WO2020052627A1 - 取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途 - Google Patents

取代的吡咯并嘧啶类cdk抑制剂的盐及其结晶和用途 Download PDF

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WO2020052627A1
WO2020052627A1 PCT/CN2019/105583 CN2019105583W WO2020052627A1 WO 2020052627 A1 WO2020052627 A1 WO 2020052627A1 CN 2019105583 W CN2019105583 W CN 2019105583W WO 2020052627 A1 WO2020052627 A1 WO 2020052627A1
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compound
formula
cancer
crystal
maleate salt
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PCT/CN2019/105583
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English (en)
French (fr)
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高鹏
徐洋平
孟庆义
刘飞
孙中英
张克茹
陈智林
江金凤
陆成晖
Original Assignee
正大天晴药业集团股份有限公司
连云港润众制药有限公司
首药控股(北京)有限公司
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Priority to CA3112496A priority Critical patent/CA3112496A1/en
Priority to CN201980053055.XA priority patent/CN112888690B/zh
Priority to JP2021514429A priority patent/JP2022500458A/ja
Priority to AU2019338032A priority patent/AU2019338032A1/en
Publication of WO2020052627A1 publication Critical patent/WO2020052627A1/zh

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application belongs to the field of medicinal chemistry, and relates to salts, crystal forms of substituted pyrrolopyrimidine CDK inhibitors, a preparation method thereof, and a pharmaceutical composition, and also relates to such compounds and pharmaceutical compositions for the treatment and / or prevention of Use in CDK6 inhibitory-related diseases.
  • WO2017162215 discloses a compound 7-cyclopentyl-6-N, N-dimethylcarbamoyl-N- (5- (1,2,3,6-4H-pyridin-4-yl) as a CDK4 / CDK6 inhibitor ) Pyridin-2-yl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine (hereinafter referred to as the compound of formula I) and its hydrochloride.
  • the drug has excellent properties in the following aspects: pharmacological activity, pharmacokinetics, bioavailability, hygroscopicity, melting point, stability, solubility, purity, easy preparation, etc., in order to meet the production, storage and preparation of the drug, etc. Needs.
  • the phenomenon of stickiness is not easy to occur, and they have advantages in terms of drug processing and stability. Therefore, there is currently a need to provide APIs with low hygroscopicity and high melting points.
  • the application provides a maleate salt of a compound of Formula I:
  • the present application provides a crystal of a compound of formula II.
  • the 2 ⁇ value is expressed at 8.63, 10.50, 14.99, 17.29, 18.71, 19.84 degrees ( °) have diffraction peaks.
  • the present application provides a method for preparing a crystal of a compound of formula II, the method comprising precipitating a compound of formula II from a solvent selected from the group consisting of methanol, ethanol, isopropanol, N-methylpyrrolidone, or Methyl sulfoxide.
  • the present application provides a crystalline composition, wherein the crystals of the compound of formula II account for more than 50% of the weight of the crystalline composition.
  • the application provides a pharmaceutical composition comprising a therapeutically effective amount of a maleate salt of the compound of Formula I, the compound of Formula II, a crystal of the compound of Formula II, or the crystalline composition.
  • the application provides a method of treating and / or preventing a CDK4- and / or CDK6-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a maleate, The compound of formula II, a crystal of the compound of formula II, the crystalline composition, or the pharmaceutical composition.
  • the present application provides the maleate salt of the compound of formula I, the compound of formula II, the crystals of the compound of formula II, the crystalline composition or the pharmaceutical composition in the preparation for treatment and Use in a medicament for the prevention of CDK4 and / or CDK6-mediated diseases.
  • the present application provides the maleate salt of the compound of formula I, the compound of formula II, the crystals of the compound of formula II, the crystalline composition or the pharmaceutical composition for treatment and / or prevention Use in CDK4 and / or CDK6-mediated diseases.
  • the application provides a maleate salt of the compound of Formula I, the compound of Formula II, the crystals of the compound of Formula II, for the treatment and / or prevention of CDK4 and / or CDK6-mediated diseases,
  • the crystalline composition or the pharmaceutical composition is provided.
  • Example 1 is an XRPD pattern of a crystal of a compound of formula II prepared in Example 2;
  • FIG. 2 is a DSC chart of a crystal of a compound of formula II prepared in Example 2.
  • FIG. 2 is a DSC chart of a crystal of a compound of formula II prepared in Example 2.
  • the application provides 7-cyclopentyl-6-N, N-dimethylcarbamoyl-N- (5- (1,2,3,6-4H-pyridin-4-yl) pyridin-2-yl) -7H-pyrrolo [2,3-d] pyrimidin-2-amine maleate (hereinafter referred to as the maleate salt of the compound of formula I) and its crystal, which has low hygroscopicity and high melting point, and At least one aspect of activity, pharmacokinetics, bioavailability, stability, solubility, purity, and ease of preparation has excellent properties.
  • the application provides a maleate salt of a compound of Formula I.
  • the molar ratio of the compound of formula I to maleic acid in the maleate salt of the compound of formula I is 1: 0.5 to 2.
  • the molar ratio of the compound of formula I to maleic acid in the maleate salt of the compound of formula I above is 1: 0.5, 1: 1, 1: 1.5, or 1: 2.
  • the molar ratio of the compound of formula I to the maleic acid in the maleate salt of the compound of the formula I is 1: 0.5 to 1 or 1: 1 to 2.
  • the molar ratio of the compound of Formula I to maleic acid is 1: 1.
  • the maleate salt of the compound of Formula I is a crystalline form.
  • the maleate salt of a compound of formula I is a compound of formula II
  • the present application provides a method for preparing a maleate salt of a compound of formula I, which comprises reacting a compound of formula I with maleic acid.
  • a method for preparing a maleate salt of a compound of formula I includes reacting a compound of formula I with maleic acid in a solvent to form a maleate salt of a compound of formula I.
  • a method for preparing a maleate salt of a compound of formula I includes reacting a compound of formula I with maleic acid in a solvent to form a salt, and precipitating from the solvent.
  • the reaction is performed in a solvent, wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, N-methylpyrrolidone, or dimethyl sulfoxide; in some embodiments, the solvent is Ethanol.
  • the present application provides a crystal of a compound of formula II, in which the X-ray powder diffraction (XRPD) pattern using Cu ⁇ K ⁇ radiation is represented by a 2 ⁇ value at 8.63, 10.50, 14.99, 17.29, 18.71, There are diffraction peaks at 19.84 degrees (°); in some embodiments, in the X-ray powder diffraction pattern of the crystals using Cu K ⁇ radiation, the 2 ⁇ values are used to represent 8.63, 10.50, 14.99, 16.14, 16.45, 17.29 There are diffraction peaks at 18.71, 19.84, 20.93 degrees (°); in some embodiments, in the crystal X-ray powder diffraction pattern using CuK ⁇ radiation, the 2 ⁇ value is used to represent 8.63, 10.50, 11.35, There are diffraction peaks at 12.44, 14.99, 16.14, 16.45, 17.29, 18.71, 19.84, 20.93, 21.74, 24.45, 27.30, 27.55, 29.26 degrees (°); in
  • the peak positions and relative intensities of the diffraction peaks are represented by the following Table 1:
  • the XRPD pattern of a crystal of a compound of formula II provided herein is shown in FIG. 1.
  • differential scanning calorimetry (DSC) of the crystal of the compound of formula II provided herein has an absorption peak at 237.67 ° C.
  • DSC differential scanning calorimetry
  • the instrument model for X-ray powder diffraction spectrometry measurement is Bruker D8 X-ray diffractometer, conditions and methods: copper target, 40kv 40mA, slit: 0.681mm / 5.5mm, scanning range: 5-40 °, time [s]: 0.1, step size: 0.02 °.
  • the instrument model for DSC spectrometry is METTLER TOLEDO DSC1, conditions and methods: heating at 10 ° C / min in the range of 30-250 ° C.
  • the instrument used for elemental analysis is a Vario MICRO elemental analyzer, method: JY / T 017-1996 General Principles of Elemental Analyzer Method.
  • the relative intensities of the diffraction peaks can vary due to the preferred orientation caused by factors such as crystal morphology, which is well known in the field of crystallography. Where the preferred orientation is affected, the peak intensity is changed, but the diffraction peak position of the crystal form cannot be changed. In addition, there may be slight errors in the position of the peaks for any given crystal form, which is also well known in the field of crystallography. For example, because the temperature of the sample is analyzed, the sample is moved, or the instrument is calibrated, the position of the peak can be moved, and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2 degrees. Therefore, it is well known to those skilled in the art to determine each crystal. This structure should take this error into account.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or melting of the crystal.
  • the error of the thermal transition temperature and melting point is typically within about 5 ° C, usually within about 3 ° C.
  • DSC peak ⁇ 5 ° C.
  • DSC provides an auxiliary method to distinguish different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be pointed out that for mixtures, the DSC peaks may vary over a wider range.
  • the melting temperature is related to the heating rate.
  • the present application provides a method for preparing a crystal of a compound of Formula II, which method includes the step of precipitating a compound of Formula II from a solvent.
  • a method of preparing a crystal of a compound of Formula II includes precipitating a compound of Formula II from a solvent selected from the group consisting of methanol, ethanol, isopropanol, N-methylpyrrolidone, or dimethylsulfoxide.
  • the solvent is ethanol.
  • a method for preparing a crystal of a compound of Formula II includes the following steps:
  • step 1) is: mixing maleic acid with a solvent, mixing a compound of formula I with a solvent, mixing the two mixtures formed above, and then reacting.
  • the molar ratio of maleic acid to the compound of formula I in step 1) is 1: 1 to 1.2.
  • the solvent is selected from the group consisting of methanol, ethanol, isopropanol, N-methylpyrrolidone, or dimethyl sulfoxide; in some embodiments, the solvent is ethanol.
  • reaction of step 1) wherein the reaction of step 1) is performed under heating conditions; in some specific embodiments, the heating temperature is 65-75 ° C.
  • step 1) is: mixing maleic acid with a solvent, mixing a compound of formula I with a solvent, mixing the above two mixtures under a heating condition for reaction, and then lowering the temperature.
  • the temperature is lowered to 20-30 ° C; in some embodiments, the temperature is lowered to 20-30 ° C and then stirred, for example, for 1 hour.
  • the method further includes separating the solid precipitated in step 2). In some specific embodiments, the method further includes drying the separated solid, for example, at a temperature of 40 to 65 ° C. Press dry.
  • the present application provides a crystalline composition comprising the crystals of the compound of formula II, wherein the crystals of the compound of formula II account for more than 50%, preferably 80% or more, more preferably 90% or more, preferably 95% or more.
  • the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a maleate salt of a compound of Formula I, a compound of Formula II, a crystal of a compound of Formula II, or Formula II Crystallized crystalline composition of a compound.
  • the pharmaceutical composition of the present application may or may not contain pharmaceutically acceptable excipients.
  • the pharmaceutical composition of the present application may further include one or more other therapeutic agents.
  • the application provides a method of treating and / or preventing a CDK4- and / or CDK6-mediated disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a maleate salt of a compound of formula I, formula A compound of Formula II, a crystal of a compound of Formula II, a crystallized crystalline composition of a compound of Formula II, or a pharmaceutical composition thereof.
  • the present application provides a maleate salt of a compound of Formula I, a compound of Formula II, a crystal of a compound of Formula II, a crystallized crystalline composition of a compound of Formula II, or a pharmaceutical composition thereof for use in therapy and / or Use in a medicament for the prevention of CDK4 and / or CDK6-mediated diseases.
  • the present application provides a maleate salt of a compound of Formula I, a compound of Formula II, a crystal of a compound of Formula II, a crystallized crystalline composition of a compound of Formula II, or a pharmaceutical composition thereof for treating and / or preventing CDK4 and And / or use in CDK6-mediated diseases.
  • the application provides a maleate salt of a compound of formula I, a compound of formula II, a crystal of a compound of formula II, a crystal of a compound of formula II for use in the treatment and / or prevention of a CDK4 and / or CDK6-mediated disease.
  • the CDK4 and / or CDK6-mediated diseases include cancer.
  • the cancer includes, but is not limited to: bladder cancer; breast cancer, such as metastatic breast cancer; colon cancer; kidney cancer; epidermal cancer; liver cancer; lung cancer, such as small cell lung cancer and non-small cell Lung cancer; Esophageal cancer; Gallbladder cancer; Ovarian cancer; Pancreatic cancer, such as exocrine pancreatic cancer; Gastric cancer; Cervical cancer; Thyroid cancer; Nasal cancer; Head and neck cancer; Prostate cancer; Skin cancer, such as squamous cell carcinoma; Lymphoid hematopoietic cells Tumors such as leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, hair cell lymphoma, and Burkitt's lymphoma; myeloid hematopoietic tumors, such as acute and
  • the "pharmaceutically acceptable excipient” refers to an inert substance that is co-administered with the active ingredient and is beneficial to the administration of the active ingredient, including, but not limited to, acceptable use for humans or animals by the State Food and Drug Administration. (E.g. livestock) any glidants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents, stabilizers Agent, isotonicity agent, solvent or emulsifier.
  • Non-limiting examples of the excipients include calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the pharmaceutical composition of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, creams, emulsions, suspensions, solutions, suppositories, injections, inhalants, Gels, microspheres and aerosols, etc.
  • the pharmaceutical composition of the present application can be prepared by methods known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a sugar-coated pill method, a grinding method, an emulsification method, a freeze-drying method, and the like.
  • Typical routes of administration of the pharmaceutical composition of the present application include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, peritoneal Intramuscular, intramuscular, subcutaneous, intravenous.
  • the preferred route of administration is oral.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the occurrence of a disease or disease state in a mammal, particularly when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
  • the term "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect.
  • the determination of an effective amount varies from person to person, depends on the age and general situation of the recipient, and also depends on the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art based on routine tests.
  • a therapeutically effective amount of a maleate salt of a compound of Formula I, a compound of Formula II, or a crystal thereof is from about 0.0001 to 20 mg / Kg body weight / day, such as from 0.001 to 10 mg / Kg body weight / day.
  • the dosage frequency of the maleate salt of the compound of formula I, the compound of formula II or its crystals is determined by the needs of the individual patient, for example, once or twice a day, or more times a day. Administration may be intermittent, for example, where the patient receives a daily dose of a maleate salt of a compound of formula I, a compound of formula II or a crystal thereof over a period of several days, followed by a period of several days or more The patient does not receive a daily dose of a maleate salt of a compound of formula I, a compound of formula II, or a crystal thereof.
  • the X-ray powder diffraction pattern using Cu and K ⁇ radiation is shown in Figure 1.
  • Differential scanning calorimetry (DSC) The figure is shown in Figure 2.
  • the elemental analysis results are as follows: calculated value (%): 61.41% C atom, 6.07% H atom, 17.90% N atom; measured value: 61.13% C atom, 6.08% H atom, 17.99% N atom.
  • a crystalline sample of the compound of formula II of Example 2 was taken and placed under influencing factor test conditions (40 ° C constant temperature incubator, 60 ° C constant temperature incubator, RH 75% and RH 92.5% high humidity environment), and left naked. Samples were taken at 5, 10, and 30 days.
  • Injection volume 10 ⁇ l; Detection wavelength: 279 nm; Flow rate: 1.1 ml / min; Column temperature: 35 ° C;
  • Phase A 30 mmol / L ammonium formate solution (pH adjusted to 7.5 with ammonia)
  • Phase B acetonitrile
  • Preparation of the sample solution Take appropriate amounts of the samples under the above test conditions, accurately weigh them, and dissolve them with a solvent (30% acetonitrile in water) to a solution containing about 1.0 mg of the compound of formula II per 1 mL. 3.
  • Test Example 3 Determination of the compound's inhibitory effect on the proliferation of human colon cancer cell line Colo-205
  • Colo-205 cells A certain number of logarithmic growth phase Colo-205 cells were seeded in 96-well culture plates. After 24 hours of growth, DMSO solutions of the compound of formula II of Example 2 at different concentrations (1, 3, 10, 30, 100, 300, 1000, 3000, 10000 nM) were added and cultured for 6 days. After the compound of formula II is finished, add MTT working solution to each well.

Abstract

本申请属于药物化学领域，涉及取代的吡咯并嘧啶类CDK抑制剂的盐，具体涉及化合物7-环戊基-6-N,N-二甲氨基甲酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺马来酸盐(式II化合物)、式II化合物的晶型、其制备方法、药物组合物，还涉及该化合物盐及其药物组合物在制备治疗与CDK4和/或CDK6抑制作用相关的疾病的药物中的用途。

Description

取代的吡咯并嘧啶类CDK抑制剂的盐及其结晶和用途
相关申请的交叉引用
本申请要求于2018年09月13日向中华人民共和国国家知识产权局提交的第201811068352.5号中国发明专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于药物化学领域，涉及取代的吡咯并嘧啶类CDK抑制剂的盐、晶型、其制备方法以及药物组合物，还涉及这类化合物及其药物组合物在治疗和/或预防与CDK4/CDK6抑制作用相关的疾病中的用途。
背景技术
WO2017162215公开了作为CDK4/CDK6抑制剂的化合物7-环戊基-6-N,N-二甲氨基甲酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺(下称式I化合物)及其盐酸盐。
Figure PCTCN2019105583-appb-000001
一般希望药物在以下方面具有优良的性质：药物活性、药代动力学、生物利用度、吸湿性、熔点、稳定性、溶解性、纯度、易制备等，以满足药物在生产、储存和制剂等方面的需求。研究发现，式I化合物及其盐酸盐是高吸湿的，其在药物生产、储存和制剂方面产生不利影响，如吸湿后显著影响药物的流动性，不易储存，甚至影响药物的稳定性，难以满足工业化生产的需求；较高熔点的药物更有利于制备固体剂型，如在制备片剂过程中，不容易发生黏冲现象，在药物的加工和稳定性等方面更具备优势。因此，目前存在提供低吸湿性和高熔点的原料药的需求。
发明概述
一方面，本申请提供了式I化合物的马来酸盐：
Figure PCTCN2019105583-appb-000002
本申请还提供了式II化合物：
Figure PCTCN2019105583-appb-000003
另一方面，本申请提供了式II化合物的结晶，在所述结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，用2θ值表示在8.63、10.50、14.99、17.29、18.71、19.84度(°)处有衍射峰。
另一方面，本申请提供了式II化合物的结晶的制备方法，所述方法包括使式II化合物从溶剂中析出，所述溶剂选自甲醇、乙醇、异丙醇、N-甲基吡咯烷酮或二甲基亚砜。
另一方面，本申请提供了结晶组合物，其中所述式II化合物的结晶占所述结晶组合物重量的50％以上。
另一方面，本申请提供了药物组合物，其包含治疗有效量的所述式I化合物的马来酸盐、所述式II化合物、所述式II化合物的结晶或所述结晶组合物。
又一方面，本申请提供了治疗和/或预防CDK4和/或CDK6介导的疾病的方法，所述方法包括给予有需要的个体治疗有效量的所述式I化合物的马来酸盐、所述式II化合物、所述式II化合物的结晶、所述结晶组合物或所述药物组合物。
又一方面，本申请提供了所述式I化合物的马来酸盐、所述式II化合物、所述式II化合物的结晶、所述结晶组合物或所述药物组合物在制备用于治疗和/或预防CDK4和/或CDK6介导的疾病的药物中的用途。
再一方面，本申请提供了所述式I化合物的马来酸盐、所述式II化合物、所述式II化合物的结晶、所述结晶组合物或所述药物组合物在治疗和/或预防CDK4和/或CDK6介导的疾病中的用途。
再一方面，本申请提供了用于治疗和/或预防CDK4和/或CDK6介导的疾病的所述式I化合物的马来酸盐、所述式II化合物、所述式II化合物的结晶、所述结晶组合物或所述药物组合物。
附图说明
图1是实施例2制备的式II化合物的结晶的XRPD图；
图2是实施例2制备的式II化合物的结晶的DSC图。
发明详述
本申请提供了7-环戊基-6-N,N-二甲氨基甲酰基-N-(5-(1,2,3,6-4H-吡啶-4-基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺的马来酸盐(下称式I化合物的马来酸盐)及其结晶，其具有低吸湿性和高熔点，且在药物活性、药代动力学、生物利用度、稳定性、溶解性、纯度、易制备等至少一方面具有优异的性质。
一方面，本申请提供了式I化合物的马来酸盐。
在一些实施方案中，上述式I化合物的马来酸盐中式I化合物与马来酸的摩尔比为1:0.5～2。
在一些实施方案中，上述式I化合物的马来酸盐中式I化合物与马来酸的摩尔比为1:0.5、1:1、1:1.5或1:2。
在一些实施方案中，上述式I化合物的马来酸盐中式I化合物与马来酸的摩尔比为1:0.5～1或1:1～2。
在一些实施方案中，所述式I化合物的马来酸盐中，式I化合物与马来酸的摩尔比为1:1。
在一些实施方案中，所述式I化合物的马来酸盐是结晶形式。
在一些实施方案中，所述式I化合物的马来酸盐为式II化合物
Figure PCTCN2019105583-appb-000004
另一方面，本申请提供了式I化合物的马来酸盐的制备方法，包括式I化合物与马来酸进行反应。
在一些实施方案中，式I化合物的马来酸盐的制备方法包括式I化合物与马来酸在溶剂中反应形成式I化合物的马来酸盐。
在一些实施方案中，式I化合物的马来酸盐的制备方法包括式I化合物与马来酸在溶剂中反应成盐，并从溶剂中析出。
在一些实施方案中，所述反应在溶剂中进行，其中所述溶剂选自甲醇、乙醇、异丙醇、N-甲基吡咯烷酮或二甲基亚砜；在一些实施方式中，所述溶剂为乙醇。
另一方面，本申请提供了式II化合物的结晶，在所述结晶的使用Cu Kα辐射的X-射线粉末衍射(XRPD)图谱中，用2θ值表示在8.63、10.50、14.99、17.29、18.71、19.84度(°)处有衍射峰；在一些实施方案中，在所述结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，用2θ值表示在8.63、10.50、14.99、16.14、16.45、17.29、18.71、19.84、20.93度(°)处有衍射峰；在一些实施方案中，在所述结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，用2θ值表示在8.63、10.50、11.35、12.44、14.99、16.14、16.45、17.29、18.71、19.84、20.93、21.74、24.45、27.30、27.55、29.26度(°)处有衍射峰；在一些实施方案中，在所述结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，用2θ值表示在8.63、10.50、11.35、12.44、14.15、14.99、16.14、16.45、17.29、17.97、18.71、19.84、20.56、20.93、21.74、21.97、22.86、23.65、24.45、25.51、26.15、27.30、27.55、29.26、30.96、31.45度(°)处有衍射峰。
在一些实施方案中，本申请的式II化合物的结晶使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射峰的峰位置及相对强度由下表1表示：
表1 式II化合物的结晶的X射线粉末衍射图谱的衍射峰的峰位置及相对强度
Figure PCTCN2019105583-appb-000005
在一些具体实施方案中，本申请提供的式II化合物的结晶的XRPD图谱如图1所示。
非限制性地，本申请提供的式II化合物的结晶的差示扫描量热(DSC)在237.67℃处有吸收峰，具体而言，式II化合物的结晶的差示扫描量热(DSC)图谱如图2所示。
本申请中，X-射线粉末衍射光谱测定的仪器型号为Bruker D8 X射线衍射仪，条件及方法：铜靶，40kv 40mA，狭缝：0.681mm/5.5mm，扫描范围：5-40°,time[s]：0.1，步长：0.02°。
本申请中，DSC光谱测定的仪器型号为METTLER TOLEDO DSC1，条件及方法：30-250℃范围内10℃/min升温。
本申请中，参考《中国药典》2015版0612熔点测定法第一法测定熔点。
本申请中，元素分析使用的仪器为Vario MICRO元素分析仪，方法：JY/T 017-1996元素分析仪方法通则。
对于任何给定的结晶形式而言，由于例如结晶形态等因素引起的优选取向，衍射峰的相对强度可以改变，这在结晶学领域中是公知的。存在优选取向影响的地方，峰强度是改变的，但是晶型的衍射峰位置是无法改变的。此外，对任何给定的晶型而言，峰的位置可能存在轻微误差，这在结晶学领域中也是公知的。例如，由于分析样品时温度的变化、样品的移动、或仪器的标定等，峰的位置可以移动，2θ值的测量误差有时约为±0.2度，因此，本领域技术人员公知在确定每种结晶结构时，应该将此误差考虑在内。
DSC测定当结晶由于其结晶结构发生变化或结晶熔融而吸收或释放热时的转变温度。对于同种化合物的同种晶型，在连续的分析中，热转变温度和熔点误差典型的在约5℃之内，通常在约3℃之内，当我们说一个化合物具有一给定的DSC峰时，这是指该DSC峰±5℃。DSC提供了一种辨别不同晶型的辅助方法。不同的结晶形态可根据其不同的转变温度特征而加以识别。需要指出的是对于混合物而言，其DSC峰可能会在更大的范围内变动。此外，由于在物质熔化的过程中伴有分解，因此熔化温度与升温速率相关。
另一方面，本申请提供式II化合物的结晶的制备方法，所述方法包括式II化合物从溶剂中析出的步骤。
在一些实施方案中，式II化合物的结晶的制备方法包括式II化合物从溶剂中析出，所述溶剂选自甲醇、乙醇、异丙醇、N-甲基吡咯烷酮或二甲基亚砜。在一些实施方式中，所述溶剂为乙醇。
在一些实施方案中，式II化合物的结晶的制备方法包括如下步骤：
Figure PCTCN2019105583-appb-000006
1)马来酸与式I化合物在溶剂中反应；
2)析出固体。
在一些实施方案中，其中步骤1)为：将马来酸与溶剂混合，将式I化合物与溶剂混合，将上述形成的两种混合物混合后进行反应。
在一些实施方式中，其中步骤1)中马来酸与式I化合物的摩尔比为1:1～1.2。
在一些实施方式中，所述溶剂选自甲醇、乙醇、异丙醇、N-甲基吡咯烷酮或二甲基亚砜；在一些实施方式中，所述溶剂为乙醇。
在一些实施方案中，其中步骤1)的反应在加热的条件下进行；在一些具体实施方案中，所述加热温度为65～75℃。
在一些实施方案中，其中步骤1)为：将马来酸与溶剂混合，将式I化合物与溶剂混合，将上述两者混合物在加热条件下混合进行反应，然后降低温度。
在一些实施方式中，其中降低温度至20～30℃；在一些具体实施方式中，降低温度至20～30℃后进行搅拌，例如搅拌1小时。
在一些实施方式中，其中步骤2)之后还包括将步骤2)中析出的固体进行分离；在一些具体的实施方式中，还包括将分离的固体进行干燥，例如在40～65℃温度下减压干燥。
又一方面，本申请提供了包含所述式II化合物的结晶的结晶组合物，其中，所述式II化合物的结晶占结晶组合物重量的50％以上，较好为80％以上，更好是90％以上，最好是95％以上。
又一方面，本申请提供了一种药物组合物，该药物组合物中包含治疗有效量的本申请所述式I化合物的马来酸盐、式II化合物、式II化合物的结晶、或式II化合物的结晶的结晶组合物。本申请的药物组合物中可含有或不含有药学上可接受的辅料。此外，本申请的药物组合物可进一步包括一种或多种其他治疗剂。
又一方面，本申请提供了一种治疗和/或预防CDK4和/或CDK6介导的疾病的方法，所述方法包括给予有需要的个体治疗有效量的式I化合物的马来酸盐、式II化合物、式II化合物的结晶、式II化合物的结晶的结晶组合物、或者其药物组合物。
又一方面，本申请提供了式I化合物的马来酸盐、式II化合物、式II化合物的结晶、式II化合物的结晶的结晶组合物、或者其药物组合物在制备用于治疗和/或预防CDK4和/或CDK6介导的疾病的药物中的用途。
又一方面，本申请提供了式I化合物的马来酸盐、式II化合物、式II化合物的结晶、式II化合物的结晶的结晶组合物、或者其药物组合物在治疗和/或预防CDK4和/或CDK6介导的疾病中的用途。
又一方面，本申请提供了用于治疗和/或预防CDK4和/或CDK6介导的疾病的式I化合物的马来酸盐、式II化合物、式II化合物的结晶、式II化合物的结晶的结晶组合物、或者其药 物组合物。
在本申请的一些实施方案中，所述CDK4和/或CDK6介导的疾病包括癌症。
在本申请的一些实施方案中，所述癌症包括但不限于：膀胱癌；乳腺癌，例如转移性乳腺癌；结肠癌；肾癌；表皮癌；肝癌；肺癌，例如小细胞肺癌和非小细胞肺癌；食道癌；胆囊癌；卵巢癌；胰腺癌，例如外分泌胰腺癌；胃癌；宫颈癌；甲状腺癌；鼻癌；头颈癌；前列腺癌；皮肤癌，例如鳞状细胞癌；淋巴系的造血细胞肿瘤，例如白血病、急性淋巴性白血病、慢性淋巴细胞白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、多发性骨髓瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特氏淋巴瘤；髓系造血细胞肿瘤，例如急性和慢性髓系白血病、骨髓增生异常综合征和早幼粒细胞白血病；甲状腺滤泡癌；源于间质细胞肿瘤，例如纤维肉瘤和横纹肌肉瘤；中枢或周围神经系统肿瘤，例如星形细胞瘤、神经母细胞瘤、神经胶质瘤和神经鞘瘤；黑素瘤；精原细胞瘤；畸胎瘤；骨肉瘤；着色性干皮病；角化棘细胞瘤；甲状腺滤泡癌；脂肪肉瘤；神经内分泌瘤；以及卡波西肉瘤。
所述“药学上可接受的辅料”是指与活性成份一同给药的、有利于活性成份给药的惰性物质，包括但不限于国家食品药品监督管理局许可的可接受的用于人或动物(例如家畜)的任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。所述辅料的非限制性实例包括碳酸钙、磷酸钙、各种糖和各类淀粉、纤维素衍生物、明胶、植物油和聚乙二醇。
本申请的药物组合物可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。本申请的药物组合物可以采用本领域已知的方法制备，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法和冷冻干燥法等等。
给予本申请的药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
术语“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
式I化合物的马来酸盐、式II化合物或其结晶的治疗有效量为从约0.0001到20mg/Kg体重/天，例如从0.001到10mg/Kg体重/天。
式I化合物的马来酸盐、式II化合物或其结晶的剂量频率由患者个体的需求决定，例如，每天1次或2次，或每天更多次。给药可以是间歇性的，例如，其中在若干天的期间内，患者接受式I化合物的马来酸盐、式II化合物或其结晶的每日剂量，接着在若干天或更多天的期间，患者不接受式I化合物的马来酸盐、式II化合物或其结晶的每日剂量。
实施例
下面的具体实施例，其目的是使本领域的技术人员能更清楚地理解和实施本申请。它们不应该被认为是对本申请范围的限制，而只是本申请的示例性说明和典型代表。本领域技术人员应该理解：还有形成本申请化合物的其它合成途径，下面提供的是非限制性的实施例。除非另有说明，本申请使用的原料都是市场上直接买到未经进一步纯化直接使用的。
实施例1 式I化合物的制备
Figure PCTCN2019105583-appb-000007
将参照WO2017162215中实施例6的制备方法得到的产物溶于加热的乙醇中，降温析出固体，过滤，滤饼减压干燥后得到式I-1化合物结晶(熔点＜210℃)。
将上述式I-1化合物(2.26Kg)加入无水甲醇(22.6L)中，于10～30℃搅拌溶清；滴加2mol/L的氢氧化钠水溶液，调节pH至9～10，滴毕，搅拌1h以上；过滤，滤饼经纯化水洗涤至洗涤液pH为7左右，湿品于45～55℃减压干燥8h以上至恒重，得式I化合物结晶(1.71Kg)。HRMS(ESI+,[M+H] +)m/z 432.2511，熔点215-217℃。
实施例2 式II化合物的制备
Figure PCTCN2019105583-appb-000008
向反应瓶中加入无水乙醇(25.5L)及式I化合物(1.7Kg)，搅拌10分钟后氮气保护下升温，反应液温度控制在65～75℃搅拌10分钟后加入马来酸(503g)无水乙醇溶液(1.7L)，继续保持温度65～75℃搅拌5小时，降温，反应液温度控制在20～30℃搅拌1小时后过滤，滤饼用无水乙醇(3.4L)淋洗，湿品于60±5℃减压干燥12小时，得式II化合物的结晶，熔点＞235℃，其使用Cu Kα辐射的X-射线粉末衍图如图1所示，差示扫描量热(DSC)图如图2所示，其元素分析结果如下：计算值(％)：61.41％C原子，6.07％H原子，17.90％N原子；测定值：61.13％C原子，6.08％H原子，17.99％N原子。
试验例1 吸湿性
实验过程：将样品(实施例1的式I化合物的结晶、实施例2的式II化合物的结晶、实施例1的式I-1化合物的结晶)约30mg置动态水蒸气吸附仪(DVS)样品盘内测定。
仪器型号：SMS DVS Advantage动态蒸汽吸附仪
测试条件：温度25℃
平衡dm/dt：0.002％/min：(时间：10min最大360min)
RH(％)测量梯度：10％
RH(％)测量梯度范围：0％～90％～0％
结果如下表2所示。
表2
Figure PCTCN2019105583-appb-000009
试验例2 稳定性
取实施例2的式II化合物的结晶样品，置于影响因素试验条件下(40℃恒温培养箱、60℃恒温培养箱、RH75％与RH92.5％的高湿环境)，裸露放置。分别于5、10、30天取样检测。
仪器：Waters e2695型高效液相色谱仪；
检测器：Waters 2489紫外吸收检测器/2998二极管阵列检测器；
色谱柱：菲罗门Titank C18(4.6×150mm，3μm)；
进样体积：10μl；检测波长：279nm；流速：1.1ml/min；柱温：35℃；
流动相：A相：30mmol/L甲酸铵溶液(用氨水调节pH至7.5)，B相：乙腈。
样品溶液的配制：分别取上述试验条件样品各适量，精密称定，用溶剂(30％乙腈水溶液)溶解成每1mL约含式II化合物1.0mg的溶液，作为检测有关物质的浓度，结果见表3。
表3
实验条件 式II化合物含量(％)
0天 99.5％
40℃_5天 99.4％
40℃_10天 99.4％
40℃_30天 99.3％
60℃_5天 99.5％
60℃_10天 99.4％
60℃_30天 99.2％
75％RH_室温5天 99.5％
75％RH_室温10天 99.5％
75％RH_室温30天 99.4％
92.5％RH_室温5天 99.5％
92.5％RH_室温10天 99.5％
92.5％RH_室温30天 99.4％
。
试验例3 测定化合物对人结肠癌细胞系Colo-205的增殖抑制作用
接种一定数量的对数生长期Colo-205细胞于96孔培养板。生长24小时后，加入不同浓度(1、3、10、30、100、300、1000、3000、10000nM)的实施例2的式II化合物的DMSO溶液，培养6天。式II化合物作用结束后，每孔加入MTT工作液，4小时后，三联液(10％十二烷基硫酸钠，5％异丁醇，0.012mol/L HCl)溶解，酶标仪(Synergy H4)570nm波长下测定OD值，以下列公式计算细胞生长抑制率：抑制率＝(OD值对照孔－OD值给药孔)/OD值对照孔×100％。
根据各浓度抑制率，应用GraphPad Prism 7软件采用非线性回归方法计算半数有效浓度IC 50。结果见表4。
表4
化合物 IC 50(Colo-205)/nM
式II化合物 301.0
。

Claims (15)

  1. 式I化合物的马来酸盐
    Figure PCTCN2019105583-appb-100001
    任选地，所述式I化合物与马来酸的摩尔比为1:0.5～2。
  2. 权利要求1所述的式I化合物的马来酸盐，其中所述式I化合物的马来酸盐为式II化合物
    Figure PCTCN2019105583-appb-100002
  3. 式II化合物的结晶，
    Figure PCTCN2019105583-appb-100003
    在所述结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，用2θ值表示在8.63、10.50、14.99、17.29、18.71、19.84度处有衍射峰；典型地，用2θ值表示在8.63、10.50、14.99、16.14、16.45、17.29、18.71、19.84、20.93度处有衍射峰；典型地，用2θ值表示在8.63、10.50、11.35、12.44、14.99、16.14、16.45、17.29、18.71、19.84、20.93、21.74、24.45、27.30、27.55、29.26度处有衍射峰；典型地，用2θ值表示在8.63、10.50、11.35、12.44、14.15、14.99、16.14、16.45、17.29、17.97、18.71、19.84、20.56、20.93、21.74、21.97、22.86、23.65、24.45、25.51、26.15、27.30、27.55、29.26、30.96、31.45度处有衍射峰。
  4. 权利要求3所述的式II化合物的结晶，其使用Cu Kα辐射的X-射线粉末衍射图谱中，衍射峰的峰位置及相对强度由下表所示：
    Figure PCTCN2019105583-appb-100004
    Figure PCTCN2019105583-appb-100005
  5. 权利要求3所述的式II化合物的结晶，其X-射线粉末衍射图谱如图1所示。
  6. 式II化合物的结晶，
    Figure PCTCN2019105583-appb-100006
    其差示扫描量热在237.67℃处有吸收峰。
  7. 权利要求6所述的式II化合物的结晶，其差示扫描量热图谱如图2所示。
  8. 权利要求3-7中任一项所述的式II化合物的结晶的制备方法，所述方法包括式II化合物从溶剂中析出，其中所述溶剂选自甲醇、乙醇、异丙醇、N-甲基吡咯烷酮或二甲基亚砜；典型地，其中所述溶剂为乙醇。
  9. 结晶组合物，其中权利要求3-7中任一项所述的式II化合物的结晶占所述结晶组合物重量的50％以上，80％以上，90％以上或95％以上。
  10. 药物组合物，其包含治疗有效量的权利要求1或2所述的式I化合物马来酸盐、权利要求3-7中任一项所述的式II化合物的结晶、或权利要求9所述的结晶组合物。
  11. 一种治疗CDK4和/或CDK6介导的疾病的方法，所述方法包括给予有需要的个体治疗有效量的权利要求1或2所述的式I化合物马来酸盐、权利要求3-7中任一项所述的式II化合物的结晶、权利要求9所述的结晶组合物、或者权利要求10所述的药物组合物。
  12. 权利要求1或2所述的式I化合物马来酸盐、权利要求3-7中任一项所述的式II化合物的结晶、权利要求9所述的结晶组合物、或者权利要求10所述的药物组合物在制备用于治疗和/或预防CDK4和/或CDK6介导的疾病的药物中的用途。
  13. 权利要求1或2所述的式I化合物马来酸盐、权利要求3-7中任一项所述的式II化合物的结晶、权利要求9所述的结晶组合物、或者权利要求10所述的药物组合物在治疗和/或预防CDK4和/或CDK6介导的疾病中的用途。
  14. 用于治疗和/或预防CDK4和/或CDK6介导的疾病的权利要求1或2所述的式I化合物马来酸盐、权利要求3-7中任一项所述的式II化合物的结晶、权利要求9所述的结晶组合物、或者权利要求10所述的药物组合物。
  15. 权利要求11所述的方法、权利要求12或13所述的用途、或者权利要求14所述的式I化合物马来酸盐、式II化合物的结晶、结晶组合物或者药物组合物，其中所述CDK4和/或CDK6介导的疾病是癌症；典型地，所述癌症选自：膀胱癌；乳腺癌；结肠癌；肾癌；表皮癌；肝癌；肺癌；食道癌；胆囊癌；卵巢癌；胰腺癌；胃癌；宫颈癌；甲状腺癌；鼻癌；头颈癌；前列腺癌；皮肤癌；淋巴系的造血细胞肿瘤；髓系造血细胞肿瘤；甲状腺滤泡癌；源于间质细胞肿瘤；中枢或周围神经系统肿瘤；黑素瘤；精原细胞瘤；畸胎瘤；骨肉瘤；着色性干皮病；角化棘细胞瘤；甲状腺滤泡癌；脂肪肉瘤；神经内分泌瘤；以及卡波西肉瘤。
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