WO2010059795A1 - Nouvelles formes d'un composé indazolo [5,4-a] pyrrolo [3,4-c] carbazole - Google Patents

Nouvelles formes d'un composé indazolo [5,4-a] pyrrolo [3,4-c] carbazole Download PDF

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Publication number
WO2010059795A1
WO2010059795A1 PCT/US2009/065099 US2009065099W WO2010059795A1 WO 2010059795 A1 WO2010059795 A1 WO 2010059795A1 US 2009065099 W US2009065099 W US 2009065099W WO 2010059795 A1 WO2010059795 A1 WO 2010059795A1
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Prior art keywords
theta
degrees
compound
crystalline form
ptsa
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PCT/US2009/065099
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English (en)
Inventor
Stephen Bierlmaier
Laurent Courvoisier
Raymond Scott Field
R. Curtis Haltiwanger
Martin J. Jacobs
Robert E. Mckean
Mehran Yazdanian
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Cephalon, Inc.
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Publication date
Priority to MX2011005055A priority Critical patent/MX2011005055A/es
Priority to CN200980146334.7A priority patent/CN102216306B/zh
Priority to ES09764381T priority patent/ES2399588T3/es
Priority to AU2009316600A priority patent/AU2009316600B2/en
Priority to EP09764381A priority patent/EP2367829B1/fr
Priority to NZ592868A priority patent/NZ592868A/xx
Application filed by Cephalon, Inc. filed Critical Cephalon, Inc.
Priority to CA2742790A priority patent/CA2742790C/fr
Priority to JP2011536622A priority patent/JP2012509282A/ja
Publication of WO2010059795A1 publication Critical patent/WO2010059795A1/fr
Priority to IL212749A priority patent/IL212749A/en
Priority to US13/105,457 priority patent/US8513272B2/en
Priority to HK12102681.6A priority patent/HK1162177A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—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 three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to compositions which contain the novel fused pyrrolocarbazole compound Compound I, pharmaceutical compositions comprising Compound I, processes to reproducibly make them and methods of treating patients using them.
  • APIs can be prepared in a variety of different forms, for example, chemical derivatives, solvates, hydrates, co-crystals, or salts.
  • APIs may also be amorphous, may have different crystalline polymorphs, or may exist in different solvation or hydration states.
  • crystalline polymorphs typically have different solubilities such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph.
  • Polymorphs can also differ in properties such as stability, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the crystalline state of an API is one of many ways in which to modulate the physical and pharmacological properties thereof.
  • fused pyrrolocarbazoles Various synthetic small organic molecules that are biologically active and generally known in the art as "fused pyrrolocarbazoles” have been prepared (See U.S. Pat. Nos. 5,475,110; 5,591,855; 5,594,009; 5,616,724; and 6,630,500). In addition, U.S. Pat. No. 5,705,511 discloses fused pyrrolocarbazole compounds which possess a variety of functional pharmacological activities.
  • the fused pyrrolocarbazoles were disclosed to be used in a variety of ways, including: enhancing the function and/or survival of cells of neuronal lineage, either singularly or in combination with neurotrophic factor(s) and/or indolocarbazoles; enhancing trophic factor-induced activity; inhibition of protein kinase C ("PKC”) activity; inhibition of trk tyrosine kinase activity; inhibition of proliferation of a prostate cancer cell-line; inhibition of the cellular pathways involved in the inflammation process; and enhancement of the survival of neuronal cells at risk of dying.
  • PLC protein kinase C
  • a specific fused pyrrolocarbazole compound having the chemical designation 11- isobutyl-2-methyl-8-(2-pyrimidinylamino)-2,5,6,l l,12,13-hexahydro-4H-indazolo[5,4- ⁇ ]pyrrolo [3,4-c]carbazol-4-one is a potent, orally-active TIE-2/VEGF-R inhibitor having anti-tumor and anti-angiogenic activity, and is represented by the following formula (I):
  • Compound I This Compound is referred to hereinafter as "Compound I”.
  • U.S. 7,169,802 describes Compound I and utility thereof.
  • Different chemical or solid state forms of Compound I can have different melting points, solubilities or rates of dissolution; these physical properties, either alone or in combination, can affect bioavailability.
  • the physical properties of the various chemical/solid state forms of Compound I can also affect other aspects of drug development, such as manufacturing, processing, and storage characteristics. In light of the potential benefits of alternative forms of APIs, a need exists to identify and prepare alternative forms of Compound I.
  • compositions comprising one or more of these chemical forms are also described, as are methods of treatment utilizing such compositions.
  • the pharmaceutical compositions of the present invention may be used in a variety of ways, including: for inhibition of angiogenesis; as antitumor agents; for enhancing the function and/or survival of cells of neuronal lineage, either singularly or in combination with neurotrophic factor(s) and/or indolocarbazoles; for enhancing trophic factor-induced activity; inhibition of kinase activity, such as trk tyrosine kinase (“trk”), vascular endothelial growth factor receptor (“VEGFR”) kinase, preferably VEGFRl and VEGFR2, mixed lineage kinase (“MLK”), dual leucine zipper bearing kinase (“DLK”), platelet derived growth factor receptor kinase (“PDGFR”), protein kinase C (“PKC
  • compositions may useful for inhibition of c-met, c-kit, and mutated Flt-3 containing internal tandem duplications in the juxtamembrane domain. Because of these varied activities, the disclosed pharmaceutical compositions find utility in a variety of settings, including research and therapeutic environments.
  • the pharmaceutical compositions of the present invention are useful for treating or preventing angiogenesis and angiogenic disorders such as cancer of solid tumors, endometriosis, retinopathy, diabetic retinopathy, psoriasis, hemangioblastoma, ocular disorders or macular degeneration.
  • the pharmaceutical compositions of the present invention are useful for treating or preventing neoplasia, rheumatoid arthritis, chronic arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.
  • the pharmaceutical compositions of the present invention are useful for treating or preventing neurodegenerative diseases and disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, chemotherapy-induced peripheral neuropathy, AIDS related peripheral neuropathy, or injuries of the brain or spinal chord.
  • the pharmaceutical compositions of the present invention are useful for treating or preventing prostate disorders such as prostate cancer or benign prostate hyperplasia.
  • compositions of the present invention are useful for treating or preventing multiple myeloma and leukemias including, but not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, and chronic lymphocytic leukemia.
  • the present invention is directed to pharmaceutical compositions which comprise one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a form of the present invention.
  • FIG. 1 is an X-ray Powder Diffractogram (XRPD) of Form pTSA-Ai
  • FIG.2 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo-Gravimetric Analysis (TGA) Thermogram overlay of Form pTSA-Ai
  • FIG. 3 is an X-ray Powder Diffractogram (XRPD) of Form pTSA-A 2
  • FIG. 4 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo-Gravimetric Analysis (TGA) Thermogram overlay of Form pTSA-A 2
  • FIG. 5 is an X-ray Powder Diffractogram (XRPD) of Form pTSA-B 2
  • FIG. 6 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo-Gravimetric Analysis (TGA) Thermogram overlay of Form pTSA-B 2
  • FIG. 7 is an X-ray Powder Diffractogram (XRPD) of Form pTSA-C 2
  • FIG. 8 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo-Gravimetric Analysis (TGA) Thermogram overlay of Form pTSA-C 2
  • FIG. 9 is an X-ray Powder Diffractogram (XRPD) of Form A 0
  • FIG. 10 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form Ao
  • FIG. 11 is an X-ray Powder Diffractogram (XRPD) of Form B 0
  • FIG. 12 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form B 0
  • FIG. 13 is an X-ray Powder Diffractogram (XRPD) of Form C 0
  • FIG. 14 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form Co
  • FIG. 15 is an X-ray Powder Diffractogram (XRPD) of Form D 0
  • FIG. 16 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form Do
  • FIG. 17 is an X-ray Powder Diffractogram (XRPD) of Form Si
  • FIG. 18 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form Si
  • FIG. 19 is an X-ray Powder Diffractogram (XRPD) of Form S 2
  • FIG. 20 is a Differential Scanning Calorimetry (DSC) Thermogram of Form S 2
  • FIG. 21 is an X-ray Powder Diffractogram (XRPD) of Form S 3
  • FIG. 22 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 3
  • FIG. 23 is an X-ray Powder Diffractogram (XRPD) of Form S 4
  • FIG. 24 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 4
  • FIG. 25 is an X-ray Powder Diffractogram (XRPD) of Form S 6
  • FIG. 26 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 6
  • FIG. 27 is an X-ray Powder Diffractogram (XRPD) of Form S 7
  • FIG. 28 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 7
  • FIG. 29 is an X-ray Powder Diffractogram (XRPD) of Form S 8
  • FIG. 30 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 8
  • FIG. 31 is an X-ray Powder Diffractogram (XRPD) of Form S 9
  • FIG. 32 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 9
  • FIG. 33 is an X-ray Powder Diffractogram (XRPD) of Form Si 0
  • FIG. 34 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 10
  • FIG. 35 is an X-ray Powder Diffractogram (XRPD) of Form Si 3
  • FIG. 36 is an X-ray Powder Diffractogram (XRPD) of Form Si 4
  • FIG. 37 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form Si 4
  • FIG. 38 is an X-ray Powder Diffractogram (XRPD) of Form S 15
  • FIG. 39 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 15
  • FIG. 40 is an X-ray Powder Diffractogram (XRPD) of Form S 16
  • FIG. 41 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 16
  • FIG. 42 is an X-ray Powder Diffractogram (XRPD) of Form S 17
  • FIG. 43 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form Sn
  • FIG. 44 is an X-ray Powder Diffractogram (XRPD) of Form Si 8
  • FIG. 45 is a Differential Scanning Calorimetry (DSC) Thermogram of Form S 18
  • FIG. 46 is an X-ray Powder Diffractogram (XRPD) of Form S 19
  • FIG. 47 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S 19
  • FIG. 48 is an X-ray Powder Diffractogram (XRPD) of Form S 20
  • FIG. 49 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Form S20
  • FIG. 50 is an X-ray Powder Diffractogram (XRPD) of Amorphous Solid (AS)
  • FIG. 51 is a Differential Scanning Calorimetry (DSC) Thermogram and Thermo- Gravimetric Analysis (TGA) Thermogram overlay of Amorphous Solid (AS)
  • FIG. 52 depicts a view of molecule A of Compound I from the single crystal structure A 0 , showing the numbering scheme employed
  • FIG. 53 depicts a view of molecule B of Compound I from the single crystal structure Form Ao, showing the numbering scheme employed
  • FIG. 54 depicts a view of the hydrogen bonded head-to-head dimer formed by the two independent molecules of Compound I in the single crystal structure Form Ao
  • FIG. 55 is an X-ray Powder Diffractogram (XRPD) of the Compound I single crystal structure Form Ao.
  • Representative XRPD peaks for the S9 form are listed in the following Table 16.
  • Representative XRPD peaks for the S 10 form are listed in the following Table 17.
  • the present invention provides a crystalline form of Compound I that is Form pTSA-Ai, Form PTSA-A 2 , Form pTSA-B 2 , Form pTSA-C 2 or a mixture thereof.
  • the crystalline form is Form pTSA-Ai.
  • the crystalline form is Form pTSA-A 2 .
  • the crystalline form is Form pTSA-B 2 .
  • the crystalline form is Form pTSA-C 2 .
  • the X-ray powder diffraction pattern of Form pTSA-Ai comprises peaks at 5.37 ⁇ 0.2 degrees 2-theta, 6.79 ⁇ 0.2 degrees 2-theta,
  • the crystalline form Form pTSA-Ai has an X-ray powder diffraction pattern substantially as depicted in FIGURE 1.
  • the crystalline form has an X-ray powder diffraction pattern substantially as depicted in FIGURE 3.
  • a further aspect pertains to a crystalline form of Compound I that is Form pTSA-B 2 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 3.75, 5.63, 8.40, 11.31 and/or 15.12 ⁇ 0.2 degrees 2-theta.
  • the crystalline form has an X-ray powder diffraction pattern substantially as depicted in FIGURE 5.
  • An additional aspect of the present invention pertains to a crystalline form of
  • Compound I that is Form pTSA-C 2 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 5.72, 8.49, 11.37, 13.26 and/or 16.95 ⁇
  • the crystalline form has an X-ray powder diffraction pattern substantially as depicted in FIGURE 7.
  • Yet another aspect of the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising Compound I Form pTSA-Ai, Compound I Form pTSA-A 2 , Compound I Form pTSA-B 2 , Compound I Form pTSA-C 2 or a mixture thereof.
  • the pharmaceutical composition comprises Form pTSA-Ai. In another aspect, the pharmaceutical composition comprises Form pTSA-A 2 . In still another aspect, the pharmaceutical composition comprises Form pTSA-B 2 . In an additional aspect, the pharmaceutical composition comprises Form pTSA-C 2 .
  • Still another aspect of the present invention pertains to a method for preparing a crystalline form of Compound I that is Form pTSA-Ai, comprising the step of crystallizing Compound I in the presence of methylene chloride to yield Form pTSA-Ai.
  • a further aspect pertains to a method for preparing a crystalline form of Compound I that is Form PTSA-A 2 , comprising the step of crystallizing Compound I in the presence of methylene chloride and pTSA acid monohydrate to yield Form pTSA-A 2 .
  • An additional aspect pertains to a method for preparing a crystalline form of Compound I that is Form pTSA-B 2 , comprising the step of crystallizing Compound I in the presence of acetone and pTSA acid monohydrate to yield Form pTSA-B 2 .
  • Still a further aspect of the present invention pertains to a method for preparing a crystalline form of Compound I that is Form pTSA-C 2 , comprising the step of crystallizing Compound I in the presence of n-propanol and p-toluenesulfonic acid monohydrate to yield Form pTSA-C 2 .
  • a further aspect of the present invention pertains to a method of treating solid tumors comprising the step of administering to a patient in need thereof a therapeutically effective amount of a crystalline form of Compound I that is Form pTSA-Ai, Form pTSA-A 2 , Form pTSA-B 2 , Form pTSA-C 2 or a mixture thereof.
  • the crystalline form is Form pTSA-Ai.
  • the crystalline form is Form pTSA-A 2 .
  • the crystalline form is Form pTSA-B 2 .
  • the crystalline form is Form pTSA-C 2 .
  • Still another aspect of the present invention pertains to a method of treating solid tumors comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising Compound I Form pTSA-Ai, Compound I Form pTSA-A 2 , Compound I Form pTSA-B 2 , Compound I Form pTSA-C 2 or a mixture thereof.
  • the pharmaceutical composition comprises Form pTSA-Ai.
  • the pharmaceutical composition comprises Form pTSA-A 2 .
  • the pharmaceutical composition comprises Form pTSA-B 2 .
  • the pharmaceutical composition comprises Form pTSA-C 2 .
  • An additional aspect of the present invention pertains to a crystalline form of Compound I that is Form Ao, Form Bo, Form Co, Form Do or a mixture thereof.
  • the crystalline form is Form A o.
  • the crystalline form is Form B 0 .
  • the crystalline form is Form Co.
  • the crystalline form is Form Do.
  • a further aspect pertains to a crystalline form of Compound I that is Form Ao, having an X-ray powder diffraction pattern substantially as depicted in FIGURE 9.
  • a further aspect pertains to a crystalline form of Compound I that is Form Bo, characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.02, 9.27, 12.34, 15.40 and/or 27.18 ⁇ 0.2 degrees 2-theta.
  • Another aspect pertains to a crystalline form of Compound I that is Form Bo, having an X-ray powder diffraction pattern substantially as depicted in FIGURE 11.
  • Still another aspect of the present invention pertains to a crystalline form of Compound I that is Form Co, characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 8.18, 15.48, 16.41, and/or 20.87 ⁇ 0.2 degrees 2-theta.
  • a further aspect pertains to a crystalline form of Compound I that is Form Co, having an X- ray powder diffraction pattern substantially as depicted in FIGURE 13.
  • a further aspect pertains to a crystalline form of Compound I that is Form Do, characterized by an X-ray diffraction pattern comprising one or more of the following peaks: 7.16, 7.51, 12.75, 21.04 and/or 26.86 ⁇ 0.2 degrees 2-theta.
  • Another aspect pertains to a crystalline form of Compound I that is Form Do, having an X-ray powder diffraction pattern substantially as depicted in FIGURE 15.
  • compositions comprising Compound I Form A 0 , B 0 , Co, D 0 or a mixture thereof.
  • the pharmaceutical composition comprises Form Ao.
  • pharmaceutical composition comprises Form Bo.
  • pharmaceutical composition comprises Form Co.
  • pharmaceutical composition comprises Form Do.
  • An additional aspect of the present invention pertains to a method for preparing a crystalline form of Compound I that is Form A 0 , comprising the step of crystallizing Compound I in the presence of isopropyl acetate to yield Form Ao.
  • a further aspect pertains to a method for preparing a crystalline form of Compound I that is Form Ao, comprising the step of crystallizing Compound I in the presence of acetic acid and isopropyl acetate to yield Form A 0 .
  • Yet another aspect pertains to a method for preparing a crystalline form of Compound I that is Form Ao, comprising the step of heating Compound I.
  • a further aspect of the present invention pertains to a method for preparing a crystalline form of Compound I that is Form B 0 , comprising the step of crystallizing Compound I in the presence of acetonitrile to yield Form Bo. Still another aspect pertains to a method for preparing a crystalline form of Compound I that is Form Co, comprising the step of crystallizing Compound I in the presence of dichloroethane to yield Form Co. An additional aspect pertains to a method for preparing a crystalline form of Compound I that is Form Do, comprising the step of crystallizing Compound I in the presence of methanol to yield Form Do.
  • An additional aspect of the present invention pertains to a method of treating solid tumors comprising the step of administering to a patient in need thereof a therapeutically effective amount of a crystalline form of Compound I that is Form Ao, Form Bo, Form Co,
  • An additional aspect of the present invention pertains to a crystalline form of Compound I that is Form S 1 , Form S 2 , Form S3, Form S 4 , Form S 6 , Form S 7 , Form Ss, Form S9, Form S 10 , Form S 13 , Form S14, Form S 15 , Form S 16 , Form Sn, Form S 18 , Form S 19 or Form S 20 , or a mixture thereof.
  • the crystalline form of Compound I is Form S 1 .
  • the crystalline form of Compound I is Form S 2 .
  • the crystalline form of Compound I is Form S 3 .
  • the crystalline form of Compound I is Form S 4 .
  • the crystalline form of Compound I is Form S 6 . In still another aspect, the crystalline form of Compound I is Form S 7 . In yet another aspect, the crystalline form of Compound I is Form Ss. In a further aspect, the crystalline form of Compound I is Form S 9 . In an additional aspect, the crystalline form of Compound I is Form S 10. In still another aspect, the crystalline form of Compound I is Form S 13 . In a further aspect, the crystalline form of Compound I is Form Si 4 . In still another aspect, the crystalline form of Compound I is Form S 15 . In an additional aspect, the crystalline form of Compound I is Form S 16 . In still another aspect, the crystalline form of Compound I is Form Si 7 . In a further aspect, the crystalline form of Compound I is Form S 18 . In yet another aspect, the crystalline form of Compound I is Form S 19 . In an additional aspect, the crystalline form of Compound I is Form S 2 o-
  • a further aspect of the present invention pertains to a crystalline form of Compound I that is Form S 1 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 5.50, 7.21, 7.76, 19.69 and/or 25.26 ⁇ 0.2 degrees 2-theta.
  • Another aspect pertains to a crystalline form of Compound I that is Form S 2 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 7.26, 14.52, 19.91 and/or 21.63 ⁇ 0.2 degrees 2-theta. Still another aspect pertains to a crystalline form of Compound I that is Form S3, characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.67, 17.40, 20.04, 20.58 and/or 25.43 ⁇ 0.2 degrees 2-theta.
  • Yet another aspect pertains to a crystalline form of Compound I that is Form S 4 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 5.55, 7.84, 18.86, 19.71 and/or 22.31 ⁇ 0.2 degrees 2-theta.
  • An additional aspect pertains to a crystalline form of Compound I that is Form S 6 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 8.10, 13.46, 17.29, 20.78 and/or 28.03 ⁇ 0.2 degrees 2-theta.
  • a further aspect pertains to a crystalline form of Compound I that is Form S 7 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.86, 13.93, 19.27, 20.87 and/or 21.06 ⁇ 0.2 degrees 2-theta.
  • Another aspect of the present invention pertains to a crystalline form of Compound I that is Form Ss, characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.35, 7.31, 21.54, 21.65 and/or 27.40 ⁇ 0.2 degrees 2-theta.
  • Still another aspect pertains to a crystalline form of Compound I that is Form S 9 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.77, 13.53, 18.81, 20.84 and 26.8 degrees 2-theta.
  • Yet another aspect pertains to a crystalline form of Compound I that is Form S 10 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 5.84, 7.64, 11.49, 20.23, and/or 23.84 ⁇ 0.2 degrees 2-theta.
  • a further aspect of the present invention pertains to a crystalline form of Compound I that is Form S 13 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.75, 7.08, 7.26, 7.60 and/or 22.70 ⁇ 0.2 degrees 2-theta.
  • An additional aspect pertains to a crystalline form of Compound I that is Form S 14, characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 7.44, 14.88, 20.20, 21.61 and/or 22.39 ⁇ 0.2 degrees 2-theta.
  • Still another aspect pertains to a crystalline form of Compound I that is Form S 15 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 7.29, 12.30, 14.59, 19.79 and/or 21.27 ⁇ 0.2 degrees 2-theta.
  • a further aspect of the present invention pertains to a crystalline form of Compound I that is Form S 16 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.50, 17.19, 20.36, 20.68 and/or 27.92 ⁇ 0.2 degrees 2-theta.
  • An additional aspect pertains to a crystalline form of Compound I that is Form Sn, characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.24, 12.68, 17.37, 18.12 and/or 21.51 ⁇ 0.2 degrees 2-theta.
  • Yet another aspect pertains to a crystalline form of Compound I that is Form S 18 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 5.91, 6.66, 16.25, 17.59 and/or 23.82 ⁇ 0.2 degrees 2-theta.
  • Still another aspect pertains to a crystalline form of Compound I that is Form S 19 , characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 8.27, 8.32, 16.53, 16.59 and 23.28 ⁇ 0.2 degrees 2-theta.
  • a further aspect of the present invention pertains to a crystalline form of Compound I that is Form S20, characterized by an X-ray powder diffraction pattern comprising one or more of the following peaks: 6.64, 6.77, 11.03, 15.27 and/or 24.27 ⁇ 0.2 degrees 2-theta.
  • An additional aspect of the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of Compound I that is Form S 1 , Form S 2 , Form S3, Form S 4 , Form S 6 , Form S 7 , Form Sg, Form S9, Form S 10 , Form S 13 , Form S14, Form S 15 , Form S 16 , Form S 17 , Form S 18 , Form S19 or Form S20, or a mixture thereof.
  • the pharmaceutical composition comprises Form S 1 .
  • the pharmaceutical composition comprises Form S 2 .
  • the pharmaceutical composition comprises Form S 3 .
  • the pharmaceutical composition comprises Form S 4 .
  • the pharmaceutical composition comprises Form S 6 .
  • the pharmaceutical composition comprises Form S 7 . In a further aspect, the pharmaceutical composition comprises Form Ss. In an additional aspect, the pharmaceutical composition comprises Form S 9 . In still another aspect, the pharmaceutical composition comprises Form S 10 . In an additional aspect, the pharmaceutical composition comprises Form S 13 . In yet another aspect, the pharmaceutical composition comprises Form S 14 . In an additional aspect, the pharmaceutical composition comprises Form S 15 . In a further aspect, the pharmaceutical composition comprises Form S 16 . In another aspect, the pharmaceutical composition comprises Form S 17 . In another aspect, the pharmaceutical composition comprises Form Sis. In an additional aspect, the pharmaceutical composition comprises Form S 19 . In still another aspect, the pharmaceutical composition comprises Form S 2 o.
  • An additional aspect of the present invention pertains to a method of treating solid tumors comprising the step of administering to a patient in need thereof a therapeutically effective amount of a crystalline form of Compound I that is Form S 1 , Form S 2 , Form S3, Form S 4 , Form S 6 , Form S 7 , Form Ss, Form S9, Form S 10 , Form S 13 , Form Si 4 , Form S 15 , Form Si 6 , Form Si 7 , Form S 18 , Form S 19 or Form S 2 o, or a mixture thereof.
  • Still another aspect of the present invention pertains to a method of treating solid tumors comprising the step of administering to a patient in need thereof a pharmaceutical composition comprising Compound I Form S 1 , Form S 2 , Form S3, Form S 4 , Form S 6 , Form S 7 , Form S 8 , Form S 9 , Form Si 0 , Form Si 3 , Form Si 4 , Form Si 5 , Form Si 6 , Form Si 7 , Form Si 8 , Form S 19 or Form S 2 o, or a mixture thereof.
  • a further aspect pertains to a method for preparing a crystalline form of Compound I that is Form Ao using a spontaneous crystallization method.
  • PEG/polaxamer is used as the crystallization solvent.
  • Still another aspect of the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of Compound I that is Form Ao, wherein said crystalline form is characterized by unit cell parameters approximately equal to the following:
  • An additional aspect of the present invention pertains to a crystalline form of Compound I that is an Ethanol Solvate single crystal.
  • the crystalline form is characterized by unit cell parameters approximately equal to the following:
  • Molecules/unit cell 2. Yet another aspect of the present invention pertains to a crystalline form of Compound I that is an NMP 1 :1 Water Solvate single crystal.
  • the crystalline form is characterized by unit cell parameters approximately equal to the following:
  • Still another aspect of the present invention pertains to a crystalline form of Compound I that is a Tetrahydrofuran Solvate single crystal.
  • the crystalline form is characterized by unit cell parameters approximately equal to the following:
  • Crystal system orthorhombic Space group: Pbcn Molecules/unit cell: 8.
  • An additional aspect of the present invention pertains to a crystalline form of
  • Compound I that is a 2-Propanol Solvate single crystal.
  • the crystalline form is characterized by unit cell parameters approximately equal to the following:
  • Molecules/unit cell 8. Still another aspect of the present invention pertains to an amorphous form of Compound I that is an Amorphous Solid (AS). In an additional aspect, the amorphous form has an X-ray powder diffraction pattern substantially as depicted in FIGURE 50. Yet another aspect pertains to a pharmaceutical composition comprising the amorphous form of Compound I that is an Amorphous Solid (AS).
  • AS Amorphous Solid
  • An additional aspect of the present invention pertains to a method for preparing Amorphous Solid (AS) comprising the step of dissolving Compound I in the presence of methanol to yield Amorphous Solid (AS). Another aspect pertains to a method for preparing Amorphous Solid (AS) comprising the step of dissolving Compound I in the presence of ethanol to yield Amorphous Solid (AS). An additional aspect pertains to a method for preparing Amorphous Solid (AS) comprising the step of grinding Compound I Form Ao to yield Amorphous Solid (AS). A further aspect pertains to a method for preparing Amorphous Solid (AS) comprising the step of quench cooling Compound I Form A 0 to yield Amorphous Solid (AS).
  • Still another aspect of the present invention pertains to a method of treating solid tumors comprising the step of administering to a patient in need thereof a therapeutically effective amount of an amorphous form of Compound I that is an Amorphous Solid (AS).
  • AS Amorphous Solid
  • amorphous means lacking a characteristic crystal shape or crystalline structure.
  • anti-solvent means a solvent in which a compound is substantially insoluble.
  • crystalline means having a regularly repeating arrangement of molecules or external face planes.
  • crystalline form refers to a solid chemical compound or mixture of compounds that provides a characteristic pattern of peaks when analyzed by x-ray powder diffraction; this includes, but is not limited to, polymorphs, solvates, hydrates, co-crystals, and de-solvated solvates.
  • the number ' 1 ' was assigned to identify mono (p ⁇ ra-toluenesulfonic acid (pTSA) crystalline salt forms such as pTSA-Ai and the number '2' was used to identify the di pTSA crystalline salt forms such as PTSA-A 2 , pTSA-B 2 and pTSA-C 2 .
  • A, B, C and D were used to identify the four polymorphic forms of Compound I free base (with the subscript '0' specifying the free base in each case).
  • the letter 'S' was used to identify each of the solvates, with numbers consecutively assigned to describe each solvate.
  • Amorphous Solid (AS) was used to identify the amorphous form of Compound I.
  • Isolating means separating a compound from a solvent, anti-solvent, or a mixture of solvent and anti-solvent to provide a solid, semisolid or syrup. This is typically accomplished by means such as centrifugation, filtration with or without vacuum, filtration under positive pressure, distillation, evaporation or a combination thereof. Isolating may or may not be accompanied by purifying during which the chemical, chiral or chemical and chiral purity of the isolate is increased.
  • Purifying is typically conducted by means such as crystallization, distillation, extraction, filtration through acidic, basic or neutral alumina, filtration through acidic, basic or neutral charcoal, column chromatography on a column packed with a chiral stationary phase, filtration through a porous paper, plastic or glass barrier, column chromatography on silica gel, ion exchange chromatography, re-crystallization, normal-phase high performance liquid chromatography, reverse-phase high performance liquid chromatography, trituration and the like.
  • polymorphic or “polymorphism” is defined as the possibility of at least two different crystalline arrangements for the same chemical molecule.
  • concentrate refers to a substance dissolved in another substance, usually the component of a solution present in the lesser amount.
  • solution refers to a mixture containing at least one solvent and at least one compound at least partially dissolved in the solvent.
  • solvate refers to a crystalline material that contains solvent molecules within the crystal structure.
  • solvent means a substance, typically a liquid, that is capable of completely or partially dissolving another substance, typically a solid.
  • Solvents for the practice of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, 1-butanol, 2-butanol, 2-butanone, butyronitrile, tert-butanol, chlorobenzene, chloroform, cyclohexane, 1-2 dichloloroethane, dichloromethane, diethylene glycol dibutyl ether, diisopropyl amine, diisopropyl ether, 1 ,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, ethyleneglycoldiemethylether, ethanol, ethyl acetate, ethylene glycol, ethyl formate,
  • therapeutically effective amount refers to the amount determined to be required to produce the physiological effect intended and associated with a given drug, as measured according to established pharmacokinetic methods and techniques, for the given administration route. Appropriate and specific therapeutically effective amounts can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques. The effective dose will vary depending upon a number of factors, including the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, the formulation of the active agent with appropriate excipients, and the route of administration.
  • pharmaceutically acceptable excipients includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art, such as in Remington: The Science and Practice of Pharmacy, 20 th ed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the crystalline forms of the present invention can be administered by any means that results in the contact of the active agent with the agent's site of action in the body of the subject.
  • the crystalline forms may be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in combination with other therapeutic agents, such as, for example, analgesics.
  • the crystalline forms of the present invention are preferably administered in therapeutically effective amounts for the treatment of the diseases and disorders described herein to a subject in need thereof.
  • a therapeutically effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques.
  • the effective dose will vary depending upon a number of factors, including the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the crystalline form selected, the formulation of the active agent with appropriate excipients, and the route of administration.
  • the crystalline forms would be administered at lower dosage levels, with a gradual increase until the desired effect is achieved.
  • Typical dose ranges are from about 0.01 mg/kg to about 100 mg/kg of body weight per day, with a preferred dose from about 0.01 mg/kg to 10 mg/kg of body weight per day.
  • a preferred daily dose for adult humans includes about 25, 50, 100 and 200 mg, and an equivalent dose in a human child.
  • the crystalline forms may be administered in one or more unit dose forms.
  • the unit dose ranges from about 1 to about 500 mg administered one to four times a day, preferably from about 10 mg to about 300 mg, two times a day.
  • an oral unit dose is one that is necessary to achieve a blood serum level of about 0.05 to 20 ⁇ g/ml in a subject, and preferably about 1 to 20 ⁇ g/ml.
  • the crystalline forms of the present invention may be formulated into pharmaceutical compositions by admixture with one or more pharmaceutically acceptable excipients.
  • the excipients are selected on the basis of the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy, 20 th ed.; Gennaro, A. R., Ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2000.
  • the compositions may be formulated to control and/or delay the release of the active agent(s), as in fast-dissolve, modified-release, or sustained- release formulations.
  • Such controlled-release, or extended-release compositions may utilize, for example biocompatible, biodegradable lactide polymers, lactide/glycolide copolymers, polyoxyethylene-polyoxypropylene copolymers, or other solid or semisolid polymeric matrices known in the art.
  • compositions can be prepared for administration by oral means; parenteral means, including intravenous, intramuscular, and subcutaneous routes; topical or transdermal means; transmucosal means, including rectal, vaginal, sublingual and buccal routes; ophthalmic means; or inhalation means.
  • parenteral means including intravenous, intramuscular, and subcutaneous routes
  • transmucosal means including rectal, vaginal, sublingual and buccal routes
  • ophthalmic means or inhalation means.
  • the compositions are prepared for oral administration, particularly in the form of tablets, capsules or syrups; for parenteral administration, particularly in the form of liquid solutions, suspensions or emulsions; for intranasal administration, particularly in the form of powders, nasal drops, or aerosols; or for topical administration, such as creams, ointments, solutions, suspensions aerosols, powders and the like.
  • the tablets, pills, powders, capsules, troches and the like can contain one or more of the following: diluents or fillers such as starch, or cellulose; binders such as microcrystalline cellulose, gelatins, or polyvinylpyrrolidones; disintegrants such as starch or cellulose derivatives; lubricants such as talc or magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or cherry flavoring.
  • Capsules may contain any of the aforementioned excipients, and may additionally contain a semi-solid or liquid carrier, such as a polyethylene glycol.
  • the solid oral dosage forms may have coatings of sugar, shellac, or enteric agents.
  • Liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as surfactants, suspending agents, emulsifying agents, diluents, sweetening and flavoring agents, dyes and preservatives.
  • compositions may also be administered parenterally.
  • the pharmaceutical forms acceptable for injectable use include, for example, sterile aqueous solutions, or suspensions.
  • Aqueous carriers include mixtures of alcohols and water, buffered media, and the like.
  • Non-aqueous solvents include alcohols and glycols, such as ethanol, and polyethylene glycols; oils, such as vegetable oils; fatty acids and fatty acid esters, and the like.
  • compositions can be added including surfactants; such as hydroxypropylcellulose; isotonic agents, such as sodium chloride; fluid and nutrient replenishers; electrolyte replenishers; agents which control the release of the active compounds, such as aluminum monostearate, and various co-polymers; antibacterial agents, such as chlorobutanol, or phenol; buffers, and the like.
  • surfactants such as hydroxypropylcellulose; isotonic agents, such as sodium chloride; fluid and nutrient replenishers; electrolyte replenishers; agents which control the release of the active compounds, such as aluminum monostearate, and various co-polymers; antibacterial agents, such as chlorobutanol, or phenol; buffers, and the like.
  • the parenteral preparations can be enclosed in ampules, disposable syringes or multiple dose vials.
  • Other potentially useful parenteral delivery systems for the active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps
  • formulations for inhalation which include such means as dry powder, aerosol, or drops. They may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for topical use are in the form of an ointment, cream, or gel.
  • these forms include a carrier, such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, or their combinations, and either an emulsifying agent, such as sodium lauryl sulfate, or a gelling agent, such as tragacanth.
  • a carrier such as petrolatum, lanolin, stearyl alcohol, polyethylene glycols, or their combinations
  • an emulsifying agent such as sodium lauryl sulfate
  • a gelling agent such as tragacanth.
  • Formulations suitable for transdermal administration can be presented as discrete patches, as in a reservoir or microreservoir system, adhesive diffusion-controlled system or a matrix dispersion-type system.
  • Formulations for buccal administration include, for example lozenges or pastilles and may also include a flavored base, such as sucrose or acacia, and other excipients such as glycocholate.
  • Formulations suitable for rectal administration are preferably presented as unit-dose suppositories
  • Powder XRD patterns were recorded on a PANalytical X Pert Pro diffractometer using Cu Ka radiation at 40 kV and 40 mA.
  • the standard X-ray powder pattern scans were collected from ca. 2 to 40° 2 ⁇ with a 0.0080° step size and 96.06 sec counting time which resulted in a scan rate of approximately 0.5°/min.
  • Typical rapid scans were from 3° to 30° 2 ⁇ with a step size of 0.167° and a counting time of 64 seconds.
  • Thermal curves were acquired using a Perkin-Elmer Series 7 DSC and TGA using Pyris software version 6.0. Solid samples of 1-11 mg were weighed into 20 ⁇ L aluminum samples pans and crimp-sealed with a pin-hole added to the top lid. The cell was purged with nitrogen and the temperature heated from 0° to 300°C at 10°C/min. TGA samples between 1-15 mg were monitored for percent weight loss as heated from 25° to 300°C at 10°C/min in a furnace purged with nitrogen at ca. 50 mL/min.
  • Thermal curves were also acquired using a Perkin-Elmer Sapphire DSC Autosampler Unit DSC and Pyris ITGA using Pyris software version 6.0. Solid samples of 1-11 mg were weighed into 20 ⁇ L aluminum open sample pans. The cell was purged with nitrogen and the temperature heated from 0° to 355°C at 10°C/min. TGA samples between 1-15 mg were monitored for percent weight loss as heated from 25° to 400 0 C at 10°C/min in a furnace purged with nitrogen at ca. 50 mL/min.
  • the solution was concentrated to about 25 mL by warming to the boiling point with stirring and chilled overnight at 2-8°C.
  • the slurry was vacuum filtered and solid allowed to dry about 4 hours in the hood at room temperature.
  • the yellow-orange solid weighed 274.1 mg (79% yield).
  • XRPD patterns were repeated at least twice to assure the reproducibility.
  • the numbers were assigned primarily based upon XRPD pattern, and as different powder patterns were found, the letters and numbers were incrementally assigned.
  • the number 1 was assigned to identify mono pTSA salt forms such as pTSA-Ai, and 2 was used for the di pTSA salt such as pTSA-A2 or pTSA-B2.
  • the DSC curves for pTSA-Ai, pTSA-A 2 , pTSA-B 2 and pTSA-C2 are distinguishing and can be used to identify the particular solid-state phase (Table 32 below).
  • Form pTSA-Ai shows a single peak at ca. 266.4°C with an enthalpy of fusion ( ⁇ H&s) of 12.92 J/g.
  • the DSC curve of form pTSA-A 2 shows a peak at ca. 278.4°C with an enthalpy of fusion ( ⁇ H&s) of 18.45 J/g.
  • Form pTSA- B 2 exhibits an endotherm at a peak temperature of ca.
  • Compound I -An was obtained as 20 mg Compound I was heated to 225°C and held for 10 minutes.
  • NMP N-methylpyrrolidone
  • the slurry that resulted was distributed among 3 -1.5 mL centrifuge tubes. The pellet was removed to weighing paper and allowed to dry overnight to give 31 mg of solid (62% recovery).
  • the XRPD diffraction patterns characteristic of Compound I solvates S 1 -S 4 , S 6 -S 10, and Si 3 -S 20 are shown in Figures 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 36, 38, 40, 42, 44, 46 and 48, respectively.
  • the XRPD diffraction pattern for the amorphous solid (AS) is shown in Figure 50.
  • DSC and/or TGA patterns for solvates Si-S 4 , S 6 -Si 0 , and Si 4 -S 2 O are shown in Figures 18, 20, 22, 24, 26, 28, 30, 32, 34, 37, 39, 41, 43, 45, 47 and 49, respectively.
  • the DSC profile of Amorphous Solid Compound I exhibits a very broad exothermic peak which is associated to a release of energy due to a crystallization process which results in the formation of polymorph Compound I -Ao and the broad endothermic peak at 328°C corresponds to its melting.
  • No glass transition event was observed when the experiment was performed between 20 0 C to 160 0 C.
  • AS exhibits a glass transition temperature (T 8 ) at ca. 155°C with the heat capacity ( ⁇ Cp) of 0.391 J/g*°C.
  • Freshly prepared AS showed two exothermic peaks due to crystallization of the amorphous phase and its transformation a stable crystal, and melted at 328° C, which is approximately the same temperature as the melting point of the intact crystal.
  • Solubility was measured by adding 25 mg of the various forms of Compound I or an amount adequate to maintain a saturated solution in water and pH 1, pH 2 (HC1/KC1 buffers). Temperature of 25°C and a stirring rate of 300 rpm were maintained by using a HEL Crystal Scan unit (HEL, UK). Samples were withdrawn at the times indicated, filtered and analyzed by HPLC for Compound I using the method described below.
  • HPLC Chromatography
  • the different solubilities of the various solid state forms of Compound I can be advantageous when preparing pharmaceutical compositions. For example, selecting one or more specific solid state or crystalline forms of Compound I in combination with one or more excipients can provide a pharmaceutical composition with a particular bioavailability profile.
  • peak heights (intensities) in a XRPD spectrum may vary and will be dependent on variables such as the temperature, crystal size or morphology, sample preparation, or sample height in the analysis well of the PANalytical X Pert Pro diffractometer or Oxford Instruments Xcalibur3 diffractometer system.
  • peak positions may vary when measured with different radiation sources.
  • Cu-Ka 1 , Mo-Ka, Co-Ka and Fe-Ka radiation having wavelengths of 1.54060 A, 0.7107 A, 1.7902 A and 1.9373 A, respectively, may provide peak positions that differ from those measured with Cu-Ka radiation.
  • ⁇ 0.2 degrees 2-theta following a series of peak positions means that all of the peaks of the group which it follows are reported in terms of angular positions with a variability of ⁇ 0.2 degrees 2-theta.
  • “6.81, 8.52, 9.73, 12.04 and/or 13.25 ⁇ 0.2 degrees 2-theta” means “6.81 ⁇ 0.2 degrees 2-theta, 8.52 ⁇ 0.2 degrees 2-theta, 9.73 ⁇ 0.2 degrees 2-theta, 12.04 ⁇ 0.2 degrees 2-theta and/or 13.25 ⁇ 0.2 degrees 2-theta”.

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Abstract

L'invention concerne des formes chimiques alternatives et/ou des formes à l'état solide du composé (I), des procédés pour les fabriquer de façon reproductible et des procédés de traitement de patients les utilisant. 1.1- isobutyl-2-methyl-8-(2-pyrimidinylamino)-2,5,6,11,12,13-hexahydro-4H-indazolo[5,4-α]pyrrolo[3,4-c]carbazole-4-one.
PCT/US2009/065099 2008-11-19 2009-11-19 Nouvelles formes d'un composé indazolo [5,4-a] pyrrolo [3,4-c] carbazole WO2010059795A1 (fr)

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CN200980146334.7A CN102216306B (zh) 2008-11-19 2009-11-19 吲唑并[5,4-a]吡咯并[3,4-c]咔唑化合物的新形式
ES09764381T ES2399588T3 (es) 2008-11-19 2009-11-19 Nuevas formas de un compuesto de indazolo[5,4-A]pirrolo[3,4-C]carbazol
AU2009316600A AU2009316600B2 (en) 2008-11-19 2009-11-19 Novel forms of an indazolo [5,4-a] pyrrolo [3,4-c] carbazole compound
EP09764381A EP2367829B1 (fr) 2008-11-19 2009-11-19 Nouvelles formes d'un composé indazolo [5,4-a] pyrrolo [3,4-c] carbazole
NZ592868A NZ592868A (en) 2008-11-19 2009-11-19 Novel forms of an indazolo [5,4-a] pyrrolo [3,4-c] carbazole compound
MX2011005055A MX2011005055A (es) 2008-11-19 2009-11-19 Nuevas formas de un compuesto de indazolo [5,4-a]pirrolo[3,4-c]car bazol.
CA2742790A CA2742790C (fr) 2008-11-19 2009-11-19 Formes nouvelles de compose d'indazolo[5,4-a]pyrrolo [3,4-c] carbazole
JP2011536622A JP2012509282A (ja) 2008-11-19 2009-11-19 インダゾロ［５，４−ａ］ピロロ［３，４−ｃ］カルバゾール化合物の新しい形態
IL212749A IL212749A (en) 2008-11-19 2011-05-05 Crystalline forms of 11-isobutyl-2-methyl-8- (2-pyrimidylamino) -13,12,11,6,5,2-hexahydro-h4-indazolo [4,5- a] pyrrolo [4,3- c ] Carbazole-4
US13/105,457 US8513272B2 (en) 2008-11-19 2011-05-11 Forms of a fused pyrrolocarbazole compound
HK12102681.6A HK1162177A1 (en) 2008-11-19 2012-03-16 Novel forms of an indazolo [5,4-a] pyrrolo [3,4-c] carbazole compound

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TWI460179B (zh) 2014-11-11
AU2009316600A1 (en) 2010-05-27
CN103965204A (zh) 2014-08-06
AR074374A1 (es) 2011-01-12
IL212749A0 (en) 2011-07-31
CN104016992B (zh) 2017-04-12
CN103965204B (zh) 2016-09-07
IL212749A (en) 2014-11-30
EP2367829A1 (fr) 2011-09-28
AU2009316600B2 (en) 2015-09-24
CN102216306A (zh) 2011-10-12
CA2742790C (fr) 2018-02-13
NZ592868A (en) 2012-08-31
US8513272B2 (en) 2013-08-20
US20110230508A1 (en) 2011-09-22
JP2018008977A (ja) 2018-01-18
JP2015231990A (ja) 2015-12-24
TW201022272A (en) 2010-06-16
CN104016992A (zh) 2014-09-03
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ES2399588T3 (es) 2013-04-02
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