceptable carrier or diluent.
43. The pharmaceutical composition according to Claim 42, further comprising one or more pharmaceutically acceptable excipients.
44. The pharmaceutical composition according to Claim 42, which is a dosage form suitable for oral administration.
45. The pharmaceutical composition according to Claim 44, wherein said dosage form is selected from a tablet, capsule or solution.
46. Use of crystalline form C of {6-[4-(4-ethyl-piperazin-1-y!methyl)-phenyl]-7H- pyrrolo[2,3-c/]pyrimidin-4-yl}-((/?)-1-phenyl-ethyl)-amine according to any one of the Claims 34-38, for the preparation of a pharmacological agent for the treatment of a tumor disease.
47. A process for the preparation of crystalline form C of {6-[4-(4-ethyl-piperazin-1- ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl}-({R)-1-phenyl-ethyt)-amine comprising:
(a) contacting {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin- 4-yl}-((R)-1-pheny!-ethy!)-amine in a solvent to form a precipitate; and
(b) isolating the precipitate.
48. The process according to Claim 47, wherein the solvent is methanol.
49. The process according to Claim 47, further comprising drying the isolated precipitate.
50. A compound which is the crystalline form C of {6-[4-(4-ethyl-piperazin-1-ylmethyl)- phenyl]-7H-pyrrolo[2,3-rf]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine produced by the process of Claim 46.
51. A compound which is amorphous {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H- pyrrolo[2,3-c/Jpyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine.
52. The compound according to Claim 51 , having substantially the same X-ray diffraction pattern as shown in FIG. 11.
53. A composition comprising {6-[4-(4-ethyl-piperazin-1-ylmethyi)-phenyl]-7H-pyrrolo[2,3- cf]pyrimidin-4-yl}-((R)-1-phenyl-ethyl)-amine as a solid, wherein at least 80% by weight of said solid {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c(]pyrimidin-4-yl}-({R)-1- phenyl-ethy!)-amine is amorphous.
54. The composition according to Claim 53, wherein at least 90% by weight of said solid {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolo[2,3-c/]pyrimidin-4-yl}-({R)-1-phenyl- ethyl)-amine is amorphous.
55. The composition according to Claim 53, wherein at least 95% by weight of said solid {6-[4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrro!o[2,3-c/lpyrimidin-4-yl}-((/?)-1-phenyl- ethyl)-amine is amorphous.
56. The composition according to Claim 53, wherein substantially all of the solid {6-[4-{4- ethyl-piperazin-1-ylmethyl)-phenyl]-7H-pyrrolot2,3-c/]pyrimidin-4-yl}-((R)-1-pheny!-ethyl)- amine is amorphous.
57. A pharmaceutical composition comprising:
(a) the compound of Claim 51 ; and
(b) a pharmaceutically acceptable carrier or diluent.
58. The pharmaceutical composition according to Claim 57, further comprising one or more pharmaceutically acceptable excipients.
59. The pharmaceutical composition according to Claim 57, is in a dosage form suitable for oral administration.
60. The pharmaceutical composition according to Claim 51 , wherein the dosage form is selected from a tablet, capsule or solution.
61. Use of amorphous {6-[4-(4-ethyl-piperazin-1 -ylmethyl)-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-4-yl}-((R)-1-phenyJ-ethyl)-amine according to any one of the Claims 51-60, for the preparation of a pharmacological agent for the treatment of a tumour disease.
EP07704035A 2006-01-23 2007-01-19 Solid forms of a pyrrolopyrimidine derivative and their use as anti-tumor agents Withdrawn EP1979357A1 (en)

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AU2002349013A1 (en) * 2001-10-29 2003-05-12 Novartis Ag Use of 7h-pyrrolo(2,3-d)pyrimidine derivatives in the treatment of solid tumor diseases
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CA2636954A1 (en) 2007-07-26
PE20071323A1 (en) 2008-02-15
AR059090A1 (en) 2008-03-12
AU2007206925A1 (en) 2007-07-26
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BRPI0706729A2 (en) 2011-04-05
RU2008134314A (en) 2010-02-27
KR20080095859A (en) 2008-10-29

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