WO2017218365A1 - Forme cristalline d'un composé de quinoléine substitué et compositions pharmaceutiques en contenant - Google Patents

Forme cristalline d'un composé de quinoléine substitué et compositions pharmaceutiques en contenant Download PDF

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Publication number
WO2017218365A1
WO2017218365A1 PCT/US2017/036909 US2017036909W WO2017218365A1 WO 2017218365 A1 WO2017218365 A1 WO 2017218365A1 US 2017036909 W US2017036909 W US 2017036909W WO 2017218365 A1 WO2017218365 A1 WO 2017218365A1
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cancer
crystalline form
pharmaceutical composition
ray powder
receptor tyrosine
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PCT/US2017/036909
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English (en)
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Ning Xi
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Sunshine Lake Pharma Co., Ltd.
Calitor Sciences, Llc
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Publication of WO2017218365A1 publication Critical patent/WO2017218365A1/fr

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • This invention relates to a crystalline form of N-(3-fluoro-4-((7-(2-hydroxy-2- methylpropoxy)quinolin-4-yl)oxy)phenyl)-l,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-lH-pyrazol e-4-carboxamide ⁇ -toluenesulfonate, the process for preparing the crystalline form thereof, and pharmaceutical compositions comprising the crystalline form, and pharmaceutical compositions comprising the crystalline form thereof.
  • This invention also relates to a method of using such a crystalline form in the treatment of hyperproliferative disorders in mammals, especially in humans.
  • Protein kinase signal transduction is of particular relevance in, for example, thyroid, gastric, kidney, brain, head and neck, lung, breast, prostate and colorectal cancers, as well as in the growth and proliferation of brain tumor cells, among many other solid and blood cancers.
  • Protein kinases can be categorized as receptor type or non-receptor type.
  • Receptor-type tyrosine kinases generally comprise of a transmenbrane receptors with diverse biological activities.
  • receptor-type tyrosine kinases see "Structural biology of protein tyrosine kinases", Cell. Mol. Life Sci., 2006, 63, 2608-2625. Since kinases and their ligands play critical roles in various cellular activities, dysregulation of protein kinase activity can lead to altered cellular properties, such as uncontrolled cell growth associated with cancer. Therefore, protein kinases are attractive targets for small molecule drug discovery.
  • Angiogenesis the formation of new capillaries from preexisting blood vessels, is a necessary process for organ development during embryogenesis and is critical for the female reproductive cycle, inflammation, and wound healing in the adult.
  • Certain diseases are known to be associated with dysregulated angiogenesis, for example ocular neovascularization, such as retinopathies (including diabetic retinopathy), age-related macular degeneration, fibrosis, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease, such as a rheumatoid or rheumatic inflammatory disease, especially arthritis (including rheumatoid arthritis), or other chronic inflammatory disorders, such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases, for example so-called solid tumors and liquid tumors (such as leukemias).
  • retinopathies including diabetic retinopathy
  • age-related macular degeneration fibrosis, psoriasis
  • hemangioblastoma hemangioblastoma
  • arteriosclerosis arteriosclerosis
  • inflammatory disease such as
  • Solid tumors are dependent on angiogenesis to grow beyond a certain critical size by inducing new capillaries sprouting from existing blood vessels to secure their nutrition, oxygen supply, and waste removal.
  • angiogenesis also promotes metastasis of tumor cells to other sites.
  • VEGFR- 1 VEGFR-1
  • VEGFR-2 KDR/Flk-1
  • VEGFR-3 VEGFR-3
  • VEGFR- 1 is thought to modulate VEGFR-2 signaling or to act as a dummy/decoy receptor to sequester VEGF away from VEGFR-2 (Stuttfeld E, Ballmer-Hofer K (2009)," Structure and function of VEGF receptor s"JUBMB Life 61 (9): 915-22).
  • VEGFR-2 is the major mediator of vascular endothelial cell (EC) mitogenesis and survival, as well as angiogenesis and microvascular permeability, it is expected that direct inhibition of the kinase activity of VEGFR-2 will result in the reduction of angiogenesis and the suppression of tumor growth. Furthermore, inhibition of VEGFR-2 targeting the genetically more stable host endothelial cells, instead of labile tumor tissues, may decrease the chance of resistance development.
  • VEGF-targeted therapy mechanisms of anti-tumor activity.
  • FLT3 Flt3, FMS-related tyrosine kinase 3
  • FLK-2 fetal liver kinase 2
  • STK-1 human stem cell kinase 1
  • FLT3 belongs to a member of the class III receptor tyrosine kinase (RTK-III) family that include KIT, PDGFR, FMS and FLTl (Stirewalt DL, et al., Nat. Rev. Cancer, 2003, 3:650-665).
  • FLT3 has been implicated in hematopoietic disorders which are pre-malignant disorders including myeloproliferative disorders, such as thrombocythemia, essential thrombocytosis (ET), myelofibrosis (MF), chronic idiopathic myelofibrosis (FMF), and polycythemia vera (PV), pre-malignant myelodysplastic syndromes.
  • myeloproliferative disorders such as thrombocythemia, essential thrombocytosis (ET), myelofibrosis (MF), chronic idiopathic myelofibrosis (FMF), and polycythemia vera (PV), pre-malignant myelodysplastic syndromes.
  • Hematological malignancies include leukemias, lymphomas (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, for instance, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL) (Matthew C. Stubbs and Scott A. Armstrong, "FLT3 as a Therapeutic Target in Childhood Acute Leukemia", Current Drug Tar gets, 2W1 , 5,703-714).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • APL acute promyelocytic leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic neutrophilic leukemia
  • CNL chronic neutrophilic leuk
  • FLT3 is over-expressed at the levels in 70-100% of cases of acute myeloid leukemias (AML), and in a high percentage of T-acute lymphocytic leukemia (ALL) cases (Griffin JD, et al., Haematol J. 2004, 5: 188-190). It is also overexpressed in a smaller subset of chronic myeloid leukemia (CML) in blast crisis. Studies have shown that the leukemic cells of B lineage ALL and AML frequently co-express FL, setting up autocrine or paracrine signaling loops that result in the constitutive activation of FLT3 (Zheng R, et. al., Blood., 2004, 103 : 267-274).
  • a high level of the FLT3 ligand is found in the serum of patients with Langerhans cell histocytosis and systemic lupus erythematosus, which further implicates FLT3 signaling in the dysregulation of dendritic cell progenitors in those autoimmune diseases (Rolland et al., J. Immunol, 2005, 174, 3067-3071; Engen et al., "Targeted Therapy of FLT3 in Treatment of AML— Current Status and Future Directions" Clin. Med., 2014, 3, 1466-1489).
  • c-Met also referred to as hepatocyte growth factor receptor (HGFR)
  • HGFR hepatocyte growth factor receptor
  • HGF hepatocyte growth factor
  • SF scatter factor
  • activated c-Met promotes a morphogenetic program, known as invasive growth, which induces cell spreading, the disruption of intercellular contacts, and the migration of cells towards their surroundings.
  • c-Met is also implicated in atherosclerosis and organ fibrosis such as lung fibrosis. Invasive growth of certain cancer cells is drastically enhanced by tumor-stromal interactions involving the HGF/c-Met pathway. Thus, extensive evidence that c-Met signaling is involved in the progression and spread of several cancers has generated considerable interest in c-Met as major targets in cancer drug development.
  • Molecular cancer therapy can our expectation be MET", Euro. J.
  • TAM receptor tyrosine kinases
  • TAM and Axl can activate standard proliferative pathways (ERK, AKT and members of the signal transducer and activator of transcription (STAT) family), their output generally promotes survival rather than proliferation.
  • ERK, AKT and members of the signal transducer and activator of transcription (STAT) family These kinases are potentially dual anticancer targets, firstly in tumor cells that have developed a non-oncogene addiction to TAM RTK survival signals and secondly in the microenvironment where MerTK and Axl inhibition may reverse innate immune suppression.
  • TAM family phosphatidylserine-sensing receptor tyrosine kinases gone awry in cancer", Nature Review Cancer, 2014, 14, 769).
  • small-molecule compounds that specially inhibit, regulate and/ or modulate the signal transduction of kinases, particularly including VEGFRs, Flt3, c-Met, Axl and Mer as described above, are desirable as a means to treat or prevent disease states associated with abnormal cell proliferationand angiogenesis.
  • One such small-molecule is N-(3-fluoro-4-((7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl)oxy)phenyl)-l,5-dimethyl-3-oxo-2 -phenyl-2,3-dihydro-lH-pyrazole-4-carboxamide, which has the chemical structureas shown in the following:
  • WO 2012118632A1 described the synthesis of
  • Different salts and solid state form of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms may provide a basis for improving formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for example, if they serve to improve bioavailability. Different salts and solid state forms of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to assess variations in the properties and characteristics of a solid active pharmaceutical ingredient.
  • the present invention provides a crystalline form of N-(3-fluoro-4-((7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl)oxy)phenyl)-l,5-dimethyl-3-oxo-2 -phenyl-2,3-dihydro-lH-pyrazole-4-carboxamide ⁇ -toluenesulfonate, and novel pharmaceutical compositions containing the crystalline form thereof.
  • the invention also encompasses the therapeutic uses of the crystalline form described herein and the therapeutic compositions containing the crystalline form described herein.
  • the techniques used to characterize the crystalline form are described in the examples herein. These techniques, alone or in combination, may be used to characterize the crystalline form disclosed herein.
  • the crystalline form may be also characterized by reference to the figures disclosed herein.
  • an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 8.33°, about 17.07°, about 18.78°, about 20.47°, about 22.09°and about 23.75°, and a differential scanning calorimetry trace comprising a maximum in endothermic heat flow at about 213 °C; or b) an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at 8.33° ⁇ 0.2°, 17.07° ⁇ 0.2°, 18.78° ⁇ 0.2°, 20.47° ⁇ 0.2°, 22.09° ⁇ 0.2° and 23.75° ⁇ 0.2°, and a differential scanning calorimetry trace comprising a maximum in endothermic heat flow at 213 °C ⁇ 3°C.
  • the crystalline form B has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 8.33°, about 11.00°, about 11.20°, about 12.71°, about 16.62°, about 17.07°, about 18.78°, about 20.47°, about 21.84°, about 22.09°, about 23.75°and about 24.27°, or at 8.33° ⁇ 0.2°, 11.00° ⁇ 0.2°, 11.20° ⁇ 0.2°, 12.71° ⁇ 0.2°, 16.62° ⁇ 0.2°, 17.07° ⁇ 0.2°, 18.78° ⁇ 0.2°, 20.47° ⁇ 0.2°, 21.84° ⁇ 0.2°, 22.09° ⁇ 0.2°, 23.75° ⁇ 0.2°and 24.27° ⁇ 0.2°.
  • the crystalline form B has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 8.33°, about 11.00°, about 11.20°, about 12.71°, about 15.31°, about 16.62°, about 17.07°, about 18.78°, about 20.47°, about 21.84°, about 22.09°, about 22.59°, about 23.56°, about 23.75°, about 24.27°, about 26.87°, about 28.06° and about 28.38°, or at 8.33° ⁇ 0.2°, 11.00° ⁇ 0.2°, 11.20° ⁇ 0.2°, 12.71° ⁇ 0.2°, 15.31° ⁇ 0.2°, 16.62° ⁇ 0.2°, 17.07° ⁇ 0.2°, 18.78° ⁇ 0.2°, 20.47° ⁇ 0.2°, 21.84° ⁇ 0.2°, 22.09° ⁇ 0.2°, 22.59° ⁇ 0.2°, 23.56°
  • the crystalline form B has an X-ray powder diffraction pattern substantially in accordance with that shown in Figure 1.
  • the crystalline form B has a differential scanning calorimetry trace substantially in accordance with that shown in Figure 2.
  • the crystalline form B has a thermal gravimetric analysis curve comprising a weight loss of about 1.08% when heated to about 150°C.
  • the crystalline form B has a thermal gravimetric analysis curve substantially in accordance with that shown in Figure 3.
  • the crystalline form B is substantially pure.
  • composition comprising the crystalline form B.
  • the composition further comprises a pharmaceutically acceptable excipient, carrier, vehicle or a combination thereof.
  • the pharmaceutical composition further comprises a therapeutic agent,
  • the therapeutic agent is melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin
  • provided herein is a method of preventing, treating or lessening the severity of a proliferative disorder in a patient by administering to the patient with the crystalline form Bdisclosed herein or the pharmaceutical composition disclosed herein.
  • the proliferative disorder is colon cancer, rectal cancer, gastric cancer, gastric adenocarcinoma, pancreatic cancer, bladder cancer, gallbladder cancer, breast cancer, kidney cancer, renal cell carcinoma, liver cancer, hepatocellular carcinoma, lung cancer, skin cancer, melanoma, thyroid cancer, osteosarcomas, soft tissue sarcoma, a cancer of the head and neck, a cancer of the central nervous system, glioma, glioblastomas, ovarian cancer, uterine cancer, endometrial carcinoma, prostate cancer, acute myeloid leukemia or acute lymphoblastic leukemia, or a metastasis thereof.
  • the invention relates to the use ofthe crystalline form B disclosed herein or the pharmaceutical composition disclosed herein in the manufacture of a medicament for the treatment ofcolon cancer, rectal cancer, gastric cancer, gastric adenocarcinoma, pancreatic cancer, bladder cancer, gallbladder cancer, breast cancer, kidney cancer, renal cell carcinoma, liver cancer, hepatocellular carcinoma, lung cancer, skin cancer, melanoma, thyroid cancer, osteosarcomas, soft tissue sarcoma, a cancer of the head and neck, a cancer of the central nervous system, glioma, glioblastomas, ovarian cancer, uterine cancer, endometrial carcinoma, prostate cancer, acute myeloid leukemia or acute lymphoblastic leukemia, or a metastasis thereof.
  • Figure 1 depicts an X-ray powder diffraction pattern of the crystalline form B of compound (I).
  • Figure 2 depicts a differential scanning calorimetry thermogram of the crystalline form B of compound (I).
  • Figure 3 depicts a thermal gravimetric analysis curve of the crystalline form B of the compound (I).
  • a crystalline form that is "substantially pure” refers to a crystalline form that is substantially free of one or more other crystalline forms, i.e., the crystalline form has a purity of at least about 60%, at least about 70%, at least about 80%>, at least about 85%>, at least about 90%), at least about 93%, at least about 95%, at least about 98%>, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%; or the crystalline form has less than 20%, less than 10%, less than 5%, less than 3%o, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% of the one or more other crystalline formsand/or impurities, based on the total volume or weight of the crystalline form and the one or more other crystalline formsand/or impurities.
  • an X-ray powder diffraction (XRPD) pattern, adifferential scanning calorimetry (DSC) thermogram or a thermal gravimetric analysis curve(TGA) that is "substantially the same asshown" in a figure refers to an X-ray powder diffraction (XRPD) pattern, adifferential scanning calorimetry (DSC) thermogram or a thermal gravimetric analysis curve(TGA) having at least 50%, at least 60%,at least 70%, at least 80%, at least 90%, at least 95%o, or at least 99% of the peaksshown in the figure.
  • 2 theta value refers to the peak position in degrees based on the experimental setup of the X-ray diffraction experiment and is a common abscissa unit in diffraction patterns.
  • the experimental setup requires that if a reflection is diffracted when the incoming beam forms an angle theta ( ⁇ ) with a certain lattice plane, the reflected beam is recorded at an angle 2 theta (2 ⁇ ).
  • 2 ⁇ theta value
  • X-ray powder diffraction pattern or "XPRD pattern” or “XRD pattern” refers to the experimentally observed diffractogram or parameters derived therefrom. Powder X-ray diffraction patterns are characterized by peak position (abscissa) and intensities (ordinate). In the area of X-ray powder diffraction (XRD), relative peak height of XRD pattern depends on many factors related to sample preparation and geometric shapes of the instrument, while peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystalline compounds described herein characterized by XRD pattern with some peak positions, have essentially the same characteristics as XRD pattern provided in appended drawings of the present invention.
  • the error margin in the scattering angle (2 ⁇ ) of the diffraction peaks is in the range of ⁇ 0.1 °, ⁇ 0.2°, ⁇ 0.3°, ⁇ 0.4°, or ⁇ 0.5°. In some embodiments, the error margin is ⁇ 0.2°.
  • the crystalline compounds disclosed herein characterized by DSC trace with some peak positions have essentially the same characteristics as DSC trace provided in appended drawings of the present invention.
  • the error margin in the melting peaks is in the range of ⁇ 1 °C, ⁇ 2°C, ⁇ 3 °C, ⁇ 4 °C,or ⁇ 5 °C. In some embodiments, the error margin is ⁇ 3 °C.
  • relative intensity refers to the intensity of a peak with respect to the intensity of the strongest peak in the X-ray powder diffraction pattern which is regarded as 100%.
  • peak refers to a feature that one skilled in the art would recognize as not attributable to background noise.
  • each number may differ by 1%, 2%, 3%, 4%, 5%, 6%,7%, 8%,9%, 10%, 15% or 20%. In some embodiments, the value of each number may differ by 1%; In other embodiments, the value of each number may differ by 2%; In other embodiments, the value of each number may differ by 3%; In other embodiments, the value of each number may differ by 4%; In other embodiments, the value of each number may differ by 5%; In other embodiments, the value of each number may differ by 6%.
  • Crystalline forms may be prepared by a variety of methods including, but not limited to, for example, crystallization or recrystallization from a suitable solvent mixture; sublimation; growth from a melt; solid state transformation from another phase; crystallization from a supercritical fluid; and jet spraying.
  • Techniques for crystallization or recrystallization of crystalline forms in a solvent mixture include, but are not limited to, for example, evaporation of the solvent; decreasing the temperature of the solvent mixture; crystal seeding of a supersaturated solvent mixture of the compound and/or salt thereof; freeze drying the solvent mixture; and adding anti-solvents (counter solvents) to the solvent mixture.
  • High throughput crystallization techniques may be employed to prepare crystalline forms including polymorphs.
  • the solvent(s) are typically chosen based on one or more factors including, but not limited to, for example, solubility of the compound; crystallization technique utilized; and vapor pressure of the solvent. Combinations of solvents may be employed.
  • the compound may be dissolved in a first solvent to afford a solution, to which anti-solvent is then added to decrease the solubility of the compound in the solution, and precipitate to form crystals.
  • An anti-solvent is a solvent in which a compound has low solubility.
  • Seed crystals may be added to any crystallization mixture to promote crystallization. Seeding may be employed to control growth of a particular polymorph and/or to control the particle size distribution of the crystalline product. Accordingly, calculation of the amount of seeds needed depends on the size of the seed available and the desired size of an average product particle as described, for example, in "Programmed Cooling Batch Crystallizers", J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-377. In general, seeds of small particle size are needed to effectively control the growth of crystals in the batch. Seeds of small particle size may be generated by sieving, milling or micronizing large crystals, or by microcrystallizing a solution. In the milling or micronizing of crystals, care should be taken to avoid changing crystallinity from the desired crystalline form (i.e., changing to an amporphous or other polymorphic form).
  • a cooled crystallization mixture may be filtered under vacuum and the isolated solid product may be washed with a suitable solvent, such as, for example, cold recrystallization solvent. After being washed, the product may be dried under a nitrogen or air purge to afford the desired crystalline form.
  • the product may be analyzed by a suitable spectroscopic or analytical technique including, but not limited to, for example, differential scanning calorimetry (DSC); X-ray powder diffraction (XRD); and thermogravimetric analysis (TGA) to assure the crystalline form of the compound has been formed.
  • DSC differential scanning calorimetry
  • XRD X-ray powder diffraction
  • TGA thermogravimetric analysis
  • 3 ⁇ 4 NMR spectra were recorded with a Bruker 400 MHz or 600 MHz spectrometer at ambient temperature. Solid-state 13 C NMR spectra were recorded with a Bruker 100 MHz spectrometer at ambient temperature (from about 21 °C to about 25°C)using TMS (0 ppm) as the reference standard. 3 ⁇ 4 NMR spectra were obtained as CDCb, DMSO-i3 ⁇ 4, CD 3 OD or ⁇ 3 ⁇ 4-acetone solutions (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard.
  • N-(3-fluoro-4-((7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl)oxy)phenyl)-l,5-dimethyl-3-oxo-2 -phenyl-2,3-dihydro-lH-pyrazole-4-carboxamide can be prepared according to the method described in WO 2012118632A1, the content of which is incorporated herein by reference in its entirety.
  • N-(3-fluoro-4-((7-(2-hydroxy-2-methylpropoxy)quinolin-4-yl)oxy)phenyl)-l,5- dimethyl-3-oxo-2-phenyl-2,3-dihydro-lH-pyrazole-4-carboxamide (10 g, 17.97 mmol) was suspended in ethanol (36 mL). After stirring at ambient temperature for 30 minutes, a solution of 4-methylbenzenesulfonic acid hydrate (4.44 g, 23.36 mmol) in water (15 mL) was added in 30 minutes. The suspension was heated to 100 °C and stirring further for 30 minutes, then water (129 mL) was added in 1 hour.
  • the resulting reaction mixture was stirred further for another 1 hour and then cooled down to ambient temperature in 2 hours.
  • the reaction mixture was stirred at ambient temperature for 12 hours and a thick oil was obtained.
  • the solvent was removed by filtering and the residue was placed in the bush funnel at ambient temperature for 12 hours to form the solid product.
  • the solid product was dried at 55 °C for 24 hours to give the title compound as a white solid (12.50 g, yield 95.4%).
  • Solid-state 13 C MR Peaks ⁇ (ppm): 167.83, 165.36, 162.39, 156.94, 155.65, 155.06, 152.86, 146.62, 144.28, 142.03, 141.29, 134.26, 131.79, 129.29, 128.33, 126.21, 124.21, 120.71, 115.77, 113.98, 108.33, 102.57, 101.59, 98.65, 73.41, 71.77, 33.94, 28.13, 25.54, 21.59, 12.66.
  • the X-ray powder diffraction (XRPD) pattern was collected on an X-ray powder diffractometer (Empyrean, PANalytical, Holland) with an automatic transmission-reflection sample holder (3* 15).
  • the scanning parameters were: continuous scan; range 3° to 40°(2 ⁇ 0.2°); step size 0.0168°; time per step 10 second. Data were collected at ambient temperature (from aboutl8 to about 32 °C).
  • Sample (usually 1-2 mg) was prepared as flat plate specimens by slightly pressed on a glass slide to obtain a flat surface.
  • the data were collected by Data Collector software, and analyzed by Data Viewer and HighScore Plus software.
  • the XRPD pattern for Compound (I), Form Bis shown in Figure 1 and peaks and their related intensities in the XRPD pattern are shown in Table 1 below.
  • the crystalline form B of Compound (I) has a differential scanning calorimetry trace that shown in Figure 2 which comprising a maximum in endothermic heat flow at 213.44 °C ⁇ 3°C.
  • the crystalline form B of Compound (I) has a thermal gravimetric analysis curvethat shown in Figure 3 which comprising a weight loss of about 1.077% when heated to about 150°C. 4. Stability Test
  • a sample of crystalline formB of compound (I) (100-200 mg) was placed on a watching glass in the form of a thin layer (thickness ⁇ 5 mm). The samples were exposed to the following conditions: high temperature (60 ⁇ 2 °C) for 10 days; high humidity (25 ⁇ 2 °C, 90% ⁇ 5%) for 10 days; illumination condition (visible light 45001x ⁇ 5001x with ultraviolet light not lower than 0.7 W-h/m 2 , 25 ⁇ 2 °C, 60% ⁇ 5% relative humidity) for 10 days; and room temperature (30 ⁇ 2 °C, 65% ⁇ 5% humidity) for 10 days, respectively.
  • the impurity contentsin the samples were determined at different time points (0, 5 and 10 days) by high performance liquid chromatography (HPLC), and the absorption peaks were normalized relative to the highest peak (corresponds to compound I) which is set to 100%.
  • HPLC high performance liquid chromatography
  • the instrument and conditions for HPLC are showed in Table 2 and the data are shown in Table 3.
  • a glass weighing bottle equipped with a stopper was tarred and the weight was recorded as mi.
  • Compound (I) in crystalline form B (about 1.0 g) was placed in the tared weighing bottle and capped with the stopper. The total weight was then recorded as m 2 .
  • the weighing bottle (without its stopper) was placed in a desiccator containing a saturated solution of ammonium chloride (80% ⁇ 2% RH) at 25 ⁇ 1°C.
  • the weighing bottle capped with its stopper was weighed on day 5 and day 10 and the weight was recorded as m 3 .
  • the hygroscopic capacity was calculate according to the following formula and the results are listed in Table 4.
  • the pharmacokinetic properties of the crystalline form B of Compound (I) disclosed herein is assessed in beagle dogs.
  • the LC/MS/MS system used in the analysis consists of an Agilent 1200 Series vacuum degasser, binary pump, well-plate autosampler, thermostatted column compartment, the Agilent G6430 Triple Quadrupole Mass Spectrometer with an electrosprayionization (ESI) source. Quantitative analysis was carried out using MRM mode. The parameters for MRM transitions are in the Table A.
  • an Agilent 6330 series LC/MS/MS spectrometer equipped with G1312A binary pumps, a G1367A autosampler and a G1314C UV detector were used in the analysis.
  • An ESI source was used on the LC/MS/MS spectrometer.
  • the analysis was done in positive ion mode as appropriate and the MRM transition for each analyte was optimized using standard solution.
  • the mobile phase was 5 mM ammonia acetate, 0.1% MeOH in water (A): 5 mM ammonia acetate, 0.1% MeOH in acetonitrile (B) (70/30, v/v).
  • the flow rate was 0.6 mL/min.
  • Column was maintained at ambient temperature. 20 ⁇ of the samples were injected.
  • the capsule of the crystalline form B of Compound (I) mixed with adjuvants was administered by gavage to beagle dogs in a dose of 7 or 10 mg/kg.
  • the blood samples (0.3 mL) were drawn at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 12 and 24 hour time points or 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hour time points and centrifuged at 3,000 or 4000 rpm for 2 to 10 min.
  • the plasma solutions were collected, and analyzed by LC -MS/MS as described above.
  • the pharmacokinetic parameters were calculated according to non-compartment model using WinNonlin procedure. The pharmacokinetic parameters are shown in Table 5.

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  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme cristalline du ρ-toluènesulfonate de N-(3-fluoro-4-((7-(2-hydroxy-2-méthylpropoxy)quinoléin-4-yl)oxy)phényl)-1,5-diméthyl-3-oxo-2-phényl-2,3-dihydro-lH-pyrazole-4-carboxamide, le procédé de préparation de cette forme cristalline et des compositions pharmaceutiques comprenant ladite forme cristalline. L'invention concerne également un procédé d'utilisation d'une telle forme cristalline et de telles compositions pharmaceutiques comprenant ladite forme cristalline dans le traitement de troubles hyperprolifératives chez les mammifères, dont, en particulier l'être humain.
PCT/US2017/036909 2016-06-16 2017-06-10 Forme cristalline d'un composé de quinoléine substitué et compositions pharmaceutiques en contenant WO2017218365A1 (fr)

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WO2020256636A1 (fr) * 2019-06-18 2020-12-24 Scinopharm Taiwan, Ltd. Nouvelle forme cristalline d'olaparib et procédé de préparation associé
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
CN113330007A (zh) * 2018-10-03 2021-08-31 特沙诺有限公司 尼拉帕利游离碱的晶体形式
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

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US20050267158A1 (en) * 2004-03-17 2005-12-01 Agouron Pharmaceuticals, Inc. Polymorphic and amorphous forms of 2,5-dimethyl-2H-pyrazole-3-carboxylic acid {2-fluoro-5-[3-((E)-2 pyridin-2-YL-vinyl)-1H-indazol-6-ylamino]-phenyl}-amide
US20120219522A1 (en) * 2011-02-28 2012-08-30 Dr. Ning XI Substituted quinoline compounds and methods of use
US20150291532A1 (en) * 2012-12-21 2015-10-15 Eisai R&D Management Co., Ltd. Amorphous form of quinoline derivative, and method for producing same

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US20050267158A1 (en) * 2004-03-17 2005-12-01 Agouron Pharmaceuticals, Inc. Polymorphic and amorphous forms of 2,5-dimethyl-2H-pyrazole-3-carboxylic acid {2-fluoro-5-[3-((E)-2 pyridin-2-YL-vinyl)-1H-indazol-6-ylamino]-phenyl}-amide
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
CN113330007A (zh) * 2018-10-03 2021-08-31 特沙诺有限公司 尼拉帕利游离碱的晶体形式
WO2020256636A1 (fr) * 2019-06-18 2020-12-24 Scinopharm Taiwan, Ltd. Nouvelle forme cristalline d'olaparib et procédé de préparation associé
US11945785B2 (en) 2021-12-30 2024-04-02 Biomea Fusion, Inc. Pyrazine compounds as inhibitors of FLT3

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