WO2019144759A1 - 靶向cdk4/6激酶抑制剂的晶型 - Google Patents

靶向cdk4/6激酶抑制剂的晶型 Download PDF

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WO2019144759A1
WO2019144759A1 PCT/CN2018/124418 CN2018124418W WO2019144759A1 WO 2019144759 A1 WO2019144759 A1 WO 2019144759A1 CN 2018124418 W CN2018124418 W CN 2018124418W WO 2019144759 A1 WO2019144759 A1 WO 2019144759A1
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compound
cancer
formula
solvent
group
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PCT/CN2018/124418
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English (en)
French (fr)
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冯玉真
房兰
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海南轩竹医药科技有限公司
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Priority to JP2020562813A priority Critical patent/JP6972390B2/ja
Priority to EP18902212.2A priority patent/EP3747880B1/en
Priority to CN201880087850.6A priority patent/CN111902405B/zh
Priority to KR1020207024721A priority patent/KR102531772B1/ko
Priority to AU2018404690A priority patent/AU2018404690B2/en
Priority to EA202091556A priority patent/EA202091556A1/ru
Priority to US16/965,503 priority patent/US11299474B2/en
Priority to CA3089243A priority patent/CA3089243C/en
Publication of WO2019144759A1 publication Critical patent/WO2019144759A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present disclosure relates to a crystalline form targeting a CDK4/6 kinase inhibitor and a process for the preparation thereof, and to pharmaceutical compositions comprising the crystalline form, and the activity of these compounds in reducing or inhibiting CDK4/6 kinase in cells, Use in the treatment and/or prevention of cancer-associated diseases mediated by CDK4/6 kinase.
  • the chemical name of the compound represented by the formula (I) is 5-((4-ethylpiperazin-1-yl)methyl)-N-(5-fluoro-4-(4-fluoro-1-isopropyl) -2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-ylpyrimidin-2-amine (hereinafter referred to as "the compound of formula (I)", in the patent application PCT/CN2014/095615 As described therein, it targets a cyclin-dependent kinase 4/6 (CDK4/6) kinase inhibitor. Studies have shown that CDK4/6 plays an irreplaceable role in the CDK subtype involved in the cell cycle.
  • the cell cycle mutations associated with cancer are mainly present in the G1 and G1/S phase transformations.
  • the complex formed by CDK4/6 and CyclinD phosphorylates the tumor suppressor gene Rb to pRb, releasing the bound transcription factor E2F, resulting in The S phase initiates the transcription of the relevant genes, prompting the cells to pass through the checkpoint and transfer from the G1 phase to the S phase.
  • Abnormalities in the cyclin D-CDK4/6-INK4-Rb pathway are present in approximately 80% of human tumors.
  • the change of this pathway accelerates the G1 phase process, which accelerates the proliferation of tumor cells and gains a survival advantage. Therefore, intervention in this pathway has become a therapeutic strategy, and CDK4/6 has become a new anti-tumor target.
  • CDK4/6 as an anti-tumor target lies in the following two aspects: (1) Most proliferating cells rely on CDK2 or CDK4/6 proliferation, but CDK4/6 inhibitors do not exhibit "pan-CDK inhibitors" Cytotoxicity, such as myelosuppression and intestinal reactions. (2) Preclinical experiments show that if the level of cyclin D is increased or P16INK4a is inactivated, the sensitivity of the cells to drugs can be increased. Since the tumor cells have the above phenomenon relative to normal cells, the drug targeting is increased to some extent. Sex.
  • crystal form plays an important role in the drug development process. Different crystal forms of the same drug have significant differences in solubility, stability and bioavailability. In order to better control the quality of the drug, the formulation is satisfied. For the requirements of production, transportation, storage, etc., we have studied the crystal form of the compound of formula (I) in order to find crystal forms with good properties.
  • the present disclosure relates to a targeted CDK4/6 kinase inhibitor 5-((4-ethylpiperazin-1-yl)methyl)-N-(5-fluoro-4-(4-fluoro) represented by formula (I) Form A of 1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyridin-2-ylpyrimidin-2-amine.
  • the present disclosure also relates to a process for the preparation of Form A, a pharmaceutical composition comprising Form A, and the activity of these compounds to reduce or inhibit CDK4/6 kinase in a cell, to treat and/or prevent mediated by CDK4/6 kinase Application in cancer-related diseases.
  • the present disclosure provides a crystalline form A of a compound of formula (I),
  • the crystalline form A of the compound of formula (I), in addition to the above characteristic peaks, is still 8.7 ⁇ 0.2 °, 10.9 ⁇ 0.2 °, 15.7 ⁇ 0.2 °, 16.4 ⁇ 0.2 °, There are characteristic peaks at 30.4 ⁇ 0.2°.
  • the crystalline form A of the compound of formula (I) is still at 16.7 ⁇ 0.2 °, 19.3 ⁇ 0.2 °, 22.2 ⁇ 0.2 °, 23.3 ⁇ 0.2 °, 24.0 on the basis of the above characteristic peaks. Characteristic peaks at ⁇ 0.2°, 25.9 ⁇ 0.2°, and 28.1 ⁇ 0.2°.
  • the crystalline form A of the compound of formula (I), which uses Cu-K alpha radiation represents the X-ray powder diffraction pattern at 2.6 ⁇ 0.2 °, 8.7 ⁇ 0.2 °, 10.0 ⁇ at 2 ⁇ angles. Characteristic peaks were present at 0.2°, 10.9 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.4 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.6 ⁇ 0.2°, and 30.4 ⁇ 0.2°.
  • the crystalline form A of the compound of formula (I), which uses Cu-K alpha radiation represents the X-ray powder diffraction pattern at 2.6 ⁇ 0.2 °, 8.7 ⁇ 0.2 °, 10.0 ⁇ at 2 ⁇ angles. 0.2°, 10.9 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.4 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.4 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.6 ⁇ 0.2°, 22.2 ⁇ Characteristic peaks were found at 0.2°, 23.3 ⁇ 0.2°, 24.0 ⁇ 0.2°, 25.9 ⁇ 0.2°, 28.1 ⁇ 0.2°, and 30.4 ⁇ 0.2°.
  • the crystalline form A of the compound of formula (I) has an X-ray powder diffraction pattern obtained substantially as shown in Figure 1 using Cu-K alpha radiation.
  • DSC differential scanning calorimetry
  • the crystalline form A of the compound of formula (I) has a differential scanning calorimetry (DSC) pattern substantially as shown in FIG.
  • the crystalline form A of the compound of formula (I) is characterized by an X-ray powder diffraction pattern substantially as shown in FIG.
  • the crystalline form A of the compound of formula (I) is characterized in that the differential scanning calorimetry chart has a draw in the range of about 195 ° C to 215 ° C, preferably in the range of 205 ⁇ 3 ° C.
  • the heat peak, more preferably, the differential scanning calorimetry chart is substantially as shown in FIG.
  • the crystalline form A of the compound of formula (I) is characterized by no significant weight loss in the range of 0 °C to 250 °C in the TGA spectrum, preferably having a heat substantially as shown in FIG. Reanalyze the graph.
  • the crystalline form A of the compound of formula (I) is characterized by having a 1 H-NMR spectrum substantially as shown in FIG.
  • the crystalline form A of the compound of formula (I) is characterized in that its crystal structure is in a substantially pure form.
  • the present disclosure also provides a process for the preparation of the crystalline form A of the compound of formula (I), which comprises the following operations:
  • the precipitated solid was collected.
  • the method of preparing Form A of the compound of Formula (I) comprises the steps of:
  • the precipitated solid was collected.
  • the method of preparing Form A of the compound of Formula (I) comprises the steps of:
  • the precipitated solid was collected and dried.
  • the process for the preparation of Form A of the compound of Formula (I) which comprises dissolving a compound of Formula (I) in an organic solvent, heating to 60 ° C to 100 ° C, and stirring until the compound is dissolved Soon, the mixture was cooled and stirred to a temperature of 0 ° C to 25 ° C to precipitate a solid, and the mixture was stirred at a constant temperature for 1 to 24 hours, filtered under suction, and dried to obtain a crystal form A.
  • the method of preparing Form A of the compound of Formula (I) comprises the steps of:
  • the compound of formula (I) is dissolved in an organic solvent and heated to 70 ° C to 100 ° C;
  • the temperature is lowered to 50 ° C to 75 ° C, seed crystals are added, the temperature is kept constant, and a solid is precipitated;
  • the seed crystal is Form A of the compound of Formula (I) or a solid that precipitates during the preparation of Form A of the compound of Formula (I).
  • the amount of the seed crystal added is from 0.1% to 3% by mass of the compound of formula (I), such as from 0.1% to 0.2%, from 0.2% to 0.5%, from 0.5% to 1%, 1%-1.5%, 1.5%-2%, 2%-2.5% or 2.5%-3%.
  • the method of preparing Form A of the compound of Formula (I) comprises dissolving the compound of Formula (I) in an organic solvent, heating to 70 ° C to 100 ° C, and cooling the compound to 50 ° C after dissolution of the compound.
  • a certain amount of seed crystals can be optionally added, constant temperature, solids appear, slowly cooled to 0 ° C ⁇ 25 ° C, constant temperature, suction filtration, and dried to obtain crystal form A.
  • the seed crystal is selected from the form A or a solid precipitated before drying in the preparation of the crystal form A, and the crystal form A can be prepared by the preparation method of the other crystal form A without seeding described in the present disclosure. .
  • the mass ratio of the seed crystal to the compound of the formula (I) is from 0.1% to 3%, preferably from 0.1% to 0.2%, from 0.2% to 0.5%, from 0.5% to 1%, from 1% to 1.5%, from 1.5% to 2%, 2 %-2.5%, 2.5%-3%.
  • the method of preparing Form A of the compound of Formula (I) comprises the steps of:
  • the compound of the formula (I) is dissolved in an organic solvent, heated to 70 ° C to 100 ° C, and after the compound is dissolved, the temperature is lowered to 50 ° C to 65 ° C, the seed crystal is added, the temperature is constant, and a solid appears, and the temperature is slowly lowered to 0 ° C to 25 ° C.
  • the seed crystal is selected from the form A or the solid before drying in the process of preparing the crystal form A
  • the mass ratio of the seed crystal to the compound of the formula (I) is 0.1 % to 3%, preferably 0.1% to 0.2%, 0.2% to 0.5%, 0.5% to 1%, 1% to 1.5%, 1.5% to 2%, 2% to 2.5%, 2.5% to 3%.
  • the seed crystal is prepared by dissolving the compound of formula (I) in an organic solvent, heating to 60 ° C to 100 ° C, and stirring until the compound is dissolved, at a constant temperature, decreasing the stirring rate, and cooling. To 50 ° C ⁇ 65 ° C, increase the stirring rate, slowly reduce the temperature to 0 ° C ⁇ 25 ° C, precipitate solids, constant temperature, stirring for 1 ⁇ 24h, suction filtration to obtain seed crystals.
  • the heating temperature is 60 ° C to 100 ° C, preferably 70 ° C to 100 ° C, preferably 80 ° C to 100 ° C, preferably 90 ° C to 100 ° C.
  • the preferred heating temperature is the temperature at which the sample dissolves and becomes clear.
  • the temperature is lowered to 0 ° C to 25 ° C, preferably 5 ° C to 10 ° C, preferably 5 ° C to 20 ° C, preferably 10 ° C to 15 ° C, Preferably, the temperature is from 15 ° C to 25 ° C, and the temperature can be optionally lowered at different temperatures during the cooling process.
  • the cooling rate is preferably 3 to 15 ° C per hour, preferably 5 to 10 ° C / h, preferably 6 ° C / h, preferably 9 ° C / h; the cooling method includes but is not limited to natural cooling and cooling, ice bath cooling, oil bath cooling In the present disclosure, natural cooling and cooling, oil bath cooling, and cooling of the refrigeration equipment are preferred in the present disclosure.
  • the stirring, the stirring mode includes, but not limited to, mechanical stirring, magnetic stirring, etc.; the stirring rate is preferably 500-100 r/min, preferably 300r/min, 150r/min (the speed can be adjusted according to the size of the stirring paddle. If the size of the stirring paddle is large, the rotation speed can be appropriately reduced), the stirring time is preferably 0.5h to 10h, preferably 0.5h to 1h, preferably 1h to 6h. It is preferably 1.5 h to 5 h.
  • the compound of the formula (I) is dissolved in an organic solvent selected from one or more of the following solvents: Any combination between:
  • an alcohol solvent selected from the group consisting of a fatty alcohol, an alicyclic alcohol, and an aromatic alcohol solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, and tert-butyl Alcohol, sec-butanol, n-pentanol, n-hexanol, ethylene glycol, propylene glycol or glycerol; said alicyclic alcohol solvent is selected from the group consisting of cyclopentanol, cyclopentanol, cyclohexanol, cyclohexane methanol or Cyclohexylethanol; the aromatic alcohol solvent is selected from the group consisting of benzyl alcohol, phenylethyl alcohol or phenylpropanol;
  • a ketone solvent selected from the group consisting of aliphatic ketones and cycloketone solvents, wherein the aliphatic ketone solvent is selected from the group consisting of methyl ethyl ketone, methyl isopropyl ketone, acetone, methyl methyl ketone or methyl isobutyl ketone;
  • the cycloketone solvent is selected from the group consisting of cyclopropanone, cyclohexanone, isophorone or N-methylpyrrolidone;
  • a nitrile solvent selected from acetonitrile or propionitrile
  • an ether solvent selected from the group consisting of a fatty ether and a cyclic ether solvent wherein the fatty ether solvent is selected from the group consisting of diethyl ether, dipropyl ether, diisopropyl ether, methyl tert-butyl ether, and ethyl butyl ether.
  • the cyclic ether solvent is selected from the group consisting of ethylene oxide, 1,2-propylene oxide, tetrahydrofuran, 2-methylfuran, dioxolane or 1,4 - dioxane;
  • An amide solvent selected from the group consisting of formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide or N,N-diethylpropyl Amide
  • a sulfoxide solvent selected from the group consisting of dimethyl sulfoxide, diethyl sulfoxide or benzyl sulfoxide;
  • the "combination between any two or more kinds of solvents" as used in the organic solvent means a solvent in which the same type or different types of solvents are mixed in a predetermined ratio in the above organic solvent.
  • Mixed solvents formed by the same type of solvent including but not limited to the following specific examples: methanol / ethanol, methanol / isopropanol, methanol / ethanol / isopropanol, methanol / tert-butanol, methanol / cyclopentanol, methanol / benzyl alcohol , ethanol / isopropanol, ethanol / tert-butanol, diethyl ether / tetrahydrofuran and the like.
  • the mixed solvent formed by the different kinds of solvents includes, but is not limited to, the following mixed solvent systems: alcohols/ketones, alcohols/ethers, alcohols/amides, ketones/amides, and the like.
  • the organic solvent is an alcohol solvent or a ketone solvent.
  • the organic solvent is selected from the group consisting of acetone, isopropanol, butanol, n-pentanol.
  • the drying method includes, but is not limited to, natural drying at room temperature, infrared lamp drying, oven drying, dryer drying, preferably in Drying under vacuum; preferably drying temperature is 30 ° C ⁇ 100 ° C, preferably 30 ° C ⁇ 80 ° C, preferably 35 ° C ⁇ 70 ° C, preferably 40 ° C ⁇ 65 ° C, preferably 35 ° C ⁇ 55 ° C; optional during the drying process
  • the drying is carried out several times at different temperatures; the preferred drying time is 5h to 48h, 10h to 36h, and 15h to 24h.
  • the present disclosure also provides pharmaceutical compositions comprising Form A of a compound of Formula (I) described herein, and optionally one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical compositions of the present disclosure may be in any pharmaceutically acceptable dosage form, such as a solution, tablet, capsule or injection, which may be administered by the injection route or orally. medicine.
  • Form A of the compound of Formula (I) described herein, or a pharmaceutical composition thereof, is preferably administered orally.
  • a pharmaceutical composition comprising a crystalline form of (I) a compound (eg, Form A) and optionally one or more pharmaceutically acceptable carriers and/or diluents described herein may be pharmaceutically Acceptable in any dosage form. It is administered to a patient in need thereof by oral, parenteral, rectal or pulmonary administration.
  • oral administration it can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution, an oral suspension, a syrup or the like.
  • a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
  • parenteral administration it can be prepared as an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection.
  • injection When the injection is prepared, it can be produced by a conventional method in the prior art of pharmacy.
  • no additive When the injection is formulated, no additive may be added, or a suitable additive may be added according to the nature of the drug.
  • rectal administration When used for rectal administration, it can be made into a suppository or the like.
  • pulmonary administration it can be prepared as an inhalant or a spray.
  • the pharmaceutical compositions described herein may also comprise one or more additional anti-neoplastic agents and/or immunosuppressive agents.
  • the additional anti-tumor agent and/or immunosuppressant is selected from one or more of the following: methotrexate, capecitabine, gemcitabine, deoxyfluorouridine, pemetrexed disodium , pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib, herceptin, bevacizumab, rituximab, trastuzumab Anti-paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, temoxi Fen, fulvestrant, triclinin, flutamide, leuprolide, anastrozole, ifosfamide, busulfan
  • the present disclosure also provides a crystalline form (e.g., Form A) of a compound of Formula (I) of the present disclosure or a pharmaceutical composition of the present disclosure for use in the treatment and/or prevention of a subject by CDK4/ Use of a 6 kinase-mediated drug for cancer-related diseases.
  • a crystalline form e.g., Form A
  • a compound of Formula (I) of the present disclosure or a pharmaceutical composition of the present disclosure for use in the treatment and/or prevention of a subject by CDK4/ Use of a 6 kinase-mediated drug for cancer-related diseases.
  • the present disclosure also provides a method of treating and/or preventing a cancer-associated disease mediated by CDK4/6 kinase in a mammal in need thereof, the method comprising administering a treatment to a mammal in need thereof And/or prophylactically effective amount of Form A of the compound of Formula (I) described herein or the pharmaceutical composition.
  • the present disclosure also provides Form A of the compound of Formula (I) for use in the treatment and/or prevention of a drug associated with a CDK4/6 kinase mediated cancer associated disease.
  • the CDK4/6 kinase-mediated cancer-related disease is selected from the group consisting of: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, Cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, thyroid cancer, bone Cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma.
  • each active ingredient in the pharmaceutical compositions of the present disclosure can be varied so that the resulting amount of active compound is effective to provide the desired therapeutic response to the particular patient, composition, and mode of administration.
  • the dosage level will be selected based on the activity of the particular compound or its crystalline form, the route of administration, the severity of the condition being treated, and the condition and past medical history of the patient to be treated. However, it is the practice in the art that the dosage of the compound or its crystalline form begins at a level below that required to achieve the desired therapeutic effect, gradually increasing the dosage until the desired effect is achieved.
  • a therapeutically and/or prophylactically effective amount of Form A of the compound of the present formula (I) may be applied in pure form.
  • Form A of the compound of formula (I) can be administered as a pharmaceutical composition comprising Form A of a compound of Formula (I) and one or more pharmaceutically acceptable excipients.
  • the phrase "therapeutically and/or prophylactically effective amount" of Form A of a compound of formula (I) as described herein refers to a sufficient amount of a compound to treat a disorder at a reasonable effect/risk ratio suitable for any medical treatment and/or prevention.
  • the total daily usage of Form A and the pharmaceutical composition of the compounds of Formula (I) of the present disclosure is to be determined by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the particular compound employed or its crystalline form of activity; Specific composition; age, weight, general health, sex and diet of the patient; time of administration, route of administration and excretion rate of the particular compound or crystalline form thereof used; duration of treatment; and specific compound or A drug whose crystalline form is used in combination or simultaneously; and similar factors well known in the medical field.
  • the dosage of the compound or its crystalline form begins at a level below that required to achieve the desired therapeutic effect, gradually increasing the dosage until the desired effect is achieved.
  • the dosage form A of the compound of formula (I) of the present disclosure for use in mammals, particularly humans may range from 0.001 to 1000 mg/kg body weight per day.
  • Form A of the compound of formula (I) described in the present disclosure may be administered alone or in the form of a pharmaceutical composition.
  • the pharmaceutical compositions described in the present disclosure may be formulated into various suitable dosage forms depending on the route of administration.
  • the use of one or more physiologically acceptable carriers, including excipients and auxiliaries, facilitates processing of the active compound or its crystalline form into preparations which can be used pharmaceutically.
  • the appropriate form of preparation will depend on the route of administration chosen and can be made according to common general knowledge in the art.
  • the preparation method is simple and convenient, and is suitable for industrial production
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of Form A of the compound of the formula (I), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2 ⁇ ).
  • XRPD X-ray powder diffraction
  • Figure 3 is a 1H-NMR chart of Form A of the compound of formula (I).
  • Preparation method 1 Take 5.0 g of the compound of the formula (I), add 75 mL of acetone, dissolve it under magnetic stirring, and immediately precipitate a white solid. After stirring for 5 h, suction and filter to obtain a white powder, which is dried under vacuum at 35 ° C for 16 h, and the obtained solid is subjected to XRPD test. , is crystal form A.
  • Preparation method 2 Take 500 mg of the compound of the formula (I), add 15 mL of isopropanol, stir in an oil bath at 80 ° C, dissolve and become clear (within 4.0 h), naturally drop to room temperature (32 ° C), precipitate a white solid, at room temperature Stirring was continued for 12 h, the temperature was lowered to 15 ° C and stirred for 4.0 h, and suction filtered. The obtained solid was dried under vacuum at 45 ° C for 16 h, and analyzed by XRPD and 1 H-NMR.
  • Preparation method 3 Take 5.0 g of the compound of the formula (I) in a 100 mL three-necked flask, add 75 mL of sec-butanol, control the temperature in an oil bath at 95 ° C, mechanically stir for 0.5 h, dissolve and become clear. Then, the temperature is lowered to 70 ° C in the oil bath, and about 25 mg of the seed crystal (that is, the crystal form A obtained in the first and second preparation methods) is added, and the white solid is gradually precipitated, and the temperature is further lowered to 60 ° C in the oil bath, the temperature is lowered for 0.5 h, and the temperature is lowered to 55 ° C.
  • the seed crystal that is, the crystal form A obtained in the first and second preparation methods
  • the purity of the crystal form A is more than 99.7%, the single maximum impurity is less than 0.08%, and almost no solvent remains.
  • X-ray reflection parameters Cu, K ⁇ ; incident slit: 0.6 mm; divergence slit: 1 mm; scanning mode: continuous; scanning range: 3.0 to 45.0 degrees; sampling step size: 0.02 degrees; scanning time per step: 19.8 s; Detector angle: 2.0 degrees.
  • Form A of the compound of formula (I) is shown in Figure 1 in an X-ray powder diffraction pattern having peaks at the following diffraction 2 ⁇ angles: 6.6 ⁇ 0.2 °, 8.7 ⁇ 0.2 °, 10.0 ⁇ 0.2 °, 10.9 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.7 ⁇ 0.2°, 16.4 ⁇ 0.2°, 16.7 ⁇ 0.2°, 17.4 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.1 ⁇ 0.2°, 20.6 ⁇ 0.2°, 22.2 ⁇ 0.2°, 23.3 ⁇ 0.2°, 24.0 ⁇ 0.2°, 25.9 ⁇ 0.2°, 28.1 ⁇ 0.2°, 30.4 ⁇ 0.2°.
  • the measurement conditions were as follows: purging with nitrogen at 50 ml/min, collecting data at a heating rate of 10 ° C/min between 25 ° C and 220 ° C, and drawing with the endothermic peak facing downward.
  • the crystal form A of the compound of the formula (I) showed an endothermic peak in the range of 195 ° C to 215 ° C, and the differential scanning calorimetry chart is shown in FIG. 2 .
  • Test conditions Purging was performed with nitrogen at 60 ml/min, and data was collected at a heating rate of 10 ° C/min between room temperature and 350 °C.
  • the crystal form A of the compound of the formula (I) has no significant weight loss in the range of 0 ° C to 250 ° C, and the TG curve thereof is shown in FIG. 2 .
  • Test sample Form A of the compound of the formula (I), which was prepared according to the above production method one, two, three or four.
  • test sample was placed under high humidity (25 ° C / RH 92.5% or 40 ° C / RH 75%) at 60 ° C for 10 days, sampling on the 5th and 10th day respectively; illumination (4500LX ⁇ 500LX)
  • the cells were allowed to stand for 10 days, and samples were taken on the 10th day, and the relevant substances and XRPD were measured and compared with the samples of 0 days.
  • the compound of formula (I) was prepared according to the preparation method of Example 1 of the specification in patent PCT/CN2014/095615.
  • Form A of the compound of formula (I) is prepared according to the above preparation method one, two, three or four.
  • Determination method According to the Chinese Pharmacopoeia 2015 edition of the four general rules 9103 drug wettability test guidelines.
  • Test sample Form A of the compound of the formula (I), which was prepared according to the above production method one, two, three or four.
  • Reagents Tween 80, ultrapure water.
  • Equipment laser particle size analyzer, sample diffuser.
  • test sample Take the appropriate amount of test sample, add 1% Tween 80 solution 0.1mL, to reduce the surface tension, use water as a dispersing agent to make a uniformly dispersed suspension, put it into the sample disperser, adjust the stirring speed to 2000rpm, ultrasonic The frequency was 7 KHz and the ultrasound was measured for 2 min.
  • the particle size distribution of the crystal form A of the compound of the formula (I) is as follows: 10% of the sample is 2.501 ⁇ m or less, 50% is 10.432 ⁇ m or less, and 90% is 59.852 ⁇ m or less.
  • Test article The compound of formula (I) (i.e., amorphous) was prepared according to the preparation method of Example 1 of the specification of Patent PCT/CN2014/095615.
  • test sample was placed under the condition of 25 ° C / RH 92.5% or 60 ° C for 10 days, and samples were taken on the 5th and 10th day respectively; the test sample was exposed to light (4500LX ⁇ 500LX) or 40 °C / RH75 After 10 days under % conditions, samples were taken on the 10th day, and the relevant substances and XRPD were measured and compared with the samples of 0 days.
  • the crystalline form A of the present disclosure exhibits good stability and low hygroscopicity characteristics, is convenient for the production of pharmaceuticals, preparation, transportation and storage of the preparation, and is more conducive to ensuring the stability and safety of the use of the medicine. Moreover, Form A has a better exposure and/or bioavailability in vivo than amorphous, and has good in vitro and in vivo effects.
  • Test sample Form A of the compound of formula (I), prepared according to the above preparation method 1, 2, 3 or 4; the compound of formula (I) is not stereotyped, according to the preparation method of the embodiment 1 of the patent PCT/CN2014/095615 preparation.
  • the crystal form A of the compound of the formula (I) and the amorphous material were separately tableted separately, the tablet weight was fixed, the tablet thickness (tableting force) was adjusted, and the tablet hardness was measured. Investigate the hardness as a function of the thickness of the tablet, and compare the compressibility.
  • Test sample Form A of the compound of formula (I), prepared according to the above preparation method 1, 2, 3 or 4; the compound of formula (I) is not stereotyped, according to the preparation method of the embodiment 1 of the patent PCT/CN2014/095615 preparation.
  • Form A and Amorphous were respectively added to the same kind and amount of auxiliary materials to prepare tablets, and disintegration and dissolution were examined under the following conditions.
  • Dissolution method paddle method (Chinese Pharmacopoeia 2015 edition fourth part 0931 dissolution and release determination method second method); medium: 0.2% SDS aqueous solution; rotation speed: 50r / min.

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Abstract

本公开涉及5-((4-乙基哌嗪-1-基)甲基)-N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-2-基)嘧啶-2-胺的晶型A，该晶型纯度高、残留溶剂少，溶解度较高，稳定性好；具有良好的性状、流动性、可压性，便于生产、检测、制剂制备、运输和储藏；制备方法操作简便，适合工业化生产，可用于治疗和/或预防CDK4/6激酶介导的癌症相关疾病。

Description

靶向CDK4/6激酶抑制剂的晶型
本申请是以CN申请号为201810084351.3，申请日为2018年01月29日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本公开涉及一种靶向CDK4/6激酶抑制剂的晶型及其制备方法，还涉及包含所述晶型的药物组合物，以及这些化合物在降低或抑制细胞中的CDK4/6激酶的活性，治疗和/或预防由CDK4/6激酶介导的癌症相关疾病中的应用。
背景技术
式(I)所示的化合物的化学名称为5-((4-乙基哌嗪-1-基)甲基)-N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-2-基)嘧啶-2-胺(以下简称为“式(I)化合物”，在专利申请PCT/CN2014/095615中已有描述)，其为靶向周期蛋白依赖性激酶4/6(cyclin-dependent kinase 4/6，CDK4/6)激酶抑制剂。研究表明，在参与细胞周期的CDK亚型中，CDK4/6发挥着不可替代的作用。与癌症有关的细胞周期突变主要存在于G1期和G1/S期转化过程中，CDK4/6与CyclinD形成的复合物使抑癌基因Rb磷酸化为pRb，释放被结合的转录因子E2F，导致与S期启动有关的基因转录，促使细胞通过检验点，并从G1期向S期转移。大约80％的人类肿瘤中有cyclin D-CDK4/6-INK4-Rb通路的异常。这条通路的改变，加速了G1期进程，使得肿瘤细胞增殖加快而获得生存优势。因此，对该通路的干预成为一种治疗策略，CDK4/6成为一种新的抗肿瘤靶点。CDK4/6作为抗肿瘤靶点的优势在于以下两个方面：(1)大多数增殖的细胞依赖CDK2或者CDK4/6增殖，但CDK4/6的抑制剂不表现出“pan-CDK抑制剂”的细胞毒性，如骨髓抑制和肠道反应。(2)临床前实验表明，如果细胞cyclin D水平升高或者P16INK4a失活，能够增加细胞对药物的敏感性，由于肿瘤细胞相对于正常细胞存在上述现象，所以一定程度上增加了药物的靶向性。
Figure PCTCN2018124418-appb-000001
晶型的研究在药物研发过程中发挥着重要的作用，同一药物的不同晶型在溶解 度、稳定性、生物利用度等方面存在着显著的差异，为了更好地控制药物的质量，满足制剂、生产、运输、存储等情况的要求，我们对式(I)化合物的晶型进行了研究，以期发现具有良好性质的晶型。
发明内容
本公开涉及式(I)所示的靶向CDK4/6激酶抑制剂5-((4-乙基哌嗪-1-基)甲基)-N-(5-氟-4-(4-氟-1-异丙基-2-甲基-1H-苯并[d]咪唑-6-基)吡啶-2-基)嘧啶-2-胺的晶型A。本公开还涉及晶型A的制备方法，包含晶型A的药物组合物，以及这些化合物在降低或抑制细胞中的CDK4/6激酶的活性，治疗和/或预防由CDK4/6激酶介导的癌症相关疾病中的应用。
在某些实施方案中，本公开提供了一种式(I)化合物的晶型A,
Figure PCTCN2018124418-appb-000002
所述的式(I)化合物的晶型A，其在使用Cu-Kα辐射、以2θ角度(°)表示的X-射线粉末衍射图谱中，在6.6±0.2°、10.0±0.2°、13.2±0.2°、17.4±0.2°、20.1±0.2°、20.6±0.2°处有特征峰。
在某些实施方案中，所述的式(I)化合物的晶型A在包含上述特征峰的基础上，还在8.7±0.2°、10.9±0.2°、15.7±0.2°、16.4±0.2°、30.4±0.2°处有特征峰。
在某些实施方案中，所述的式(I)化合物的晶型A在包含上述特征峰的基础上还在16.7±0.2°、19.3±0.2°、22.2±0.2°、23.3±0.2°、24.0±0.2°、25.9±0.2°、28.1±0.2°处有特征峰。
在某些实施方案中，所述的式(I)化合物的晶型A，其使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图在6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、17.4±0.2°、20.1±0.2°、20.6±0.2°、30.4±0.2°处有特征峰。
在某些实施方案中，所述的式(I)化合物的晶型A，其使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图在6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、16.7±0.2°、17.4±0.2°、19.3±0.2°、20.1±0.2°、20.6±0.2°、22.2±0.2°、23.3±0.2°、24.0±0.2°、25.9±0.2°、28.1±0.2°、30.4±0.2°处有特征峰。
在某些实施方案中，所述的式(I)化合物的晶型A，其具有基本上如图1所示的 使用Cu-Kα辐射获得的X-射线粉末衍射图。
在某些实施方案中，所述的式(I)化合物的晶型A，其在差示扫描量热分析(DSC)图谱中，在约195℃～215℃处存在一个吸热峰。
在某些实施方案中，所述的式(I)化合物的晶型A，其在差示扫描量热分析(DSC)图谱中，在205±3℃处存在一个吸热峰。
在某些实施方案中，所述的式(I)化合物的晶型A，其具有基本上如图2所示的差示扫描量热分析(DSC)图谱。
在某些实施方案中，所述的式(I)化合物的晶型A，其特征在于，其X-射线粉末衍射图基本如图1所示。
在某些实施方案中，所述的式(I)化合物的晶型A，其特征在于，其差示扫描量热分析图在大约195℃至215℃范围、优选在205±3℃范围具有吸热峰，更优选其差示扫描量热分析图基本如图2所示。
在某些实施方案中，所述的式(I)化合物的晶型A，其特征在于，在TGA图谱中，0℃-250℃范围无明显失重现象，优选具有基本如图2所示的热重分析图。
在某些实施方案中，所述的式(I)化合物的晶型A，其特征在于，具有基本如图3所示的 1H-NMR图谱。
在某些实施方案中，所述的式(I)化合物的晶型A，其特征在于，其晶体结构为基本纯净的形式。
在某些实施方案中，本公开还提供了制备所述的式(I)化合物晶型A的方法，其包括以下操作：
将式(I)化合物溶于有机溶剂中，
搅拌，
收集析出的固体。
在某些实施方案中，所述的制备式(I)化合物晶型A的方法包括以下操作：
将式(I)化合物溶于有机溶剂中，加热至60℃～100℃，搅拌使化合物溶解；
降温至0℃～25℃，恒温搅拌1～24h；
收集析出的固体。
在某些实施方案中，所述的制备式(I)化合物晶型A的方法包括以下操作：
将式(I)化合物溶于有机溶剂中，加热至60℃～100℃，搅拌使化合物溶解；
降温至30℃～55℃，析出固体；
降温至0℃～25℃，恒温搅拌1～24h；
收集析出的固体，干燥。
在某些实施方案中，所述的制备式(I)化合物晶型A的方法，该方法包括将式(I)化合物溶于有机溶剂中，加热至60℃～100℃、并搅拌至化合物溶解为止，降温并搅拌至0℃～25℃析出固体，恒温、搅拌1～24h，抽滤，干燥得到晶型A。
在某些实施方案中，所述的制备式(I)化合物晶型A的方法包括以下操作：
将式(I)化合物溶于有机溶剂中，加热至70℃～100℃；
化合物溶解后，降温至50℃～75℃，加入晶种，保持恒温，析出固体；
缓慢降温至0℃～25℃，恒温，收集析出的固体，干燥得到晶型A。
在某些实施方案中，所述晶种为式(I)化合物晶型A或在制备式(I)化合物晶型A的过程中析出的固体。
在某些实施方案中，所加入的所述晶种的量为式(I)化合物的质量的0.1％～3％，例如0.1％～0.2％，0.2％-0.5％，0.5％-1％，1％-1.5％，1.5％-2％，2％-2.5％或2.5％-3％。
在某些实施方案中，所述的制备式(I)化合物晶型A的方法包括式(I)化合物溶于有机溶剂中，加热至70℃～100℃，化合物溶解后，降温至50℃～65℃时，可任选的加入一定量晶种，恒温，出现固体，缓慢降温至0℃～25℃，恒温、抽滤，干燥得到晶型A。所述晶种选自晶型A或在制备晶型A的过程中干燥之前析出的固体，所述的晶型A可由本公开所述的不加晶种的其他晶型A的制备方法制备得到。晶种与式(I)化合物的质量比为0.1％-3％，优选0.1％～0.2％，0.2％-0.5％，0.5％-1％，1％-1.5％，1.5％-2％，2％-2.5％，2.5％-3％。
在某些实施方案中，所述的制备式(I)化合物晶型A的方法包括以下操作：
将式(I)化合物溶于有机溶剂中，加热至70℃～100℃，化合物溶解后，降温至50℃～65℃时，加入晶种，恒温，出现固体，缓慢降温至0℃～25℃，恒温、抽滤，干燥得到晶型A，所述晶种选自晶型A或在制备晶型A的过程中干燥之前的固体，所述晶种与式(I)化合物的质量比为0.1％～3％，优选0.1％～0.2％，0.2％-0.5％，0.5％-1％，1％-1.5％，1.5％-2％，2％-2.5％，2.5％-3％。
在某些实施方案中，所述的晶种的制备方法包括将式(I)化合物溶于有机溶剂中，加热至60℃～100℃、并搅拌至化合物溶解为止，恒温，降低搅拌速率，降温至50℃～65℃，提高搅拌速率，缓慢降温至0℃～25℃，析出固体，恒温、搅拌1～24h，抽滤即得晶种。
在某些实施方案中，所述的晶型A及晶种的制备方法中，加热温度是60℃～100℃，优选70℃～100℃，优选80℃～100℃，优选90℃～100℃，优选的加热温度为至样品溶解并变得清澈时的温度。
在某些实施方案中，所述的晶型A及晶种的制备方法中，降温至0℃～25℃，优选5℃～10℃，优选5℃～20℃，优选10℃～15℃，优选15℃～25℃，降温过程中可以任选的在不同温度进行多次降温。其降温速率优选每小时降温3～15℃，优选5～10℃/h，优选6℃/h，优选9℃/h；其降温方式包括但不限于自然冷却降温、冰浴降温、油浴降温、使用制冷设备降温等，本公开中优选自然冷却降温、油浴降温、制冷设备降温。
在某些实施方案中，所述的晶型A及晶种的制备方法中，所述搅拌，其搅拌方式包括但不限于机械搅拌、磁力搅拌等；其搅拌速率优选500～100r/min，优选300r/min，150r/min(可视搅拌桨尺寸调节转速，若搅拌桨尺寸较大，可适当减小转速)，其搅拌时间优选0.5h～10h，优选0.5h～1h，优选1h～6h，优选1.5h～5h。
在某些实施方案中，所述的晶型A及晶种制备方法中，将式(I)化合物溶于有机溶剂中，所述的有机溶剂选自下列溶剂中的一种或者两种以上溶剂之间的任一组合：
(1)醇类溶剂，选自脂肪醇、脂环醇及芳香醇类溶剂，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正戊醇、正己醇、乙二醇、丙二醇或丙三醇；所述的的脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇或环己乙醇；所述芳香醇类溶剂选自苯甲醇、苯乙醇或苯丙醇；
(2)酮类溶剂，选自脂肪酮类及环酮类溶剂，所述的脂肪酮类溶剂选自甲乙酮、甲基异丙基酮、丙酮、甲基丁酮或甲基异丁酮；所述的环酮类溶剂选自环丙酮、环己酮、异佛尔酮或N-甲基吡咯烷酮；
(3)腈类溶剂，选自乙腈或丙腈；
(4)醚类溶剂，选自脂肪醚类及环醚类溶剂，所述脂肪醚类溶剂选自乙醚、二丙醚、二异丙醚、甲基叔丁基醚、乙基丁基醚、乙基叔丁基醚、二丁醚或二戊醚，环醚类溶剂选自环氧乙烷、1,2-环氧丙烷、四氢呋喃、2-甲基呋喃、二氧戊环或1,4-二氧六环；
(5)酰胺类溶剂，选自甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二甲基丙酰胺或N,N-二乙基丙酰胺；
(6)亚砜类溶剂，选自二甲基亚砜、二乙基亚砜或苄苯亚砜；
以上所指的醇类、酮类、腈类、醚类、酰胺类以及亚砜类溶剂中并不局限于所列出的具体实例，凡是属于上述分类中的溶剂都可以实现本公开的功能，即制备得到式(I)所示的化合物的晶型A。
有机溶剂中所述的“两种以上溶剂之间的任一组合”是指上述有机溶剂中同一种类或不同种类的溶剂按照一定比例混合形成的溶剂。同一种类溶剂形成的混合溶剂，包括但不限于以下具体实例：甲醇/乙醇、甲醇/异丙醇、甲醇/乙醇/异丙醇、甲醇/叔丁醇、甲醇/环戊醇、甲醇/苯甲醇、乙醇/异丙醇、乙醇/叔丁醇、乙醚/四氢呋喃等。所述的不同种类溶剂形成的混合溶剂，包括但不限于以下混合溶剂体系：醇类/酮类、醇类/醚类、醇类/酰胺类、酮类/酰胺类等。
在某些实施方案中，所述的有机溶剂为醇类溶剂或酮类溶剂。
在某些实施方案中，所述的有机溶剂选自：丙酮、异丙醇、丁醇、正戊醇。
在某些实施方案中，所述的晶型A及晶种的制备方法中，所述的干燥方式包括但不限于室温下自然晾干、红外灯干燥、烘箱烘干、干燥器干燥，优选在真空条件下干燥；优选的干燥温度为30℃～100℃，优选30℃～80℃，优选35℃～70℃，优选40℃～65℃，优选35℃～55℃；干燥过程中可以任选的在不同温度进行多次干燥；优选的干燥时间为5h～48h，10h～36h，15h～24h。
在某些实施方案中，本公开还提供药物组合物，其含有本公开所述的式(I)化合物的晶型A，以及任选的一种或多种药用载体和/或稀释剂。在某些实施方案中，本公开所述的药物组合物可以为药学上可接受的任一剂型，例如溶液剂、片剂、胶囊或注射剂，这些药物组合物可以通过注射途径给药或口服给药。在某些实施方案中，本公开所述的式(I)化合物的晶型A或其药物组合物优选通过口服给药。
在某些实施方案中，本公开所述的含有(I)化合物晶型(例如晶型A)与任选的一种或多种药用载体和/或稀释剂的药物组合物可以为药学上可接受的任一剂型。以口服、肠胃外、直肠或经肺给药等方式施用于需要其的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入添加剂，也可根据药物的性质加入适宜的添加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
在某些实施方案中，本公开所述的药物组合物还可以包含一种或多种额外的抗肿瘤剂和/或免疫抑制剂。所述额外的抗肿瘤剂和/或免疫抑制剂，选自下述中的一种或多种：甲氨蝶呤、卡培他滨、吉西他滨、去氧氟尿苷、培美曲塞二钠、帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼、赫赛汀、贝伐单抗、利妥昔单抗、曲妥珠单抗、紫杉醇、长春瑞滨、多西他赛、多柔比星、羟基喜树碱、丝裂霉素、表柔比星、吡柔比星、博来霉素、来曲唑、他莫西芬、氟维司群、曲谱瑞林、氟他胺、亮丙瑞林、阿那曲唑、异环磷酰胺、白消安、环磷酰胺、卡莫司汀、尼莫司汀、司莫司汀、氮芥、马法兰、瘤可宁、卡铂、顺铂、奥沙利铂、络铂、拓扑特肯、喜树碱、拓扑替康、依维莫司、西罗莫斯、特癌适、6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤、菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素和氨鲁米特。
在某些实施方案中，本公开还提供了本公开式(I)化合物晶型(例如晶型A)或者本公开的药物组合物在制备用于治疗和/或预防受试者中由CDK4/6激酶介导的癌症相关疾病的药物中的用途。
在某些实施方案中，本公开还提供一种在有需要的哺乳动物中治疗和/或预防由CDK4/6激酶介导的癌症相关疾病的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的本公开所述的式(I)化合物的晶型A或所述药物组合物。
在某些实施方案中，本公开还提供所述的式(I)化合物的晶型A，其用于治疗和/或预防由CDK4/6激酶介导的癌症相关疾病的药物。
本公开中，所述CDK4/6激酶介导的癌症相关疾病选自：脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、肉瘤。
本公开所用的术语“约”，例如在用于修饰某一数值或数值范围时，是指包括该数值或数值范围以及该数值或数值范围的本领域技术人员可接受的误差范围，例如该误差范围为±10％、±5％、±4％、±3％、±2％、±1％、±0.5％等。
可改变本公开药物组合物中各活性成分的实际剂量水平，以便所得的活性化合物量能有效针对具体患者、组合物和给药方式得到所需的治疗反应。剂量水平须根据具体化合物或其结晶型的活性、给药途径、所治疗病况的严重程度以及待治疗患者的病 况和既往病史来选定。但是，本领域的做法是，化合物或其结晶型的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。
当用于上述治疗和/或预防或其他治疗和/或预防时，治疗和/或预防有效量的本公开式(I)化合物的晶型A，可以以纯形式应用。或者，所述式(I)化合物的晶型A可以以含有式(I)化合物的晶型A与一种或多种药物可接受赋形剂的药物组合物给药。词语“治疗和/或预防有效量”的本公开所述式(I)化合物的晶型A指以适用于任何医学治疗和/或预防的合理效果/风险比治疗障碍的足够量的化合物。但应认识到，本公开所述式(I)化合物的晶型A和药物组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定，所述因素包括所治疗的障碍和该障碍的严重程度；所采用的具体化合物或其结晶型的活性；所采用的具体组合物；患者的年龄、体重、一般健康状况、性别和饮食；所采用的具体化合物或其结晶型的给药时间、给药途径和排泄率；治疗持续时间；与所采用的具体化合物或其结晶型组合使用或同时使用的药物；及医疗领域公知的类似因素。例如，本领域的做法是，化合物或其结晶型的剂量从低于为得到所需治疗效果而要求的水平开始，逐渐增加剂量，直到得到所需的效果。一般说来，本公开所述式(I)化合物的晶型A用于哺乳动物特别是人的剂量可以介于0.001～1000mg/kg体重/天。
本公开所述式(I)化合物的晶型A可以单独或以药物组合物的形式给药。本公开所述的药物组合物可根据给药途径配成各种适宜的剂型。使用一种或多种生理学上可接受的载体，包含赋形剂和助剂，它们有利于将活性化合物或其结晶型加工成可以在药学上使用的制剂。适当的制剂形式取决于所选择的给药途径，可以按照本领域熟知的常识进行制造。
本公开式(I)化合物的晶型，尤其是晶型A的主要优点包括：
(1)制备方法操作简便，适合工业化生产；
(2)具有良好的性状、流动性、可压性，便于生产、检测、制剂制备、运输和储藏；
(3)纯度高、残留溶剂少，溶解度较高，稳定性好，质量易控；
(4)对CDK4/6酶具有良好的抑制活性，在体内具有良好暴露量和/或生物利用度；
(5)具有良好的体内外药效，可用于治疗和/或预防CDK4/6激酶介导的癌症相关疾病。
附图说明
此处所说明的附图用来提供对本公开的进一步理解，构成本申请的一部分，本公开的示意性实施例及其说明用于解释本公开，并不构成对本公开的不当限定。在附图中：
图1是式(I)化合物晶型A的X-射线粉末衍射(XRPD)图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图2是式(I)化合物的晶型A的TGA-DSC分析图，右侧纵坐标表示重量(％)，左侧纵坐标表示热流(W/g)，横坐标表示温度T(℃)。
图3是式(I)化合物晶型A的1H-NMR图谱。
具体实施方式
下面结合本公开的具体实施例来进一步说明本公开的实质性内容，应理解，以下实施例仅用于说明本公开，但并不以此来限定本公开的保护范围。下面实施例中未注明具体条件者，按照常规条件或制造商建议的进行。所用药品或试剂未注明生产厂商者，均为可以通过市购获得的常规产品。
虽然以下实施例中所使用的许多材料和操作方法是本领域公知的，但是本公开仍然在此作尽可能详细描述。本领域技术人员清楚，如果未特别说明，下面实施例中所用的材料和操作方法是本领域公知的。
以下实施例或实验例中所用到的式(I)化合物按照专利申请PCT/CN2014/095615中说明书实施例1的制备方法制备获得。
制备实施例：
式(I)化合物的晶型A的制备方法
制备方法一：取式(I)化合物5.0g，加入丙酮75mL，磁力搅拌下溶解立即析出白色固体，经搅拌5h后，抽滤，得白色粉末经35℃真空干燥16h后，所得固体经XRPD测试，为晶型A。
制备方法二：取式(I)化合物500mg，加入异丙醇15mL，油浴80℃搅拌，溶解并且变的清澈(4.0h内)，自然降至室温(32℃)，析出白色固体，室温下继续搅拌12h，降温至15℃搅拌4.0h，抽滤，所得固体经45℃真空干燥16h，经XRPD、 1H-NMR分析，所得固体为晶型A。
制备方法三：取式(I)化合物5.0g于100mL三口瓶中，加入仲丁醇75mL，油浴 控温95℃，机械搅拌0.5h，溶解并且变的清澈。然后降温至油浴70℃，加入晶种(即制备方法一、二所得晶型A)约25mg，开始慢慢析出白色固体，继续降温至油浴60℃，恒温0.5h，降温至55℃，恒温0.5h，继续降至约20℃，搅拌1.5h，抽滤，甲基叔丁基醚淋洗(2×10mL)，所得固体经65℃真空干燥24h， 1H-NMR检测显示无溶剂残留，经XRPD分析为晶型A。
制备方法四：
1)晶种制备：取式(I)化合物40g和300g正戊醇，加热至75℃，搅拌桨转速R＝300r/min，约0.5h后原料开始溶解，完全溶解并且变的清澈后，继续保持75℃稳定0.5h。降低搅拌速率至R＝150r/min，澄清溶液在约0.5h内快速降温至55℃。到达55℃后，提高搅拌速率至R＝300r/min，继续以9℃/h速率降温直至5℃，体系缓慢混浊析出固体，到达5℃后恒温2小时，抽滤，所得固体即为晶种。
2)晶型A制备方法：将式(I)化合物50g分散于300g正戊醇中，加热至85℃，完全溶解并且变的清澈，快速降温至58℃(85-58℃/h)，添加0.1g上述1)中所得晶种，恒温60min，此时体系缓慢混浊直至变为白色固体，以6℃/h速率缓慢降温直至5℃，继续恒温过夜，然后抽滤，所得固体放入真空干燥装置，100℃干燥6h，干燥所得固体经65℃真空干燥24h， 1H-NMR检测显示无溶剂残留，经XRPD分析为晶型A。
针对制备方法一至四得到的产品进行检测，晶型A纯度大于99.7％，单个最大杂质小于0.08％，几乎无溶剂残留。
XRPD测试
所用仪器：Bruker D2X射线粉末衍射仪。
X射线反射参数：Cu，Kα；入射狭缝：0.6mm；发散狭缝：1mm；扫描模式：连续；扫描范围：3.0～45.0度；取样步长：0.02度；每步扫描时间：19.8s；探测器角度：2.0度。
式(I)化合物的晶型A在X-射线粉末衍射图示于图1中，该晶型在以下衍射2θ角度处有峰：6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、16.7±0.2°、17.4±0.2°、19.3±0.2°、20.1±0.2°、20.6±0.2°、22.2±0.2°、23.3±0.2°、24.0±0.2°、25.9±0.2°、28.1±0.2°、30.4±0.2°。
差示扫描量热法
通过差示扫描量热法(DSC)研究式(I)化合物的晶型A的固态热性能。
所用仪器：Q2000差示扫描量热仪，购自TA。
测定条件：用氮气以50毫升/分钟吹扫，在25℃至220℃之间以10℃/分钟加热速率收 集数据，在吸热峰朝下的情况下绘图。
测定结果：式(I)化合物的晶型A在195℃至215℃范围内出现吸热峰，其差示扫描量热分析图如图2所示。
热重分析
所用仪器：Q50热重分析仪，购自TA。
测试条件：用氮气以60毫升/分钟吹扫，在室温至350℃之间以10℃/分钟加热速率收集数据。
测定结果：式(I)化合物的晶型A在0℃-250℃范围内无明显失重现象，其TG曲线如图2所示。
核磁分析( 1H-NMR)
仪器：Bruker Advance III 400；溶剂：氘代DMSO。
测定结果：式(I)化合物的晶型A的 1H-NMR如图3所示。
性质测试试验例：
实验例1晶型A的性质考察
1)稳定性试验
供试品：式(I)化合物的晶型A，按照上述制备方法一、二、三或四制备。
实验方法：将供试品在高湿(25℃/RH92.5％或40℃/RH75％)条件下，60℃条件下放置10天，分别于第5、10天取样；光照(4500LX±500LX)条件下放置10天，于第10天取样，测定有关物质及XRPD，与0天的样品进行比较。
有关物质：按照《中国药典》2015年版二部附录V D高效液相色谱法测定。
XRPD测定：按照《中国药典》2015年版四部0451X射线衍射法测定。
式(I)化合物晶型A的稳定性实验结果如表1所示。
表1式(I)化合物晶型A稳定性考察结果
Figure PCTCN2018124418-appb-000003
Figure PCTCN2018124418-appb-000004
2)式(I)化合物及晶型A的引湿性试验
供试品：
式(I)化合物，按照专利PCT/CN2014/095615中说明书实施例1的制备方法制备。
式(I)化合物的晶型A，按照上述制备方法一、二、三或四制备。
测定方法：依据中国药典2015年版四部通则9103药物引湿性试验指导原则测定。
引湿性实验结果见表2
表2引湿性检测结果
Figure PCTCN2018124418-appb-000005
3)晶型A的粒度测定试验
供试品：式(I)化合物的晶型A，按照上述制备方法一、二、三或四制备。
试剂：吐温80、超纯水。
仪器设备：激光粒度分析仪、样品分散器。
测定方法：
取供试品适量，加入1％吐温80溶液0.1mL，用以降低表面张力，以水为分散剂制成分散均匀的混悬液，放入样品分散器中，调节搅拌转速为2000rpm，超声频率7KHz，超声2min，测定。
实验结果:
式(I)化合物的晶型A的粒度分布如下：样品中10％处于2.501μm以下，50％处于10.432μm以下，90％处于59.852μm以下。
实验例2式(I)化合物无定型的稳定性考察
供试品：式(I)化合物(即无定型)，按照专利PCT/CN2014/095615中说明书实施例1的制备方法制备。
实验方法：
将供试品在25℃/RH92.5％条件下或60℃条件下放置10天，分别于第5、10天取样；将供试品在光照(4500LX±500LX)条件下或40℃/RH75％条件下放置10天，于第10天取样，测定有关物质及XRPD，与0天的样品进行比较。
有关物质：按照《中国药典》2015年版二部附录V D高效液相色谱法测定。
XRPD测定：《中国药典》2015年版四部0451X射线衍射法。
式(I)化合物无定型的稳定性实验结果见表3。
表3无定型的稳定性考察结果
Figure PCTCN2018124418-appb-000006
实验结论：
在60℃或光照条件下放置10天，晶型A的性状、有关物质、XRPD等性质均无明显变化；而无定型在光照条件下，有关物质高达10.54％。
结果表明，本公开的晶型A显示出良好的稳定性和低吸湿性特点，便于药品的生产、制剂的制备、运输和储藏，更有利于保证药物使用的稳定性和安全性。并且，晶型A相比无定型，在体内具有良好暴露量和/或生物利用度，具有良好的体内外药效。
实验例3式(I)化合物无定型及其晶型A的可压性实验考察
供试品：式(I)化合物的晶型A，按照上述制备方法一、二、三或四制备；式(I)化合物无定型，按照专利PCT/CN2014/095615中说明书实施例1的制备方法制备。
实验方法：
分别取式(I)化合物的晶型A和无定型原料适量单独压片，固定片重，调节压片厚度(压片力)，测定片剂硬度。考察硬度随压片厚度变化，对比可压性。
实验结果见表4。
表4可压性实验结果
Figure PCTCN2018124418-appb-000007
注：(1)表中“/”表示在该压片厚度下，片剂无法成型。
(2)压片厚度越小，表示压片力越大。
从表4的实验结果看出，相同压片厚度下，晶型A压片硬度较无定型大。且随压片厚度降低(压片力增大)，晶型A压片硬度最高可达5.4kg左右，无定型最大硬度为2.75kg左右，且在压片过程中无定型易出现粘壁现象，导致片剂表面粗糙或有缺痕，并且无定型还容易产生顶裂(capping)现象，说明晶型A可压性优于无定型，更有利于制剂产品开发。
实验例4式(I)化合物无定型及其晶型A的释放实验考察
供试品：式(I)化合物的晶型A，按照上述制备方法一、二、三或四制备；式(I)化合物无定型，按照专利PCT/CN2014/095615中说明书实施例1的制备方法制备。
实验方法：
取40mg晶型A和无定型分别加入相同种类和用量的辅料压制成片，在以下条件下考察崩解和溶出度。
溶出方法：桨法(中国药典2015年版第四部0931溶出度与释放度测定法第二法)；介质：0.2％SDS水溶液；转速：50r/min。
实验结果见表5和表6。
表5崩解时限
Figure PCTCN2018124418-appb-000008
表6溶出度
Figure PCTCN2018124418-appb-000009
表5和6实验结果显示，晶型A崩解和溶出较快且60min溶出完全，无定型崩解和溶出速率相较于晶型A大大降低，说明晶型A更具适用于制剂的开发。
最后应当说明的是：以上实施例仅用以说明本公开的技术方案而非对其限制；尽管参照较佳实施例对本公开进行了详细的说明，所属领域的普通技术人员应当理解：依然可以对本公开的具体实施方式进行修改或者对部分技术特征进行等同替换；而不脱离本公开技术方案的精神，其均应涵盖在本公开请求保护的技术方案范围当中。

Claims (17)

  1. 式(I)所示化合物的晶型A，其在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图谱在6.6±0.2°、10.0±0.2°、13.2±0.2°、17.4±0.2°、20.1±0.2°、20.6±0.2°处有特征峰，
    Figure PCTCN2018124418-appb-100001
  2. 如权利要求1所述的晶型A，其在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图在6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、17.4±0.2°、20.1±0.2°、20.6±0.2°、30.4±0.2°处有特征峰。
  3. 如权利要求1或2所述的晶型A，其在使用Cu-Kα辐射，以2θ角度表示X-射线粉末衍射图在6.6±0.2°、8.7±0.2°、10.0±0.2°、10.9±0.2°、13.2±0.2°、15.7±0.2°、16.4±0.2°、16.7±0.2°、17.4±0.2°、19.3±0.2°、20.1±0.2°、20.6±0.2°、22.2±0.2°、23.3±0.2°、24.0±0.2°、25.9±0.2°、28.1±0.2°、30.4±0.2°处有特征峰。
  4. 如权利要求1至3任一项所述的晶型A，其具有基本上如图1所示的使用Cu-Kα辐射获得的X-射线粉末衍射图。
  5. 如权利要求1至4任一项所述的晶型A，其在差示扫描量热分析(DSC)图谱中，在约195℃～215℃处存在一个吸热峰。
  6. 如权利要求1至5任一项所述的晶型A，其在差示扫描量热分析(DSC)图谱中，在205±3℃处存在一个吸热峰。
  7. 如权利要求1至6任一项所述的晶型A，其具有基本上如图2所示的差示扫描量热分析(DSC)图谱。
  8. 制备权利要求1-7任一项所述的式(I)化合物晶型A的方法，包括以下操作：
    将式(I)化合物溶于有机溶剂中，
    搅拌，
    收集析出的固体。
  9. 如权利要求8所述的制备方法，包括以下操作：
    将式(I)化合物溶于有机溶剂中，加热至60℃～100℃，搅拌使化合物溶解；
    降温至0℃～25℃，恒温搅拌1～24h；
    收集析出的固体，
    优选地，所述制备方法包括以下操作：
    将式(I)化合物溶于有机溶剂中，加热至60℃～100℃，搅拌使化合物溶解；
    降温至30℃～55℃，析出固体；
    降温至0℃～25℃，恒温搅拌1～24h；
    收集析出的固体，干燥，
    优选地，所述制备方法包括以下操作：将式(I)化合物溶于有机溶剂中，加热至60℃～100℃，并搅拌至化合物溶解为止，继续搅拌并降温至0℃～25℃，析出固体，恒温、搅拌1～24h，抽滤，干燥得到晶型A。
  10. 制备权利要求1-7任一项所述的式(I)化合物晶型A的方法，包括以下操作：
    将式(I)化合物溶于有机溶剂中，加热至70℃～100℃；
    化合物溶解后，降温至50℃～75℃，加入晶种，保持恒温，析出固体；
    缓慢降温至0℃～25℃，恒温，收集析出的固体，干燥得到晶型A，
    其中所述晶种为式(I)化合物晶型A或在制备式(I)化合物晶型A的过程中析出的固体，
    优选地，所加入的所述晶种的量为式(I)化合物的质量的0.1％～3％，例如0.1％～0.2％，0.2％-0.5％，0.5％-1％，1％-1.5％，1.5％-2％，2％-2.5％或2.5％-3％，
    优选地，所述的制备方法包括以下操作：
    将式(I)化合物溶于有机溶剂中，加热至70℃～100℃，化合物溶解后，降温至50℃～65℃时，加入晶种，恒温，出现固体，缓慢降温至0℃～25℃，恒温、抽滤，干燥得到晶型A，所述晶种选自晶型A或在制备晶型A的过程中干燥之前的固体，所述晶种与式(I)化合物的质量比为0.1％～3％，优选0.1％～0.2％，0.2％-0.5％，0.5％-1％，1％-1.5％，1.5％-2％，2％-2.5％，2.5％-3％。
  11. 如权利要求8-10任一项所述的制备晶型A的方法，其中
    所述的有机溶剂选自下列溶剂中的一种或者两种以上溶剂之间的任一组合：
    (1)醇类溶剂，选自脂肪醇、脂环醇及芳香醇类溶剂，所述脂肪醇类溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、仲丁醇、正戊醇、正己醇、乙二醇、丙二醇或丙三醇；所述的脂环醇类溶剂选自环戊醇、环戊甲醇、环己醇、环己甲醇或环己乙醇；所述芳香醇类溶剂选自苯甲醇、苯乙醇或苯丙醇；
    (2)酮类溶剂，选自脂肪酮类及环酮类溶剂，所述的脂肪酮类溶剂选自甲乙酮、 甲基异丙基酮、丙酮、甲基丁酮或甲基异丁酮；所述的环酮类溶剂选自环丙酮、环己酮、异佛尔酮或N-甲基吡咯烷酮；
    (3)腈类溶剂，选自乙腈或丙腈；
    (4)醚类溶剂，选自脂肪醚类及环醚类溶剂，所述脂肪醚类溶剂选自乙醚、二丙醚、二异丙醚、甲基叔丁基醚、乙基丁基醚、乙基叔丁基醚、二丁醚或二戊醚，环醚类溶剂选自环氧乙烷、1,2-环氧丙烷、四氢呋喃、2-甲基呋喃、二氧戊环或1,4-二氧六环；
    (5)酰胺类溶剂，选自甲酰胺、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二甲基丙酰胺或N,N-二乙基丙酰胺；
    (6)亚砜类溶剂，选自二甲基亚砜、二乙基亚砜或苄苯亚砜，
    优选地，所述的有机溶剂为醇类溶剂或酮类溶剂，
    优选地，所述的有机溶剂选自：丙酮、异丙醇、丁醇、正戊醇。
  12. 药物组合物，其含有权利要求1-7任一项所述的式(I)化合物的晶型A，以及任选的一种或多种药用载体和/或稀释剂。
  13. 如权利要求12所述的药物组合物，其中还包含一种或多种额外的抗肿瘤剂和/或免疫抑制剂，所述额外的抗肿瘤剂和/或免疫抑制剂，选自下述中的一种或多种：甲氨蝶呤、卡培他滨、吉西他滨、去氧氟尿苷、培美曲塞二钠、帕唑帕尼、伊马替尼、埃罗替尼、拉帕替尼、吉非替尼、凡德他尼、赫赛汀、贝伐单抗、利妥昔单抗、曲妥珠单抗、紫杉醇、长春瑞滨、多西他赛、多柔比星、羟基喜树碱、丝裂霉素、表柔比星、吡柔比星、博来霉素、来曲唑、他莫西芬、氟维司群、曲谱瑞林、氟他胺、亮丙瑞林、阿那曲唑、异环磷酰胺、白消安、环磷酰胺、卡莫司汀、尼莫司汀、司莫司汀、氮芥、马法兰、瘤可宁、卡铂、顺铂、奥沙利铂、络铂、拓扑特肯、喜树碱、拓扑替康、依维莫司、西罗莫斯、特癌适、6-巯基嘌呤、6-硫鸟嘌呤、硫唑嘌呤、菌素D、柔红霉素、阿霉素、米托蒽醌、争光霉素、普卡霉素和氨鲁米特。
  14. 如权利要求1-7任一项所述的式(I)化合物的晶型A在制备用于治疗和/或预防受试者中由CDK4/6激酶介导的癌症相关疾病的药物中的用途。
  15. 一种在有需要的哺乳动物中治疗和/或预防由CDK4/6激酶介导的癌症相关疾病的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的权利要求1-7任一项所述的式(I)化合物的晶型A或权利要求12-13任一项所述药物组合物。
  16. 如权利要求1-7任一项所述的式(I)化合物的晶型A，其用于治疗和/或预防 由CDK4/6激酶介导的癌症相关疾病的药物。
  17. 如权利要求14所示的用途，权利要求15所述的治疗和/或预防方法或权利要求15所述的式(I)化合物的晶型A，其中所述CDK4/6激酶介导的癌症相关疾病选自：脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、前列腺癌、雌性生殖道癌、原位癌、淋巴瘤、神经纤维瘤、甲状腺癌、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、前列腺肿瘤、肥大细胞肿瘤、多发性骨髓瘤、黑色素瘤、胶质瘤、肉瘤。
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