WO2024027565A1 - 螺环胺类芳基磷氧化合物的晶型及其制备方法 - Google Patents

螺环胺类芳基磷氧化合物的晶型及其制备方法 Download PDF

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WO2024027565A1
WO2024027565A1 PCT/CN2023/109709 CN2023109709W WO2024027565A1 WO 2024027565 A1 WO2024027565 A1 WO 2024027565A1 CN 2023109709 W CN2023109709 W CN 2023109709W WO 2024027565 A1 WO2024027565 A1 WO 2024027565A1
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crystal form
compound
formula
solvent
preparation
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PCT/CN2023/109709
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French (fr)
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丁兆峰
付强
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齐鲁制药有限公司
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a crystal form of a spirocyclic amine arylphosphorus oxide compound and a preparation method thereof.
  • Protein kinases play a dominant regulatory role in almost all types of cellular biological activities. They include proliferation, apoptosis, cytoskeletal rearrangements, differentiation, development, immune response, nervous system function and conduction. In addition, many diseases and/or disorders are associated with aberrant, aberrant or dysregulated activity of one or more kinases.
  • Anaplastic lymphoma kinase is part of the receptor protein family of tyrosine kinases (RTKs).
  • the ALK gene provides instructions for the tyrosine kinase receptor protein to transmit signals from the cell surface to the cell through a signal transduction process. This process begins when the cell surface kinase is stimulated, which then dimerizes. After dimerization, the kinase is tagged with a phosphate group, a process called phosphorylation. This process activates the kinase. The activated kinase can transfer the phosphate group to another protein in the cell and continue to transmit the phosphorylation to a series of downstream proteins. This signaling pathway is important for many cellular processes, such as cell growth and division (proliferation) or maturation (differentiation).
  • anaplastic lymphoma kinase Although the specific function of anaplastic lymphoma kinase is unclear, it is generally believed that it can help regulate the proliferation of nerve cells in their early development.
  • Mutations in the anaplastic lymphoma kinase ALK gene are changes in amino acids, the basic building blocks of proteins. At least 16 mutations in the ALK gene have been identified in some patients with neuroblastoma, a type of tumor made of immature nerve cells (neuroblasts). Neuroblastoma and other cancers occur due to genetic mutations in some key genes (these key genes control cell proliferation and differentiation), which cause cells to grow and divide uncontrollably and form tumors.
  • the most common mutation in neuroblastoma is at position 1275, where arginine is replaced by glutamic acid (written as Arg1275Gln or R1275Q).
  • the Arg1275Gln mutation is found in both hereditary and disseminated neuroblastoma and is the only common ALK mutation found in both conditions.
  • anaplastic lymphoma kinase no longer requires extracellular stimulation for phosphorylation. Therefore, the kinase and downstream signaling pathways are continuously switched on (constitutively activated). Constitutive activation of anaplastic lymphoma kinase increases the proliferation of immature neural cells, ultimately leading to neuroblastoma. Rearrangements of the ALK gene on chromosome 2 increase the risk of other cancers. These rearrangements are somatic mutations, which occur throughout a person's life and only become apparent when cells become cancerous.
  • translocation is the exchange of genetic material between chromosome 2 and another chromosome.
  • ALK anaplastic large cell lymphoma
  • ALCL anaplastic large cell lymphoma
  • T cells The most common translocation in ALCL occurs between chromosomes 2 and 5, called t(2,5).
  • This translocation fuses the ALK gene with the NPM gene and forms an NPM-ALK fusion protein.
  • IMT inflammatory myofibroblastic tumor
  • IMT is a rare cancer characterized by solid tumors composed of inflammatory cells and a type of myofibroblast that is important in wound healing. Approximately half of people with IMT involve ALK gene translocations.
  • inversion Another type of rearrangement, called inversion, occurs when chromosome 2 breaks into two pieces and the resulting piece of DNA is inverted and reinserted into the chromosome.
  • Non-small cell lung cancer is the most common type of lung cancer.
  • chromosome 2 is inverted. This inversion fuses the ALK gene with another gene called EML4, forming the EML4-ALK fusion protein.
  • EML4-ALK fusion protein The fusion protein produced by these rearranged genes has the dual functions of anaplastic lymphoma kinase and chaperone protein.
  • ALK has always been a popular target for anti-tumor research and development, and Mesatros summarized the progress in this field (Expert Opin.Ther Patents 2014, 24(4),1).
  • Crizotinib is the first ALK inhibitor approved by the FDA for the treatment of ALK-positive lung cancer. Although the initial response to crizotinib is very effective, most patients relapse during the first year of treatment due to the development of drug resistance. On April 29, 2014, the FDA approved ceritinib for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), including patients who are effective and resistant to crizotinib.
  • ALK anaplastic lymphoma kinase
  • NSCLC metastatic non-small cell lung cancer
  • Patents include WO2014033136, WO2014025128, WO2014006554, WO2014002922, WO2013192512, WO2013177092, WO2013148857, WO2013138210, WO2012139499, WO2012140114.
  • the present invention provides crystalline form Q4 of the compound of formula (I), using Cu-K ⁇ radiation, its X-ray powder diffraction pattern has 2 ⁇ values of 10.19, 14.27, 14.79, 16.14, 19.45, 27.32 at 1, 2 and 3 There are characteristic peaks at 1, 4 or 5, and the 2 ⁇ error range is ⁇ 0.2°.
  • the crystalline form Q4 of the compound of formula (I) uses Cu-K alpha radiation, and its X-ray powder diffraction pattern has 2 ⁇ values of 10.19, 14.27, 14.79, 16.14, 19.45, and 27.32 There is a characteristic peak at 2 ⁇ , and the 2 ⁇ error range is ⁇ 0.2°.
  • the crystalline form Q4 uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has 2 ⁇ values of 10.19, 14.27, 14.79, 16.14, 17.99, 18.28, 19.45, 21.79, 22.12 , 22.34, 24.40, and 27.32, there are characteristic peaks at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11, and the 2 ⁇ error range is ⁇ 0.2° .
  • the crystalline form Q4 uses Cu-K ⁇ radiation, and its X-ray powder diffraction pattern has 2 ⁇ values of 10.19, 14.27, 14.79, 16.14, 17.99, 18.28, 19.45, 21.79, 22.12 There are characteristic peaks at , 22.34, 24.40, and 27.32, and the 2 ⁇ error range is ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form Q4 is basically as shown in Figure 1.
  • the X-ray powder diffraction peak analysis data of the crystalline form Q4 is shown in Table 1.
  • the TGA-DSC spectrum of the crystalline form Q4 has endothermic peaks at 208.5 ⁇ 2°C and 224.5 ⁇ 2°C, and an exothermic peak at 212.3 ⁇ 2°C.
  • the TGA-DSC spectrum of the crystalline form Q4 is basically as shown in Figure 2.
  • the DVS spectrum of the crystalline form Q4 is basically as shown in Figure 3.
  • the present invention also provides a method for preparing the crystal form Q4 of the compound of formula (I).
  • the method includes: adding the crystal form A of the compound of formula (I) into a solvent, stirring at room temperature, and filtering; the solvent is selected from water and alcohol solvents. Or their mixture, preferably methanol, water and mixed solvents thereof; wherein the mixed solvent of methanol/water is selected from methanol/water (9:1 ⁇ 1:1, v/v), preferably methanol/water (4:1, v /v).
  • the present invention also provides another method for preparing the crystal form Q4 of the compound of formula (I).
  • the method includes: adding the compound of formula (I) to an alcohol solvent, heating and dissolving, filtering, adding Q4 seed crystals after cooling, and then slowly Cool to -20°C ⁇ 30°C, filter and dry.
  • the alcoholic solvent is preferably methanol; the temperature to which the temperature is slowly cooled is preferably -10°C to 10°C, and more preferably -5°C.
  • the present invention also provides a pharmaceutical composition, which contains the crystalline form Q4 of the compound of formula (I) described in any one of the above-mentioned items of the present invention, and optionally one or more pharmaceutically acceptable carriers.
  • the present invention also provides the use of the crystal form Q4 of the compound of formula (I) described in any one of the above in the preparation of drugs for the treatment and/or prevention of cancer related to ALK and/or EGFR and their mutations, or , use in a drug for the treatment of cancer in combination with inhibitors of ROS1, BRAF, c-MET, HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 and/or VEGFR, or use in a drug for the treatment of cancer in combination with cytotoxics.
  • the present invention also provides the use of the above pharmaceutical composition in the preparation of drugs for the treatment and/or preventive treatment of cancers related to ALK and/or EGFR and their mutations, or, with ROS1, BRAF, c-MET, HER2, Use of KRAS/MEK, PIK3CA, FDFR, DDR2 and/or VEGFR inhibitors in combination with drugs for the treatment of cancer, or in combination with cytotoxic drugs for the treatment of cancer.
  • the present invention also provides a treatment and/or preventive treatment of cancers associated with ALK and/or EGFR and their mutations, or with ROS1, BRAF, c-MET, HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 and/or Or a method for treating cancer in combination with a VEGFR inhibitor, or a method for treating cancer in combination with a cytotoxin, which method includes administering to the patient a therapeutically and/or prophylactically effective amount of crystalline form Q4 of the compound of formula (I) above.
  • the cancer is non-small cell lung cancer.
  • the active compound represented by the crystalline form Q4 of the compound of formula (I) of the present invention can be used as the only anti-cancer drug, or can be used in combination with one or more other anti-tumor drugs. Combination therapy is accomplished by administering the individual treatment components simultaneously, sequentially, or spaced apart.
  • composition refers to a product containing a specified amount of an ingredient and a product resulting directly or indirectly from a combination of specified amounts of each of the specified ingredients.
  • compositions may be particularly specially formulated for oral administration, for parenteral injection, or for rectal administration in solid or liquid form.
  • pharmaceutically acceptable carrier refers to a medium generally accepted in the art for delivering biologically active agents to animals, especially mammals, including, for example, adjuvants, excipients, or Excipients such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, aromatics, antibacterial agents, antifungal agents, Lubricants and dispersants.
  • the formulation of pharmaceutically acceptable carriers depends on a number of factors within the purview of one of ordinary skill in the art.
  • compositions can be formulated into many dosage forms for convenient administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions, or It is an injectable dry powder that can be used after adding drug solvent before injection).
  • oral preparations such as tablets, capsules, solutions or suspensions
  • injectable preparations such as injectable solutions or suspensions, or It is an injectable dry powder that can be used after adding drug solvent before injection.
  • terapéuticaally and/or prophylactically effective amount refers to a compound of the invention or a pharmaceutically acceptable salt thereof which is a sufficient amount of the compound to treat a disorder with a reasonable effect/risk ratio suitable for any medical treatment and/or prevention.
  • the total daily dosage of the compound represented by formula (I) of the present invention or its pharmaceutically acceptable salts and compositions must be determined by the attending physician within the scope of reliable medical judgment.
  • the specific therapeutically effective dosage level will be determined by a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; The patient's age, weight, general health, sex, and diet; the timing, route of administration, and excretion rate of the specific compound employed; the duration of treatment; medications used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical field.
  • X-ray powder diffraction patterns have one or more measurement errors depending on slight changes in measurement conditions.
  • the structure of the crystals, crystals or crystal forms disclosed or claimed in the present invention may vary depending on test conditions, purity, equipment Other common variables known to those skilled in the art exhibit similar, but not identical, analytical properties within reasonable error limits.
  • the diffraction angle (2 ⁇ ) in powder X-ray powder diffraction usually produces an error within the range of ⁇ 0.20°. Therefore, the present invention not only includes crystals with completely consistent diffraction angles in powder X-ray powder diffraction, but also includes Crystals with consistent diffraction angles within an error range of ⁇ 0.20°.
  • the crystalline form of the compound of formula (I) of the present invention is not limited to crystals having the same X-ray powder diffraction pattern as shown in the accompanying drawings, and has substantially the same X-ray powder diffraction pattern as shown in the accompanying drawings. Any crystal with a ray powder diffraction pattern falls within the scope of the present invention.
  • examples of alcoholic solvents or alcohols include, but are not limited to, methanol, ethanol, propanol, isopropanol and n-butanol.
  • the X-ray powder diffraction pattern of the crystal form Q4 has characteristic peaks at 1, 2, 3, 4 and 5 with a 2 ⁇ value of 10.19, 14.27, 14.79, 16.14, 19.45 or 27.32,
  • the 2 ⁇ error range is ⁇ 0.2°, where 1, 2, 3, 4 and 5 refer to crystals with any 1, 2, 3, 4 or 5 characteristic peaks that are the same as crystal form Q4. All types are included in the scope of the present invention.
  • DSC data can reflect changes in the form of a substance. Strong endothermic peaks can indicate that the substance has dehydrated or desolvated, or has undergone crystallization, or has melted. When reflecting the melting state, the corresponding temperature is usually understood as the substance. melting point. This value will be affected by compound purity, sample weight, heating rate, particle size, and calibration and maintenance of the test equipment. Those skilled in the art can understand that the temperature when a substance transforms from a solid state to a liquid state is usually a temperature range rather than a fixed point value.
  • the temperature corresponding to the endothermic peak can be characterized by the onset value or peak value or other reasonable values. or the melting point of a substance.
  • the maximum endothermic transition temperature of the crystal form may be within the range of the above-disclosed specific value ⁇ 5.0°C, preferably within the range of ⁇ 2.0°C.
  • the present invention also uses thermal gravimetric analysis (TGA) to analyze the relationship between the degree of decomposition, sublimation, and evaporation (loss of weight) of the crystal form and temperature.
  • TGA thermal gravimetric analysis
  • the temperature at which the crystal form decomposes, sublimates, or evaporates can be within the range of ⁇ 3.0°C of the specific numerical value disclosed above, for example, within the range of ⁇ 2.0°C.
  • “Stability” of a crystalline form includes “chemical stability” and/or “physical stability”. “Chemical stability” refers to the degree of degradation reaction of the crystal form under certain temperature, humidity, and light conditions. “Chemical stability” reflects the stability of the crystal form under storage conditions. “Physical stability” refers to the degree to which the crystal form is converted into a solid form under certain specific conditions, such as high temperature, high humidity, grinding, tableting, desolvation, and adsorption of solvents, into another crystal form. Therefore, “physical stability” can reflect to a certain extent the stability of the crystal form during the use of preparations and other processes.
  • Deliquescence Absorbing enough water to form a liquid
  • weight gain by absorbing moisture is not less than 15.0%
  • the moisture-attracting weight gain is less than 15.0% but not less than 2.0%;
  • weight gain due to moisture attraction is less than 2.0% but not less than 0.2%;
  • weight gain due to moisture absorption is less than 0.2%.
  • Hygroscopicity directly affects the physical and chemical stability of drugs, and high hygroscopicity can easily cause chemical degradation and crystalline transformation.
  • high hygroscopicity will reduce the fluidity of the drug, thereby affecting the drug processing technology.
  • drugs with high hygroscopicity need to maintain low humidity during the production and storage process, which puts forward higher requirements for production and requires high costs.
  • high hygroscopicity can easily cause changes in the content of active ingredients in drugs, affecting the quality of the drugs.
  • APIs and preparations will encounter seasonal differences, climate differences in different regions, and high temperature and humidity conditions caused by weather factors during storage, transportation, and production.
  • a crystal form with better stability is helpful to avoid the impact of deviation from the storage conditions on the label on the quality of the drug.
  • the transformation of the crystal form will cause changes in the absorption of the drug, affect bioavailability, changes in bioavailability, and even cause toxic and side effects of the drug.
  • Good stability can ensure that there are basically no impurities produced during the storage process of the drug, ensure consistent and controllable quality of raw materials and preparations, and minimize changes in drug quality caused by changes in crystal form or the production of impurities.
  • the "stirring” is accomplished by conventional methods in the field, such as magnetic stirring or mechanical stirring.
  • the stirring speed is 50-1800 rpm.
  • magnetic stirring is preferably 300-900 rpm
  • mechanical stirring is preferably 300-900 rpm.
  • it is 100-300 rpm.
  • the "drying” can be performed at room temperature or higher.
  • the drying temperature is room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, forced air oven or vacuum oven.
  • the crystalline structures of the present invention can be prepared by a variety of methods, including crystallization or recrystallization from a suitable solvent, sublimation, growth from a melt, solid state conversion from another phase, crystallization from a supercritical fluid, and jet spraying.
  • Techniques for crystallizing or recrystallizing a crystalline structure from a solvent mixture including solvent evaporation, lowering the temperature of the solvent mixture, seeding of a supersaturated solvent mixture of the molecule and/or salt, lyophilizing the solvent mixture, adding an antisolvent to the solvent mixture wait.
  • Reaction temperature units are degrees Celsius or °C. Unless otherwise specified, room temperature refers to 25 ⁇ 5°C.
  • the solid sample is analyzed with an X-ray powder diffractometer (X'Pert PRO). Take an appropriate amount of fine powder of the test sample, place it in the groove of the sample holder, and press it into a flat and dense plane with a glass piece.
  • the XRPD measurement parameters are shown in Table 2. .
  • Thermogravimetry-differential scanning calorimetry analysis of solids was performed using a simultaneous thermal analyzer from Mettler Toledo. Use a small spoon to take an appropriate amount of the test sample and place it in the crucible, spread it evenly, weigh it, heat the sample according to the parameters listed in Table 3, and use STARe to analyze the data.
  • the hygroscopicity of the samples was measured using the DVS Intrinsic dynamic moisture adsorption instrument. Place the sample into the tared sample basket, the instrument automatically weighs, and analyzes the sample according to the parameters in Table 4.
  • HPLC determination uses Waters e2695 high performance liquid chromatography to perform high performance liquid chromatography analysis on the samples.
  • Particle size analysis of solid powders was performed using Malvern's laser scattering particle size analyzer. Take an appropriate amount of solid powder and place it in the injector, test the sample according to the parameters listed in Table 5, and use Mastersizer-v3.60 to analyze the data.
  • Test method Take an appropriate amount of the test sample, spread it evenly on the conductive tape, spray gold, and observe under the electron microscope.
  • the tap density is measured using SVM203 Tapped Density Meter.
  • Figure 1 is the XRPD spectrum of the crystal form Q4 of the compound of formula (I);
  • FIG. 1 is the TGA-DSC spectrum of the crystal form Q4 of the compound of formula (I);
  • Figure 3 is the DVS spectrum of the crystal form Q4 of the compound of formula (I);
  • Figure 4 shows the XRPD comparison spectra of the crystal form Q4DVS of the compound of formula (I) before and after testing;
  • Figure 5 is a 500 times magnified SEM spectrum of the crystal form Q4 of the compound of formula (I);
  • Figure 6 is a 500-fold magnified SEM spectrum of the compound of formula (I), Form A;
  • Figure 7 is a PSA spectrum of the crystalline form Q4 of the compound of formula (I).
  • Example 1 Referring to the method of Example 1 in the document CN110407877, 60.54g of the compound of formula (I), 218.0g of absolute ethanol and 121.1g of purified water were put into the reaction kettle under nitrogen protection and stirring. Raise the temperature to reflux, keep warm and stir until dissolved. Hot filter, wash with a mixture of 9.7g absolute ethanol and 6.1g purified water, and transfer the filtrate to the crystallization kettle. Under nitrogen protection, stir at 80 ⁇ 5°C for 25 minutes, cool to 67.5 ⁇ 2.5°C, and add seed crystals; cool to 60 ⁇ 5°C, stir for 1 hour, keep stirring for 30 minutes when it drops to 40 ⁇ 5°C, and cool to 15 ⁇ 5°C.
  • TGA-DSC spectrum is basically as shown in Figure 2.
  • TGA shows no obvious weight loss before melting, indicating that crystal form Q4 is anhydrous; there are endothermic peaks at 208.5°C and 224.5°C, and an exothermic peak at 212.3°C. .
  • TGA-DSC spectrum is shown in Figure 2.
  • TGA has no obvious weight loss before melting, indicating that crystal form Q4 is anhydrous; there are endothermic peaks at 208.5°C and 224.5°C, and an exothermic peak at 212.3°C.
  • Crystalline form Q4 has a weight gain of 0.10% at a humidity of 80% RH and has no or almost no hygroscopicity.
  • the XRPD comparison before and after the DVS test is shown in Figure 4. No crystal transfer occurred before and after the test.
  • the SEM results are shown in Figure 5.
  • the crystal form Q4 is a rod-shaped crystal with a relatively uniform size distribution.
  • the SEM results of Form A are shown in Figure 6.
  • Form A is a massive crystal with uneven sizes and serious agglomeration.
  • the PSA results are shown in Figure 6.
  • the crystal form Q4 has a good unimodal distribution.
  • crystal form Q4 of the present invention has better fluidity than the crystalline form A, and the larger particle size crystalline form Q4 has better fluidity. Therefore, compared with crystal form A, crystal form Q4 has obvious advantages in the uniformity of powder mixing of raw materials and the preparation of solid dosage forms. See Table 7 below for liquidity evaluation criteria.
  • Crystalline form Q4 shows no obvious degradation under high temperature, high humidity, or light conditions, and does not undergo crystal transformation, showing good stability.
  • crystalline form Q4 has a weight gain of 0.10% under the humidity condition of 80% RH, and has no or almost no hygroscopicity.
  • the moisture-induced weight gain of crystalline form Q4 is smaller than the moisture-induced weight gain of crystalline forms A, B, and C disclosed in reference CN110407877 (the weight gain under 90% RH humidity conditions is 0.17%, 0.70%, and 0.62%, respectively).
  • crystal form Q4 has smaller hygroscopicity, and does not have defects such as chemical degradation of the drug, crystal form transformation, and poor fluidity caused by high hygroscopicity, which is more beneficial. Drug processing technology.
  • crystal form Q4 and crystal form A of the compound of formula (I) disperse it in water, artificial gastric fluid (SGF, Simulated Gastric Fluid), artificial intestinal fluid under fed state (FeSSIF, Fed State Simulated Intestinal Fluid), and fasting respectively.
  • Suspensions were made in FaSSIF (Fasted State Simulated Intestinal Fluid), equilibrated at 200 rpm for 24 hours, and then tested for sample content (mg/mL) and XRPD in the solution using high performance liquid chromatography. The results are as shown in the table Shown in 10.
  • crystal form Q4 and crystal form A in water, SGF, and FeSSIF The solubility of crystal form Q4 and crystal form A in water, SGF, and FeSSIF is similar; the solubility of crystal form Q4 in FaSSIF is better than that of crystal form A, indicating that crystal form Q4 has better bioavailability in the fasting state. Crystal form Q4 and crystal form A did not transform before and after the test and had good stability.

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Abstract

本发明涉及式(I)化合物(2-((5-氯-2-((2-甲氧基-4-(9-甲基-3,9-二氮杂-螺[5.5]十一烷-3-基)苯基)氨基)嘧啶-4-基)氨基)苯基)二甲基氧膦的晶型。本发明还涉及所述晶型的药用组合物、制药用途及其制备方法。

Description

螺环胺类芳基磷氧化合物的晶型及其制备方法
本申请要求于2022年8月1日提交中国专利局、申请号为202210915901.8、发明名称为“螺环胺类芳基磷氧化合物的晶型及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于药物化学领域，具体涉及一种螺环胺类芳基磷氧化合物的晶型及其制备方法。
背景技术
蛋白激酶几乎在所有类型的细胞生物活动中起主导调控作用。它们包括增殖，凋亡，细胞骨架重排，分化，发育，免疫反应，神经系统功能和传导。此外，许多疾病和(或)机能紊乱与一种或多种激酶的活性失常，异常或失调相关。
间变性淋巴瘤激酶(ALK)是酪氨酸激酶(RTKs)受体蛋白家族的一部分。ALK基因提供了指令使得酪氨酸激酶受体的蛋白，通过一个信号转导的过程，把信号从细胞表面传输到细胞内。这一过程始于当所述细胞表面激酶受到刺激，然后激酶发生二聚化。二聚化后，激酶被磷酸基标记，这一过程称为磷酸化。这一过程使激酶激活。激活的激酶能够将磷酸基团转移到细胞内的另一个蛋白上，并且继续将磷酸化传递到下游一系列蛋白。这种信号传导途径对许多细胞过程非常重要，如细胞生长和分裂(增殖)或成熟(分化)。
虽然对间变性淋巴瘤激酶的特异功能还不清楚，但一般认为在神经细胞早期发展中，它能够帮助调节神经细胞的增殖。
间变性淋巴瘤激酶ALK基因的突变是蛋白质的基本单元-氨基酸发生变化。在一些神经母细胞瘤，以及一种由未成熟的神经细胞(成神经细胞)组成的肿瘤病人中，已经鉴定出至少16个突变的ALK基因。神经母细胞瘤和其他癌症发生是由于一些关键基因(这些关键基因控制着细胞的增殖及分化)发生基因突变，使细胞生长和分裂不可控制而形成肿瘤。
神经母细胞瘤最常见的突变是在位置1275上，精氨酸被谷氨酸取代(写为Arg1275Gln或R1275Q)。Arg1275Gln突变在遗传性和分散性的神经母细胞瘤上都有发现，并且也是在这两种情况下发现的唯一共同的ALK基因突变。
突变或过度表达的间变性淋巴瘤激酶不再需要从细胞外刺激而磷酸化。因此，激酶和下游信号传导通路是不间断接通的(组成性激活)。间变性淋巴瘤激酶的组成性活化可提高未成熟神经细胞的增殖，最后导致神经母细胞瘤。ALK基因在2号染色体上的重排，增加了患有其它癌症的风险。这些重排是体细胞的突变，也就是体细胞的突变存在人的一生中，并且只在细胞发生癌变时才显现出来。
一种类型的重排称为易位，是在2号染色体和其他染色体之间的交换遗传物质。在患有间变性大细胞淋巴瘤(ALCL)的人群中，已鉴定出至少15种涉及ALK基因的易位。间变性大细胞淋巴瘤是发生在称为T细胞的免疫细胞中，是一种罕见的癌症形式。ALCL中最常见的易位发生染色体2和5号染色体之间，称为t(2，5)。这种易位使ALK基因与NPM基因融合，并形成NPM-ALK的融合蛋白。此外，在炎性肌纤维母细胞瘤(IMT)中已经鉴定了至少七种ALK基因易位。IMT是一种罕见的癌症，其特征是实体瘤由炎性细胞和一种对伤口愈合非常重要的肌纤维母细胞的组成。大约有一半IMT的人群涉及到ALK基因易位。
另一种类型的重排称为反转，反转发生在当2号染色体断裂成两部分，所得片断的DNA被倒置，并重新插入到染色体中。非小细胞肺癌是一种最常见肺癌，在一小部分患者中，是2号染色体发生了反转。这种反转使ALK基因与另一个称为EML4的基因融合，形成EML4-ALK融合蛋白。由这些重排的基因产生的融合蛋白具有间变性淋巴瘤激酶和伴侣蛋白的双重功能。
ALK一直是抗肿瘤研发热门靶标，Mesatros总结了在这一领域的进展情况(Expert Opin.Ther Patents 2014,24(4),1)。Crizotinib是FDA批准的第一个ALK抑制剂，用于治疗ALK阳性肺癌。尽管经Crizotinib的最初响应非常有效，但多数患者由于产生耐药性而在治疗的第一年发生复发。2014年4月29日，FDA批准Ceritinib用于治疗间变性淋巴瘤激酶(ALK)阳性的转移性非小细胞肺癌(NSCLC)，包括对crizotinib有效以及耐药的患者。还有一些化合物正在临床研究中用于治疗癌症，如alectinib，AP-26113等。一些杂环化合物也已披露，用于各种癌症的治疗。专利包括WO2014033136，WO2014025128，WO2014006554，WO2014002922，WO2013192512，WO2013177092，WO2013148857，WO2013138210，WO2012139499，WO2012140114。
然而，尽管有一半以上的NSCLC患者对Crizotinib疗效良好，耐药总是会随用药时间而产生，从而药物失去其有效性。虽然近几年来，国内外都在大力开发用于治疗非小细胞肺癌的ALK抑制剂，但其疗效并不令人满意。因此非常迫切需要开发新型的，更加有效安全的ALK抑制剂。
已发现螺环胺类芳基磷氧化合物对ALK、ALK突变体与EGFR的突变酶展现出优于AP26113的抑制活性；并且该类化合物在ALK阳性病人中获得的NSCLC细胞系PDX模型及Crizotinib耐药PDX模型上也都展现出了比参考化合物AP26113更好的体内药效。因此，通过进一步研发该类化合物的结晶形式和制备方法，以及其结晶形式的药物组合物，对ALK酶异常所引起的疾病，可能会提供更加有效的治疗。
发明内容
本发明提供式(I)化合物的结晶形式Q4，使用Cu-Kα辐射，其X-射线粉末衍射图谱在2θ值为10.19、14.27、14.79、16.14、19.45、27.32的1处、2处、3处、4处或5处有特征峰，2θ误差范围为±0.2°。
在本发明的一些方案中，所述的式(I)化合物的晶型Q4，使用Cu-Kα辐射，其X-射线粉末衍射图谱在2θ值为10.19、14.27、14.79、16.14、19.45、27.32处有特征峰，2θ误差范围为±0.2°。
在本发明的一些方案中，所述的晶型Q4，使用Cu-Kα辐射，其X-射线粉末衍射图谱在2θ值为10.19、14.27、14.79、16.14、17.99、18.28、19.45、21.79、22.12、22.34、24.40、27.32的1处、2处、3处、4处、5处、6处、7处、8处、9处、10处、11处有特征峰，2θ误差范围为±0.2°。
在本发明的一些方案中，所述的晶型Q4，使用Cu-Kα辐射，其X-射线粉末衍射图谱在2θ值为10.19、14.27、14.79、16.14、17.99、18.28、19.45、21.79、22.12、22.34、24.40、27.32处有特征峰，2θ误差范围为±0.2°。
在本发明的一些方案中，所述的晶型Q4，其X-射线粉末衍射图谱基本如图1所示。
在本发明的一些方案中，所述的晶型Q4，其X-射线粉末衍射峰解析数据如表1所示。
表1式(I)晶型Q4的XRPD衍射峰解析数据


在本发明的一些方案中，所述的晶型Q4，其TGA-DSC图谱在208.5±2℃、224.5±2℃处有吸热峰，在212.3±2℃处有放热峰。
在本发明的一些方案中，所述的晶型Q4，其TGA-DSC图谱基本如图2所示。
在本发明的一些方案中，所述的晶型Q4，其DVS图谱基本如图3所示。
本发明还提供式(I)化合物晶型Q4的制备方法，所述方法包括：将式(I)化合物的晶型A加入溶剂中，室温搅拌，过滤；所述溶剂选自水、醇类溶剂或它们的混合，优选甲醇、水及其混合溶剂；其中甲醇/水的混合溶剂选自甲醇/水(9:1～1:1，v/v)，优选甲醇/水(4:1，v/v)。
本发明还提供式(I)化合物晶型Q4的另一种制备方法，所述方法包括：将式(I)化合物加入到醇类溶剂中加热溶解，过滤，降温后加入Q4晶种，然后缓慢降温至-20℃～30℃，抽滤，干燥。所述醇类溶剂优选甲醇；所述缓慢降温至的温度，优选-10℃～10℃，更优选-5℃。
本发明还提供一种药物组合物，其包含本发明上述任一项所述的式(I)化合物的晶型Q4，以及任选一种或多种可药用的载体。
本发明还提供上述任一项所述的式(I)化合物的晶型Q4在制备用于治疗和/或预防治疗与ALK和/或EGFR以及它们的突变相关的癌症的药物中的用途，或，与ROS1、BRAF、c-MET、HER2、KRAS/MEK、PIK3CA、FDFR、DDR2和/或VEGFR抑制剂联合治疗癌症的药物的用途，或，与细胞毒素联合治疗的癌症的药物中的用途。
本发明还提供上述药物组合物在制备用于治疗和/或预防治疗与ALK和/或EGFR以及它们的突变相关的癌症的药物中的用途，或，与ROS1、BRAF、c-MET、HER2、KRAS/MEK、PIK3CA、FDFR、DDR2和/或VEGFR抑制剂联合治疗癌症的药物的用途，或，与细胞毒素联合治疗的癌症的药物中的用途。
本发明还提供一种治疗和/或预防治疗与ALK和/或EGFR以及它们的突变相关的癌症，或，与ROS1、BRAF、c-MET、HER2、KRAS/MEK、PIK3CA、FDFR、DDR2和/或VEGFR抑制剂联合治疗的癌症，或，与细胞毒素联合治疗的癌症的方法，所述方法包括向患者施用治疗和/或预防有效量的上述式(I)化合物的晶型Q4。
在本发明的一些方案中，上述癌症是非小细胞肺癌。
说明和定义
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。
本发明式(I)化合物的晶型Q4所示的活性化合物可作为唯一的抗癌药物使用，或者可以与一种或多种其他抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
术语“组合物”是指包含指定量成分的产品，以及直接或间接从指定量的各指定成分的组合产生的产品。
本领域技术人员可以使用已知的可药用的载体，将本发明的式(I)化合物的晶型制备成适合的药物组合物。所述药物组合物可特别专门配制成以固体或液体形式供口服给药、供胃肠外注射或供直肠给药。
术语“可药用的载体”是指本领域通常可接受的用于将生物活性药剂递送给动物、特别是哺乳动物的介质，根据给药方式和剂型的性质包括例如佐剂、赋形剂或赋形物，例如稀释剂、防腐剂、填充剂、流动调节剂、崩解剂、润湿剂、乳化剂、助悬剂、甜味剂、调味剂、芳香剂、抗菌剂、抗真菌剂、润滑剂和分散剂。药学上可接受的载体在本领域普通技术人员的眼界范围内根据大量因素配制。
所述的药物组合物可配制成许多剂型，便于给药，例如，口服制剂(如片剂、胶囊剂、溶液或悬浮液)；可注射的制剂(如可注射的溶液或混悬液，或者是可注射的干燥粉末，在注射前加入药物溶媒后即可使用)。
术语“治疗和/或预防有效量”是指本发明化合物或其药学上可接受的盐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，本发明式(I)所示化合物或其药学上可接受的盐和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组合使用或同时使用的药物；及医疗领域公知的类似因素。
本领域公知，X-射线粉末衍射图谱根据测量条件的微小变化，而具有一种或多种测量误差，本发明公开或要求保护的结晶、晶体或晶型的结构可能根据试验条件、纯度、设备和本领域技术人员已知的其它常见变量在合理误差范围内表现出类似但不完全相同的分析特性。例如，粉末X-射线粉末衍射中的衍射角(2θ)通常产生±0.20°的范围内的误差，所以，本发明不仅包括粉末X-射线粉末衍射中的衍射角完全一致的结晶，还包括在±0.20°的误差范围内衍射角一致的结晶。本发明式(I)化合物的结晶形式并不仅限于具有与附图中所示的X-射线粉末衍射图谱相同的X射线粉末衍射图谱的晶体，具有基本上与附图中所示相同的X-射线粉末衍射图谱的任何晶体均属于本发明范围内。
本发明中，醇类溶剂或醇的实例包括但不限于甲醇、乙醇、丙醇、异丙醇和正丁醇。
本发明中，所述晶型Q4的X-射线粉末衍射图谱在2θ值为10.19、14.27、14.79、16.14、19.45或27.32的1处、2处、3处、4处、5处有特征峰，2θ误差范围为±0.2°，其中1处、2处、3处、4处、5处是指有任意1个、2个、3个、4个或5个特征峰与晶型Q4相同的晶型都包含在本发明范围内。
文中出现的“与附图中所示X-射线粉末衍射图谱基本上相同的X-射线粉末衍射图谱”。应了解，在该上下文中使用的术语“基本上相同”亦意指示X-射线粉末衍射图谱的2θ角度值可因伴随这些测量的固有实验变化而具有轻微变化，两者为同一晶体形式。
应当理解用不同类型设备或用不同的测试条件可能给出稍微不同的DSC图谱和吸热转变温度读数。DSC数据可以反应物质形态的变化，强烈的吸热峰可以表示物质发生了脱水或脱溶剂，或者发生了转晶、或者发生了熔融等；当反映熔融状态时，对应的温度即通常理解为物质的熔点。该数值将受化合物纯度、样品重量、加热速度、粒径和测试设备的校验和维修的影响。本领域技术人员可以理解，物质由固态转化为液体状态时的温度通常为一个温度范围，而非固定点值，因此无论以onset值或peak值或其他合理数值均可以表征吸热峰对应的温度或物质的熔点。晶型的最大吸热转变温度可以在上述公开的具体数值±5.0℃的范围内，优选±2.0℃的范围内。
本发明还采用热失重分析(TGA)对晶型发生分解或升华、蒸发的程度(失去重量)与温度的关系进行了分析。应当理解同种晶型受样品纯度、粒径、不同类型设备、不同的测试方法等的影响，所得到的数值存在一定误差。晶型发生分解或升华、蒸发时的温度可以在上述公开的具体数值±3.0℃的范围内，例如±2.0℃的范围内。
晶型的“稳定性”包括“化学稳定性”和/或“物理稳定性”。“化学稳定性”是指该晶型在一定温度、湿度、光照条件下发生降解反应的程度，“化学稳定性”反映了该晶型在储存条件下的稳定性。“物理稳定性”是指该晶型在某些特定条件下发生固态形式转化的程度，例如在高温、高湿、研磨、压片、脱溶剂、吸附溶剂的条件下，转化为另外一种晶型，因此“物理稳定性”可以在一定程度上反应晶型在制剂等使用过程中的稳定程度。
关于引湿性特征描述与引湿性增重的界定(中国药典2020年版通则9103药物引湿性试验指导原则)：
潮解：吸收足量水分形成液体；
极具引湿性：引湿增重不小于15.0％；
有引湿性：引湿增重小于15.0％但不小于2.0％；
略有引湿性：引湿增重小于2.0％但不小于0.2％；
无或几乎无引湿性：引湿增重小于0.2％。
引湿性直接影响药物的物理化学稳定性，引湿性高易引起化学降解和晶型转变。此外，引湿性高会降低药物的流动性，从而影响药物的加工工艺。不仅如此，引湿性高的药物在生成和保存过程中需要维持低的湿度，对生成提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。
原料药和制剂在储存、运输、生产过程中会遇到季节差异、不同地区气候差异和天气因素带来的高温和高湿条件。具有较好稳定性的晶型，有利于避免偏离标签上的贮藏条件对药物质量的影响。
晶型的转变会导致药物的吸收发生变化，影响生物利用度，生物利用度的改变，甚至引起药物的毒副作用等。良好的稳定性可以确保药物在储存过程中基本没有杂质产生，保证原料药和制剂质量一致可控，最大程度地减少药物由于晶型改变或杂质产生引起的药物质量变化。
本发明中，所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
所述“干燥”可以在室温或更高的温度下进行。干燥温度为室温到约60℃，或者到50℃，或者到40℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
本发明的结晶结构可以通过各种方法制备，包括从合适的溶剂中结晶或重结晶、升华、从熔融体中生长、从另一相固态转化、从超临界流体中结晶和射流喷雾等。结晶结构从溶剂混合物中结晶或重结晶的技术，包括溶剂蒸发、降低溶剂混合物的温度、该分子和/或盐的过饱和溶剂混合物的引晶、冻干溶剂混合物、向溶剂混合物中加入反溶剂等。
反应温度单位为摄氏度或℃。如无特别说明，室温指25±5℃。
若无特别指明，本发明的式(I)或式(I)化合物均指：
仪器及分析方法：
1.X-射线粉末衍射(XRPD)
固体样品用X-射线粉末衍射仪(X’Pert PRO)进行分析，取供试品细粉适量，置于样品架凹槽中，用玻璃片压制成平整致密的平面，XRPD测量参数见表2。
表2 XRPD测量参数
使用梅特勒托利多的同步热分析仪对固体进行热重-差示扫描量热连用分析。用小勺取供试品适量置于坩埚中，使铺布均匀，称重其重量，按照表3中所列参数对样品进行加热，使用STARe对数据进行分析。
表3 TGA-DSC分析方法参数
2.动态水分吸脱附分析(DVS)
使用DVS Intrinsic动态水分吸附仪对样品的吸湿性进行测定。将样品置于已去皮的样品篮中，仪器自动称重，按照表4中的参数对样品进行分析。
表4 DVS分析方法参数
3.核磁共振氢谱(1H-NMR)
1H-NMR的测定是用Bruker AVANCE NEO 400核磁仪器，测定溶剂为氘代二甲基亚砜(DMSO-d6)。
4.高效液相色谱(HPLC)
HPLC的测定使用Waters e2695高效液相色谱仪对样品进行高效液相色谱分析。
5.粒度分析(PSA)
使用Malvern的激光散射粒度分布仪对固体粉末进行粒度分析。取固体粉末适量置于进样器中，按照表5中所列参数对样品进行检测，使用Mastersizer-v3.60对数据进行分析。
表5 PSA分析方法参数

6.扫描电镜
仪器型号：ZEISS Sigma 300扫描电镜。
测试方法：取适量供试品，均匀铺布于导电胶带上，喷金，于电镜视野下观察。
7.振实密度
振实密度的测定使用SVM203 Tapped Density Meter进行测试。
附图说明
图1为式(I)化合物晶型Q4的XRPD谱图；
图2为式(I)化合物晶型Q4的TGA-DSC谱图；
图3为式(I)化合物晶型Q4的DVS谱图；
图4为式(I)化合物晶型Q4DVS测试前后的XRPD对比谱图；
图5为式(I)化合物晶型Q4的500倍放大SEM谱图；
图6为式(I)化合物晶型A的500倍放大SEM谱图；
图7为式(I)化合物晶型Q4的PSA谱图。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度或℃。如无特别说明，室温指25±5℃。
参考实施例1式(I)化合物晶型A的制备方法
参考文献CN110407877中实施例1的方法，将60.54g式(I)化合物、218.0g无水乙醇和121.1g纯化水在氮气保护并搅拌下投入反应釜中。升温至回流，保温搅拌至溶解。热过滤，用9.7g无水乙醇和6.1g纯化水的混合液洗涤，滤液一并转入结晶釜中。氮气保护下，80±5℃搅拌25分钟，降温至67.5±2.5℃，加入晶种；降温至60±5℃，搅拌1小时，降至40±5℃时保温搅拌30分钟，降温至15±5℃。保温15±5℃，控制35±5分钟加入302.7g纯化水，保温搅拌2.5小时。过滤，滤饼用120.1g纯化水洗涤，所得固体50～60℃真空干燥，得55.59g固体，经XRPD检测为晶型A。
实施例1 式(I)化合物晶型Q4的制备方法
将43.1mg式(I)化合物晶型A加入1mL甲醇中，室温搅拌23h。过滤，将所得固体进行XRPD表征，该固体为晶型Q4，其XRPD谱图基本如图1所示。
实施例2 式(I)化合物晶型Q4的制备方法
将2.72g式(I)化合物晶型A加入16mL甲醇/水(4:1，v/v)中，室温搅拌46h。过滤，60℃真空干燥5h。将所得固体进行XRPD、TGA/DSC表征，该固体为晶型Q4，其XRPD谱图基本如图1所示。
TGA-DSC谱图基本如图2所示，TGA显示在熔融前无明显失重，表明晶型Q4为无水物；在208.5℃、224.5℃处有吸热峰，在212.3℃处有放热峰。
实施例3 式(I)化合物晶型Q4的制备方法
将30.12g式(I)化合物加入360mL甲醇中，64℃溶清，热滤。降温至55℃，加入306.8mg的Q4晶种，保温0.5h。6h缓慢降温至-5℃，保温0.5h。抽滤，室温真空干燥16h。将所得固体，进行XRPD、TGA-DSC、DVS、SEM、PSA表征，该固体为晶型Q4，其XRPD谱图如图1所示。
TGA-DSC谱图如图2所示，TGA在熔融前无明显失重，表明晶型Q4为无水物；在208.5℃、224.5℃处有吸热峰，在212.3℃处有放热峰。
DVS谱图如图3所示，晶型Q4在80％RH湿度增重0.10％，无或几乎无引湿性。DVS测试前后的XRPD对比如图4所示，测试前后未发生转晶。
SEM结果如图5所示，晶型Q4为棒状晶体，大小分布较均匀。作为对比，晶型A的SEM结果如图6所示，晶型A为块状晶体，大小不均且团聚较严重。
PSA结果如图6所示，所得晶型Q4的D90＝145.2μm，D50＝62.6μm，D10＝10.8μm，晶型Q4具有较好的单峰分布。
实施例4流动性测试
测试不同晶型、不同粒径原料药的松密度、振实密度，计算卡尔指数。具体结果及流动性评价如表6所示。
表6晶型Q4和晶型A的流动性比较

上述结果表明，基本相同的粒径条件下，本发明的晶型Q4相比于晶型A具有更好的流动性，且大粒径的晶型Q4的流动性更佳。因此，相比于晶型A，晶型Q4在原料药的混粉均一性、固体制剂的制备等方面具有明显优势。流动性评价标准参见下表7。
表7流动性评价标准
实施例5稳定性试验
考察式(I)化合物的晶型Q4在高温、高湿度及光照条件下的稳定性。在特定条件下放置5天、10天后使用HPLC测试纯度和XRPD检测，实验结果如表8所示。
表8晶型Q4的稳定性试验结果

晶型Q4在高温、高湿、光照条件下均无明显降解，且未发生转晶，具有良好的稳定性。
实施例6引湿性实验
参照2020版中国药典中的《药物引湿性试验指导原则》，测试式(I)化合物的晶型Q4的水分吸附/脱附数据。晶型Q4的DVS曲线如图3所示，其引湿性数据如表9所示。
表9晶型Q4的引湿性
从引湿性数据可以看出，晶型Q4在80％RH湿度条件下增重0.10％，属于无或几乎无引湿性。通过对比可见，晶型Q4的引湿增重小于参考文献CN110407877中批露的晶型A、B、C(90％RH湿度条件下增重分别为0.17％、0.70％、0.62％)的引湿增重。由此可见，晶型Q4相比于晶型A、B和C具有更小的引湿性，不存在因引湿性大造成的药物的化学降解和晶型转变及流动性差等缺陷，从而更有利于药物的加工工艺。
实施例7溶解度实验
37℃下，取适量式(I)化合物晶型Q4和晶型A分别分散于水、人工胃液(SGF，Simulated Gastric Fluid)、进食状态下的人工肠液(FeSSIF，Fed State Simulated Intestinal Fluid)、空腹状态下的人工肠液(FaSSIF，Fasted State Simulated Intestinal Fluid)中制成悬浮液，以200rpm转速平衡24h后分别用高效液相色谱法测试溶液中样品的含量(mg/mL)和XRPD，结果如表10所示。
表10晶型Q4和晶型A在4种介质的平衡溶解度和XRPD检测结果
晶型Q4与晶型A在水、SGF、FeSSIF中溶解度相近；晶型Q4在FaSSIF的中溶解度比晶型A更优，表明晶型Q4在空腹状态下具有更好的生物利用度。晶型Q4和晶型A在测试前后均未转晶，具有良好的稳定性。

Claims (10)

  1. 式(I)化合物的晶型Q4，
    其特征在于，使用Cu-Kα辐射，所述晶型Q4的X-射线粉末衍射图谱在2θ值为10.19、14.27、14.79、16.14、19.45、27.32处有特征峰，2θ误差范围为±0.2°。
  2. 根据权利要求1所述的晶型Q4，其特征在于，使用Cu-Kα辐射，其X-射线粉末衍射图谱在2θ值为10.19、14.27、14.79、16.14、17.99、18.28、19.45、21.79、22.12、22.34、24.40、27.32处有特征峰，2θ误差范围为±0.2°。
  3. 根据权利要求1-2中任一项所述的晶型Q4，其特征在于，其X-射线粉末衍射图谱基本如图1所示。
  4. 根据权利要求1-3中任一项所述的晶型Q4，其特征在于，其TGA-DSC图谱在208.5±2℃、224.5±2℃处有吸热峰，在212.3±2℃处有放热峰。
  5. 根据权利要求1-4中任一项所述的晶型Q4，其特征在于，其TGA-DSC图谱基本如图2所示。
  6. 根据权利要求1-5中任一项所述的晶型Q4，其特征在于，其DVS图谱基本如图3所示。
  7. 权利要求1-6任一项所述的晶型Q4的制备方法，所述方法包括将式(I)化合物的晶型A加入溶剂中，室温搅拌，过滤，其中所述溶剂选自水、醇类溶剂或它们的混合；优选为甲醇、甲醇/水(9:1～1:1，v/v)的混合溶剂；
    或者，所述方法包括将式(I)化合物加入到醇类溶剂中加热溶解，过滤，降温后加入晶种，然后缓慢降温至-20℃～30℃，抽滤，干燥；所述醇类溶剂优选为甲醇。
  8. 一种药物组合物，含有权利要求1-6任一项所述的晶型Q4，及任选地一种或多种可药用的载体。
  9. 权利要求1至6任一项所述的晶型Q4在制备用于治疗和/或预防治疗与ALK和/或EGFR以及它们的突变相关的癌症、与ROS1、BRAF、c-MET、HER2、KRAS/MEK、PIK3CA、 FDFR、DDR2和/或VEGFR抑制剂联合治疗的癌症、或与细胞毒素联合治疗的癌症的药物中的应用。
  10. 根据权利要求9的用途，其中所述癌症是非小细胞肺癌。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016000581A1 (zh) * 2014-07-04 2016-01-07 南京明德新药研发股份有限公司 螺环芳基磷氧化物和芳基磷硫化物
CN106928275A (zh) * 2015-12-29 2017-07-07 齐鲁制药有限公司 螺环胺类芳基磷氧化合物的制备方法及其中间体和晶型
CN110407877A (zh) * 2018-04-28 2019-11-05 齐鲁制药有限公司 新颖螺环芳基磷氧化物的多晶型

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016000581A1 (zh) * 2014-07-04 2016-01-07 南京明德新药研发股份有限公司 螺环芳基磷氧化物和芳基磷硫化物
CN106928275A (zh) * 2015-12-29 2017-07-07 齐鲁制药有限公司 螺环胺类芳基磷氧化合物的制备方法及其中间体和晶型
CN110407877A (zh) * 2018-04-28 2019-11-05 齐鲁制药有限公司 新颖螺环芳基磷氧化物的多晶型

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIU XILE, ZHANG LU, WAN HAIWEN, ZHU ZHENZHEN, JIN JING, QIN YUXIN, MAO WEIFENG, YAN KANG, FANG DOUGLAS, JIANG WEN, HU LIHONG, CHEN: "Discovery and preclinical evaluations of WX-0593, a novel ALK inhibitor targeting crizotinib-resistant mutations", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 66, 1 June 2022 (2022-06-01), Amsterdam NL , pages 128730, XP093135060, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2022.128730 *

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