WO2019166012A1 - 作为c-Met激酶抑制剂的化合物的结晶及其制备方法和用途 - Google Patents

作为c-Met激酶抑制剂的化合物的结晶及其制备方法和用途 Download PDF

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WO2019166012A1
WO2019166012A1 PCT/CN2019/076683 CN2019076683W WO2019166012A1 WO 2019166012 A1 WO2019166012 A1 WO 2019166012A1 CN 2019076683 W CN2019076683 W CN 2019076683W WO 2019166012 A1 WO2019166012 A1 WO 2019166012A1
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compound
formula
crystal
degrees
type
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PCT/CN2019/076683
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English (en)
French (fr)
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龚峰
黄体聪
臧海山
张士博
赵锐
刘飞
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正大天晴药业集团股份有限公司
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Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202210285508.5A priority Critical patent/CN115057815A/zh
Priority to US16/977,054 priority patent/US11279676B2/en
Priority to EP23198543.3A priority patent/EP4279138A3/en
Priority to AU2019227391A priority patent/AU2019227391A1/en
Priority to EP19761595.8A priority patent/EP3766870B1/en
Priority to CN201980016201.1A priority patent/CN111936467B/zh
Priority to JP2020568585A priority patent/JP2021517162A/ja
Publication of WO2019166012A1 publication Critical patent/WO2019166012A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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

  • This application belongs to the field of medicinal chemistry and relates to the crystallization of compounds as c-Met kinase inhibitors, in particular to N-(4-((7-(1-(cyclopentylamino)cyclopropyl)methoxy)) Crystallization of -6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide and preparation method thereof , crystalline compositions, pharmaceutical compositions, and the use of said crystallization treatments for diseases associated with inhibition of growth factor receptor (eg, c-Met) protein tyrosine kinase activity.
  • growth factor receptor eg, c-Met
  • c-Met kinases are prototypic members of the heterodimeric receptor tyrosine kinase (RTKs) subfamily, and RTKs include Met, Ron, and Sea.
  • RTKs include Met, Ron, and Sea.
  • the anti-angiogenic and anti-proliferative activity of c-Met makes it an attractive target.
  • the endogenous ligand for c-Met is hepatocyte growth factor (HGF), which can interfere with the formation of colonies in vitro, also known as discrete factor (SF).
  • HGF hepatocyte growth factor
  • SF discrete factor
  • HGF is a derivatized cytokine that induces receptor activation by autophosphorylation leading to increased receptor-dependent signaling in normal and tumor cells (Sonnenberg et al, J. Cell Biol., 123: 223-235, 1993; Matsumato Etc., Crit. Rev. Oncog., 3: 27-54, 1992; Stoker et al, Nature, 327
  • WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino))cyclopropyl)methoxy)-6-methoxyquinolin-4 as a c-Met kinase inhibitor -yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide (hereinafter referred to as a compound of formula I) and a process for the preparation thereof,
  • the drug has excellent properties in terms of pharmacokinetics, bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, etc., to meet the needs of the drug in terms of production, storage, and formulation.
  • pharmacokinetics bioavailability, hygroscopicity, stability, solubility, purity, ease of preparation, etc.
  • the application provides Form A crystals of a compound of Formula I,
  • the present application provides Form B crystals of a compound of Formula I, in the X-ray powder diffraction pattern of Cu-type radiation using Cu Ka radiation, at about 7.44, 8.93, 10.44, and 17.84 degrees in the 2 theta angle. There are diffraction peaks.
  • the present application provides Form C crystals of a compound of Formula I, in the X-ray powder diffraction pattern of Cu-type radiation using Cu Ka radiation, expressed at 27.3 degrees at about 7.38, 10.33, and 17.84 degrees. Diffraction peaks.
  • the present application provides a Form D crystal of a compound of Formula I, in an X-ray powder diffraction pattern of Cu-type radiation using Cu Ka radiation, at about 7.44, 13.38, 16.43, 20.14, There are diffraction peaks at 20.88 and 21.45 degrees.
  • the present application provides Form E crystals of a compound of Formula I, in an X-ray powder diffraction pattern of Cu-type radiation using Cu Ka radiation, expressed at about 4.51, 6.64, and 10.66 degrees in terms of 2 ⁇ angles. Diffraction peaks.
  • the present application provides a crystalline composition comprising a crystal of a compound of formula I, wherein the crystal of the compound of formula I comprises more than 50% by weight, preferably more than 80%, more preferably 90% by weight of the crystalline composition. % or more, preferably 95% or more, and the crystal of the compound of the formula I is a type A crystal of the compound of the formula I, a type B crystal of the compound of the formula I, a type C crystal of the compound of the formula I, a type D crystal of the compound of the formula I Or a Form E crystal of a compound of formula I, or a mixture thereof.
  • the application provides a pharmaceutical composition comprising a therapeutically effective amount of a crystal of a compound of formula I or a crystalline composition as described above, wherein the crystal of the compound of formula I is a crystalline form of a compound of formula I, a compound of formula I Form B crystal, Form C crystal of the compound of Formula I, Form D crystal of the compound of Formula I or Form E crystal of the compound of Formula I, or a mixture thereof.
  • the application provides crystallization of a compound of formula I or the use of a crystalline composition as described above or a pharmaceutical composition as described above for the manufacture of a medicament for the treatment and/or prevention of a c-Met kinase mediated disease, wherein
  • the crystal of the compound I is a Form A crystal of the compound of Formula I, a Form B crystal of the compound of Formula I, a Form C crystal of the compound of Formula I, a Form D crystal of the compound of Formula I, or an E Form crystal of the compound of Formula I, or a mixture thereof.
  • the application provides a method of treating a c-Met kinase mediated disease, the method comprising administering to a mammal in need of such treatment, preferably a human, a crystallization of a therapeutically effective amount of a compound of formula I or a crystalline composition as described above Or a pharmaceutical composition as described above, wherein the crystal of the compound of formula I is a Form A crystal of a compound of Formula I, a Form B crystal of a compound of Formula I, a Form C crystal of a compound of Formula I, a Form D crystal of a compound of Formula I, or a compound of Formula I Form E crystals, or mixtures thereof.
  • the application provides crystallization of a compound of formula I or a crystalline composition thereof, or a pharmaceutical composition as described above, for use in the prevention and/or treatment of a c-Met kinase mediated disease, wherein the crystallization of the compound of formula I is Form A of the compound I, Form B of the compound of Formula I, Form C of the compound of Formula I, Form D of the compound of Formula I, or Form E of the compound of Formula I, or mixtures thereof.
  • Figure 1 is an XRPD pattern of Form A crystal of the compound of Formula I prepared in Example 1;
  • Figure 2 is a DSC chart of Form A crystal of the compound of Formula I prepared in Example 1;
  • FIG. 3 is a thermogravimetric analysis (TGA) diagram of Form A crystal of the compound of Formula I prepared in Example 1;
  • Figure 4 is an XRPD pattern of Form B crystal of the compound of Formula I prepared in Example 2;
  • Figure 5 is a DSC chart of Form B crystal of the compound of Formula I prepared in Example 2;
  • FIG. 6 is a thermogravimetric analysis (TGA) diagram of Form B crystal of the compound of Formula I prepared in Example 2;
  • Figure 7 is an XRPD pattern of Form C crystal of the compound of Formula I prepared in Example 3.
  • Figure 8 is a DSC chart of Form C crystal of the compound of Formula I prepared in Example 3.
  • FIG. 9 is a thermogravimetric analysis (TGA) diagram of Form C crystal of the compound of Formula I prepared in Example 3;
  • Figure 10 is an XRPD pattern of Form D crystal of the compound of Formula I prepared in Example 4.
  • Figure 11 is a DSC chart of the Form D crystal of the compound of Formula I prepared in Example 4.
  • FIG. 12 is a thermogravimetric analysis (TGA) diagram of Form D crystals of the compound of Formula I prepared in Example 4;
  • Figure 13 is an XRPD pattern of Form E crystal of the compound of Formula I prepared in Example 5;
  • Figure 14 is a DSC chart of Form E crystal of the compound of Formula I prepared in Example 5;
  • FIG. 15 is a thermogravimetric analysis (TGA) chart of Form E crystals of the compound of Formula I prepared in Example 5.
  • the present application provides N-(4-((7-((1-(cyclopentylamino))cyclopropyl)methoxy)-6-methoxyquinolin-4-yl)oxy)- Crystallization of 3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide (hereinafter referred to as crystallization of the compound of formula I) in pharmacokinetics, bioavailability, hygroscopicity At least one aspect of properties, stability, solubility, purity, ease of preparation, etc., has excellent properties.
  • the crystallization of the compound of formula I provided herein comprises N-(4-((7-((1-(cyclopentylamino))cyclopropyl)methoxy)-6-) Form A crystal of oxyquinolino-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylamide (hereinafter referred to as compound of formula I) Form A crystal), N-(4-((7-((1-(cyclopentylamino))cyclopropyl)methoxy)-6-methoxyquinolin-4-yl)oxy B-form crystal of (-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethylformamide (hereinafter referred to as B-form of the compound of formula I), N-(4-( (7-((1-(Cyclopent
  • the application provides Form A crystals of a compound of Formula I, in an X-ray powder diffraction pattern (XRPD) using Cu Ka radiation, expressed at 2[Theta] angles at about 13.38, 15.71, 16.47, 20.15, 20.86, and 21.43 degrees.
  • XRPD X-ray powder diffraction pattern
  • diffraction peaks preferably having diffraction peaks at about 9.25, 10.45, 13.38, 14.03, 15.71, 16.47, 17.20, 17.85, 18.16, 18.48, 19.80, 20.15, 20.86, 21.43, 22.53, 23.43 and 24.87 degrees, more preferably at Diffraction peaks at about 9.25, 10.45, 12.48, 13.38, 14.03, 15.71, 16.47, 17.20, 17.85, 18.16, 18.48, 18.85, 19.80, 20.15, 20.86, 21.43, 21.79, 22.53, 23.43, 24.87, 25.47 and 29.07 degrees; Most preferably at about 9.25, 9.64, 10.45, 11.27, 12.48, 13.38, 14.03, 15.71, 16.47, 17.20, 17.85, 18.16, 18.48, 18.85, 19.80, 20.15, 20.86, 21.43, 21.79, 22.53, 23.43, 24.25, 24.87, There are diffraction peaks at about
  • the differential scanning calorimetry (DSC) of the Form A crystal of the compound of Formula I of the present application has an endothermic peak at about 177.50 ° C, specifically, the differential scanning amount of Form A crystal of the compound of Formula I.
  • the thermal (DSC) pattern is shown in Figure 2.
  • thermogravimetric analysis (TGA) pattern of Form A crystals of a compound of Formula I of the present application is shown in FIG.
  • the present application provides a Form B crystal of a compound of Formula I having a diffraction peak at about 7.44, 8.93, 10.44, and 17.84 degrees in an X-ray powder diffraction pattern using Cu K ⁇ radiation, preferably There are diffraction peaks at about 7.44, 8.93, 10.26, 10.44, 10.70, 11.17, 12.65, 12.96, 14.35, 15.49, 16.34, 17.84, 18.28, 18.73, 20.96, 21.88, 22.42, 23.03, 24.17, 25.27 and 26.16 degrees.
  • the differential scanning calorimetry (DSC) of the Form B crystal of the compound of Formula I of the present application has an endothermic peak at about 125.70 ° C and 174.07 ° C, specifically, the difference in Form B crystal of the compound of Formula I.
  • the scanning calorimetry (DSC) pattern is shown in Figure 5.
  • thermogravimetric analysis (TGA) pattern of Form B crystals of a compound of Formula I of the present application is shown in FIG.
  • the present application provides a Form C crystal of a compound of Formula I, having an X-ray powder diffraction pattern of Cu Ka radiation, having a diffraction peak at about 7.38, 10.33, and 17.84 degrees, expressed as an angle of 2 ⁇ , preferably at about There are diffraction peaks at 7.38, 8.80, 10.33, 11.15, 15.30, 17.84, 18.18, 19.76, 21.03 and 21.86 degrees, most preferably at about 7.38, 8.80, 10.33, 11.15, 11.71, 12.33, 12.58, 12.88, 13.50, 14.28, 15.30. There are diffraction peaks at 16.04, 16.33, 16.55, 17.84, 18.18, 18.43, 19.76, 21.03, 21.86, 22.83, 25.34 and 25.86 degrees.
  • the compound of Formula I in a Form C crystal of a compound of Formula I, is in the form of a dioxane compound of Formula I; in particular, the dioxane compound of Formula I
  • the molar ratio of the compound of formula I to dioxane is from 1 to 10:1, preferably from 2 to 8:1, more preferably from 2 to 3:1, most preferably from about 2.33:1.
  • the differential scanning calorimetry (DSC) of the Form C crystal of the compound of Formula I of the present application has an endothermic peak at about 174.16 ° C, specifically, the differential scanning amount of the Form C crystal of the compound of Formula I.
  • the thermal (DSC) pattern is shown in Figure 8.
  • thermogravimetric analysis (TGA) pattern of Form C crystals of a compound of Formula I of the present application is shown in FIG.
  • the present application provides a Form D crystal of a compound of Formula I, which is represented by an X-ray powder diffraction pattern of Cu Ka radiation at about 7.44, 13.38, 16.43, 20.14, 20.88, and 21.45 degrees.
  • the diffraction peaks are preferably at about 7.07, 7.44, 8.92, 9.23, 10.46, 13.38, 14.06, 15.76, 16.43, 17.21, 17.84, 18.17, 18.47, 19.82, 20.14, 20.88, 21.45, 21.82, 22.49, 23.44, 24.87, 25.44 and There are diffraction peaks at 29.09 degrees, most preferably at about 7.07, 7.44, 8.05, 8.92, 9.23, 9.64, 10.46, 11.24, 12.63, 13.38, 14.06, 15.76, 16.43, 17.21, 17.84, 18.17, 18.47, 18.77, 19.82, 20.14.
  • the differential scanning calorimetry (DSC) of the Form D crystal of the compound of Formula I of the present application has an endothermic peak at about 176.14 ° C, specifically, the differential scanning amount of the D-type crystal of the compound of Formula I.
  • the thermal (DSC) pattern is shown in Figure 11.
  • thermogravimetric analysis (TGA) pattern of the Form D crystal of the compound of Formula I of the present application is shown in FIG.
  • the present application provides an E-type crystal of a compound of formula I, which has a diffraction peak at about 4.51, 6.64, and 10.66 degrees in an X-ray powder diffraction pattern of Cu Ka radiation, preferably at about 4.51, 6.64, 9.03, 9.64, 10.66, 16.69 and 17.12 degrees have diffraction peaks, more preferably about 4.51, 6.64, 9.03, 9.64, 10.66, 13.26, 13.59, 15.20, 15.85, 16.69, 17.12, 19.33, 20.49, 22.12.
  • the differential scanning calorimetry (DSC) of the Form E crystal of the compound of Formula I of the present application has an endothermic peak at about 136.34 ° C, specifically, the differential scanning amount of the E-form crystal of the compound of Formula I.
  • the thermal (DSC) pattern is shown in Figure 14.
  • thermogravimetric analysis (TGA) pattern of the Form E crystal of the compound of Formula I of the present application is shown in FIG.
  • the instrument model for X-ray powder diffraction spectrometry is Bruker D2 X-ray diffractometer, conditions and methods: 30kv 10mA, slit: 0.6/3/Ni/8, 2theta: 4-40°, time[s ]: 0.1, step size: 0.02°.
  • the instrument model for DSC spectrometry is METTLER TOLEDO DSC1, conditions and methods: 10 ° C / min temperature rise in the range of 30-300 ° C.
  • the instrument model for TGA spectroscopy is a PerKinElmerPyris Type 1 thermogravimetric analyzer, conditions and methods: 20 ° C / min temperature rise in the range of 25-700 ° C.
  • the relative intensity of the diffraction peaks can vary due to preferred orientations such as crystalline morphology and the like, which is well known in the art of crystallography. Where there is a preferred orientation effect, the peak intensity is altered, but the diffraction peak position of the crystal form cannot be changed. In addition, there may be slight errors in the position of the peak for any given crystal form, which is also well known in the art of crystallography. For example, the position of the peak can be shifted due to changes in temperature at the time of analyzing the sample, movement of the sample, or calibration of the instrument, etc., and the measurement error of the 2 ⁇ value is sometimes about ⁇ 0.2 degrees, and therefore, it is known to those skilled in the art to determine each crystal. This error should be taken into account when constructing the structure.
  • DSC measures the transition temperature when crystallization absorbs or releases heat due to changes in its crystal structure or crystal melting.
  • the thermal transition temperature and melting point error is typically within about 5 ° C, usually within about 3 ° C, when we say a compound has a given DSC At the peak or melting point, this means the DSC peak or melting point ⁇ 5 °C.
  • DSC provides an auxiliary method for identifying different crystal forms. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be noted that for the mixture, the DSC peak or melting point may vary over a larger range.
  • the melting temperature is related to the rate of temperature increase due to decomposition during the melting of the substance.
  • the present application provides a method of preparing a Form A crystal of a compound of Formula I, the method comprising the steps of:
  • the solvent A in the step (1) is selected from the group consisting of toluene, methyl ethyl ketone, acetonitrile, a mixed solvent of acetonitrile and water or ethyl acetate, preferably toluene.
  • the solvent A is selected from the group consisting of a mixed solvent of acetonitrile and water, wherein the volume fraction of acetonitrile in the mixed solvent is from 65% to 95%.
  • the solvent A has a volume of from 1 to 50 mL, preferably from 2 to 15 mL, based on 1 g of the compound of formula I.
  • the solvent A has a volume of 5 mL based on 1 g of the compound of formula I.
  • the step (1) is carried out at a temperature ranging from 0 ° C to the boiling point of the solvent system after mixing, preferably the step (1) is carried out at the boiling temperature of the solvent system after mixing.
  • the step (2) precipitates a solid under standing, shaking or stirring, preferably step (2) with stirring.
  • Step (2) can be carried out at room temperature.
  • the method for preparing the Form A crystal further comprises separating the solid precipitated in the step (2), for example, by filtration; in some embodiments of the present application, further comprising separating The solid is dried, and the drying temperature may be 60 °C.
  • the present application provides a method of preparing a Form B crystal of a compound of Formula I, the method comprising the steps of:
  • the solvent B in the step (1) is selected from the group consisting of methanol, ethanol, acetone, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, a mixed solvent of acetone and water, or a mixed solvent of ethanol and methyl ethyl ketone, preferably Ethanol; wherein the volume fraction of methanol in the mixed solvent of methanol and water is 95%; wherein the volume fraction of ethanol in the mixed solvent of ethanol and water is 65%-95%; wherein the mixed solvent of acetone and water The volume fraction of acetone in the medium is 65%-95%; wherein the volume fraction of butanone in the mixed solvent of ethanol and methyl ethyl ketone is not more than 30%.
  • the solvent B has a volume of from 1 to 50 mL, preferably from 5 to 20 mL, based on 1 g of the compound of formula I.
  • the volume of solvent B is 8.75 mL based on 1 g of the compound of formula I.
  • the step (1) is carried out at a temperature ranging from 0 ° C to the boiling point of the solvent system after mixing, preferably the step (1) is carried out at the boiling temperature of the solvent system after mixing.
  • the step (2) precipitates a solid under standing, shaking or stirring, preferably step (2) with stirring.
  • Step (2) can be carried out at room temperature.
  • the method for preparing the Form B crystal further comprises separating the solid precipitated in the step (2), for example, by filtration; in some embodiments of the present application, further comprising separating
  • the solid is dried, and the drying temperature may be 60 ° C; the drying may be carried out under reduced pressure.
  • the present application provides a process for the preparation of Form C crystals of a compound of Formula I, the method comprising the steps of:
  • the solvent C in the step (1) is dioxane.
  • the solvent C has a volume of from 1 to 100 mL, preferably from 5 to 20 mL, based on 1 g of the compound of formula I.
  • the volume of solvent C is 7.5 mL based on 1 g of the compound of formula I.
  • the step (1) is carried out at a temperature ranging from 0 ° C to the boiling point of the solvent system after mixing, preferably the step (1) is carried out at the boiling temperature of the solvent system after mixing.
  • the step (2) precipitates a solid under standing, shaking or stirring, preferably step (2) with stirring.
  • Step (2) can be carried out at room temperature.
  • the method for preparing the C-type crystal further comprises separating the solid precipitated in the step (2), for example, by filtration; in some embodiments of the present application, further comprising separating The solid is dried, and the drying temperature may be 60 °C.
  • the present application provides a process for the preparation of a Form D crystal of a compound of Formula I, the method comprising the steps of:
  • the solvent D in the step (1) is a mixed solvent of ethanol and water; wherein the volume fraction of ethanol in the mixed solvent of ethanol and water is 55%.
  • the solvent D has a volume of from 1 to 50 mL, preferably from 5 to 20 mL, based on 1 g of the compound of formula I.
  • the solvent D has a volume of 10 mL based on 1 g of the compound of formula I.
  • the step (1) is carried out at a temperature ranging from 0 ° C to the boiling point of the solvent system after mixing, preferably the step (1) is carried out at the boiling temperature of the solvent system after mixing.
  • step (2) precipitates a state of solids in a standing, shaking or stirring state, preferably step (2) is carried out under stirring.
  • Step (2) can be carried out at room temperature.
  • the method for preparing the D-form crystal further comprises separating the solid precipitated in the step (2), for example, by filtration; in some embodiments of the present application, further comprising separating
  • the solid is dried, and the drying temperature may be 45 ° C; the drying may be carried out under reduced pressure.
  • the present application provides a process for the preparation of a Form E crystal of a compound of Formula I, the method comprising the steps of:
  • the solvent E in the step (1) is a mixed solvent of methanol and water; wherein the volume fraction of methanol in the mixed solvent of methanol and water is 75% to 85%.
  • the solvent E has a volume of from 1 to 50 mL, most preferably from 5 to 20 mL, based on 1 g of the compound of Formula I.
  • the solvent E has a volume of 10 mL based on 1 g of the compound of formula I.
  • the step (1) is carried out at a temperature ranging from 0 ° C to the boiling point of the solvent system after mixing, preferably the step (1) is carried out at the boiling temperature of the solvent system after mixing.
  • the step (2) precipitates a solid under standing, shaking or stirring, preferably step (2) with stirring.
  • Step (2) can be carried out at room temperature.
  • the method for preparing the E-form crystal further comprises separating the solid precipitated in the step (2), for example, by filtration; in some embodiments of the present application, further comprising separating The solid is dried.
  • the present application provides a crystalline composition comprising the crystal of the compound of formula I, wherein the crystal of the compound of formula I comprises more than 50% by weight, preferably more than 80%, more preferably 90% by weight of the crystalline composition. More preferably, more than 95%, wherein the crystal of the compound of formula I is a Form A crystal of a compound of Formula I, a Form B crystal of a compound of Formula I, a Form C crystal of a compound of Formula I, a Form D of a compound of Formula I Crystalline or Form E crystals of the compound of Formula I, or mixtures thereof.
  • the application provides a pharmaceutical composition comprising a therapeutically effective amount of a crystal of a compound of formula I as described herein, or a crystalline composition as described above, wherein the crystal of the compound of formula I is Form A of the compound of formula I, Form B of the compound of Formula I, Form C of the compound of Formula I, Form D of the compound of Formula I, or Form E of the compound of Formula I, or mixtures thereof.
  • the pharmaceutical compositions of the present application may or may not contain pharmaceutically acceptable excipients.
  • the pharmaceutical compositions of the present application may further comprise one or more additional therapeutic agents.
  • the "pharmaceutically acceptable excipient” means an inert substance which is administered together with the active ingredient and which facilitates administration of the active ingredient, including but not limited to the acceptable use by the State Food and Drug Administration for human or animal use. Any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, disintegrant, suspending agent, stabilizing (eg livestock) Agent, isotonic agent, solvent or emulsifier.
  • Non-limiting examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • compositions of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, Gels, microspheres and aerosols, etc.
  • Typical routes of administration of the pharmaceutical compositions of the present application include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, peritoneal Internal, intramuscular, subcutaneous, intravenous administration.
  • a preferred route of administration is oral administration.
  • the application provides the use of a crystallization of a compound of Formula I, or a crystalline composition thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment and/or prevention of a c-Met kinase mediated disease, wherein
  • the crystallization of the compound of formula I is a Form A crystal of a compound of Formula I, a Form B crystal of a compound of Formula I, a Form C crystal of a compound of Formula I, a Form D crystal of a compound of Formula I, or an E Form crystal of a compound of Formula I, or mixture.
  • the application provides crystallization of a compound of Formula I, or a crystalline composition, or a pharmaceutical composition thereof, for use in the treatment and/or prevention of a c-Met kinase mediated disease, wherein said compound of Formula I
  • the crystals are Form A crystals of the compound of Formula I, Form B crystals of the compound of Formula I, Form C crystals of the compound of Formula I, Form D crystals of the compound of Formula I, or Form E crystals of the compound of Formula I, or mixtures thereof.
  • the application provides a method of treating a c-Met kinase mediated disease, the method comprising administering to a mammal in need of such treatment, preferably a human, a crystallization of a therapeutically effective amount of a compound of formula I, or a combination of crystals thereof Or a pharmaceutical composition as described above, wherein the crystal of the compound of formula I is a Form A crystal of a compound of Formula I, a Form B crystal of a compound of Formula I, a Form C crystal of a compound of Formula I, a Form D crystal of a compound of Formula I or Form E of the compound of formula I, or a mixture thereof.
  • terapéuticaally effective amount refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect.
  • the determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • the application provides crystallization of a compound of Formula I, or a crystalline composition thereof, or a pharmaceutical composition thereof, for preventing or treating a c-Met kinase mediated disease, wherein the crystallization of the compound of Formula I is Formula I Form A crystal of the compound, Form B crystal of the compound of Formula I, Form C crystal of the compound of Formula I, Form D crystal of the compound of Formula I or Form E crystal of the compound of Formula I, or mixtures thereof.
  • the c-Met kinase mediated disease described above is a cancer, such as lung cancer.
  • the type A crystal, the B type crystal, the D type crystal and the E type crystal of the compound of the formula I are tested according to the "Guidelines for Drug Humidity Test" of the Fourth Edition of the Chinese Pharmacopoeia 2015 Edition, respectively, and the sample is wetted. The weight gain is shown in Table 6.
  • Example 1 Less than 0.2
  • Example 2 Less than 0.2
  • Example 4 Less than 0.2
  • Example 5 Less than 0.2
  • a type crystal, a type B crystal, a type D crystal and an E type crystal of the compound of the formula I were each about 80 mg, and directly pressed into a tablet under high pressure (core diameter 4 mm, pressure 150 kg, maintenance time 2 min, repeated three times). 700 ml of a 0.01 mol/L hydrochloric acid solution was used as a medium to measure the intrinsic dissolution rate of the drug substance. The results are shown in Table 7.
  • Test sample Form A crystal, B crystal, D crystal and E crystal of the compound of formula I, respectively filled in No. 9 gavage capsule
  • SD rats weighing 180-200 g, were adapted to 3-5 days and were randomly divided into 4 groups, 4 rats in each group.
  • the A-form, B-form and D-form crystals of the compound of formula I were administered orally at a dose of 20 mg/kg.
  • E-type crystals Rats were fasted for 12 h before administration, and given food for 4 h after administration. Drinking water was free before and after the experiment and during the experiment.
  • the time points after administration were 0.167h (10min), 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 24h, and about 0.3mL of blood was collected from the orbital venous plexus in the EDTA-K2 centrifuge tube, 4 Store at °C, centrifuge at 4 ° C, 4000 rpm, 10 min for 1 h, and store at -20 ° C for testing.
  • LC-MS/MS Liquid chromatography-tandem mass spectrometry
  • IS internal standard
  • protein precipitation method to extract the analyte and internal standard from the plasma
  • reversed-phase chromatography column to separate compounds
  • Analytes were quantified by electrospray ionization (ESI) using a tandem quadrupole mass spectrometer.

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Abstract

本申请属于药物化学领域，涉及作为c-Met激酶抑制剂的化合物的结晶，具体涉及N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的结晶、及其制备方法、结晶组合物、药物组合物，以及所述结晶治疗与抑制生长因子受体蛋白酪氨酸激酶活性相关的疾病的用途。本申请的结晶在药代动力学、生物利用度、吸湿性、稳定性、溶解性、纯度、易制备等至少一方面具有优异的性质。

Description

作为c-Met激酶抑制剂的化合物的结晶及其制备方法和用途
相关申请的交叉引用
本申请要求于2018年03月02日向中国国家知识产权局提交的第201810174767.4号中国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，涉及作为c-Met激酶抑制剂的化合物的结晶，具体涉及N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的结晶及其制备方法、结晶组合物、药物组合物，以及所述结晶治疗与抑制生长因子受体(例如c-Met)蛋白酪氨酸激酶活性相关的疾病的用途。
背景技术
c-Met激酶是异质二聚体受体酪氨酸激酶(RTKs)亚科的原型成员，RTKs包括Met、Ron和Sea。c-Met的抗血管生成和抗增殖的活性使其成为一个有吸引力的靶点。c-Met的内源性配体是肝细胞生长因子(HGF)，因其体外可以干扰集落的形成又名离散因子(SF)。HGF是一种衍生化细胞因子，通过自身磷酸化诱导受体活化使得在正常细胞和肿瘤细胞中的受体依赖信号增加(Sonnenberg等，J.Cell Biol.,123:223-235,1993；Matsumato等，Crit.Rev.Oncog.,3:27-54,1992；Stoker等，Nature,327:239-242,1987)。已证实抗HGF抗体或者HGF拮抗剂也能抑制肿瘤转移。
WO2012034055公开了作为c-Met激酶抑制剂的N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺(下称式I化合物)及其制备方法，
Figure PCTCN2019076683-appb-000001
一般希望药物在以下方面具有优良的性质：药代动力学、生物利用度、吸湿性、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。目前对提供具有改善性质的式I化合物存在需求。
发明概述
一方面，本申请提供了式I化合物的A型结晶，
Figure PCTCN2019076683-appb-000002
在所述A型结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约13.38、15.71、16.47、20.15、20.86和21.43度处有衍射峰。
另一方面，本申请提供了式I化合物的B型结晶，在所述B型结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约7.44、8.93、10.44和17.84度处有衍射峰。
另一方面，本申请提供了式I化合物的C型结晶，在所述C型结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约7.38、10.33和17.84度处有衍射峰。
另一方面，本申请提供了式I化合物的D型结晶，在所述D型结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约7.44、13.38、16.43、20.14、20.88和21.45度处有衍射峰。
另一方面，本申请提供了式I化合物的E型结晶，在所述E型结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约4.51、6.64和10.66度处有衍射峰。
再一方面，本申请提供了包含式I化合物的结晶的结晶组合物，其中所述式I化合物的结晶占所述结晶组合物重量的50％以上，较好是80％以上，更好是90％以上，最好是95％以上，并且所述式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
又一方面，本申请提供了药物组合物，其包含治疗有效量的式I化合物的结晶或者上述结晶组合物，其中所述式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
再一方面，本申请提供了式I化合物的结晶或上述结晶组合物或上述药物组合物在制备用于治疗和/或预防c-Met激酶介导的疾病的药物中的用途，其中所述式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
另一方面，本申请提供了治疗c-Met激酶介导的疾病的方法，所述方法包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式I化合物的结晶或上述结晶组合物或上述药物组合物，其中所述式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
又一方面，本申请提供了用于预防和/或治疗c-Met激酶介导的疾病的式I化合物的结晶或上述结晶组合物或上述药物组合物，其中所述式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
附图说明
图1为实施例1制备的式I化合物的A型结晶的XRPD图；
图2为实施例1制备的式I化合物的A型结晶的DSC图；
图3为实施例1制备的式I化合物的A型结晶的热重分析(TGA)图；
图4为实施例2制备的式I化合物的B型结晶的XRPD图；
图5为实施例2制备的式I化合物的B型结晶的DSC图；
图6为实施例2制备的式I化合物的B型结晶的热重分析(TGA)图；
图7为实施例3制备的式I化合物的C型结晶的XRPD图；
图8为实施例3制备的式I化合物的C型结晶的DSC图；
图9为实施例3制备的式I化合物的C型结晶的热重分析(TGA)图；
图10为实施例4制备的式I化合物的D型结晶的XRPD图；
图11为实施例4制备的式I化合物的D型结晶的DSC图；
图12为实施例4制备的式I化合物的D型结晶的热重分析(TGA)图；
图13为实施例5制备的式I化合物的E型结晶的XRPD图；
图14为实施例5制备的式I化合物的E型结晶的DSC图；和
图15为实施例5制备的式I化合物的E型结晶的热重分析(TGA)图。
发明详述
本申请提供了N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的结晶(下称式I化合物的结晶)，其在药代动力学、生物利用度、吸湿性、稳定性、溶解性、纯度、易制备等至少一方面具有优异的性质。
根据本申请的具体实施方案，本申请提供的式I化合物的结晶包括N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的A型结晶(下称式I化合物的A型结晶)、N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的B型结晶(下称式I化合物的B型结晶)、N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的C型结晶(下称式I化合物的C型结晶)、N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的D型结晶(下称式I化合物的D型结晶)、N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺的E型结晶(下称式I化合物的E型结晶)。
一方面，本申请提供了式I化合物的A型结晶，其使用Cu Kα辐射的X-射线粉末衍射图谱(XRPD)中，以2θ角度表示在约13.38、15.71、16.47、20.15、20.86和21.43度处有衍射峰，优选在约9.25、10.45、13.38、14.03、15.71、16.47、17.20、17.85、18.16、18.48、19.80、20.15、20.86、21.43、22.53、23.43和24.87度处有衍射峰，更优选在约9.25、10.45、12.48、13.38、14.03、15.71、16.47、17.20、17.85、18.16、18.48、18.85、19.80、20.15、20.86、21.43、 21.79、22.53、23.43、24.87、25.47和29.07度处有衍射峰；最优选在约9.25、9.64、10.45、11.27、12.48、13.38、14.03、15.71、16.47、17.20、17.85、18.16、18.48、18.85、19.80、20.15、20.86、21.43、21.79、22.53、23.43、24.25、24.87、25.47、26.54、26.76、27.78、29.07、30.51、31.99、33.01、34.65、35.10和36.00度处有衍射峰。
进一步地，本申请的式I化合物的A型结晶的使用Cu Kα辐射的粉末X-射线衍射图谱中，衍射峰的峰位置及相对强度由下表1表示：
表1 A型结晶的X射线粉末衍射图谱的衍射峰的峰位置及相对强度
编号 2θ(度) 相对强度(I/I 0) 编号 2θ(度) 相对强度(I/I 0)
1 9.25 19.1 18 21.43 99.9
2 9.64 5.6 19 21.79 15.0
3 10.45 40.2 20 22.53 29.9
4 11.27 6.1 21 23.43 21.4
5 12.48 4.5 22 24.25 6.0
6 13.38 100 23 24.87 42.5
7 14.03 23.1 24 25.47 16.7
8 15.71 50.6 25 26.54 9.5
9 16.47 73.9 26 26.76 11.2
10 17.20 34.2 27 27.78 4.7
11 17.85 25.4 28 29.07 12.1
12 18.16 29.7 29 30.51 4.4
13 18.48 45.3 30 31.99 2.3
14 18.85 12.1 31 33.01 2.5
15 19.80 53.4 32 34.65 4.6
16 20.15 76.8 33 35.10 3.9
17 20.86 65.1 34 36.00 3.9
在一具体实施方案中，本申请的式I化合物的A型结晶的XRPD图谱如图1所示。
非限制性地，本申请的式I化合物的A型结晶的差示扫描量热(DSC)在约177.50℃处有吸热峰，具体而言，式I化合物的A型结晶的差示扫描量热(DSC)图谱如图2所示。
非限制性地，本申请的式I化合物的A型结晶的热重分析(TGA)图谱如图3所示。
另一方面，本申请提供了式I化合物的B型结晶，其使用Cu Kα辐射的X-射线粉末衍射图中，以2θ角度表示在约7.44、8.93、10.44和17.84度处有衍射峰，优选在约7.44、8.93、10.26、10.44、10.70、11.17、12.65、12.96、14.35、15.49、16.34、17.84、18.28、18.73、20.96、21.88、22.42、23.03、24.17、25.27和26.16度处有衍射峰，最优选在约7.44、8.93、9.48、10.26、10.44、10.70、11.17、11.85、12.65、12.96、13.57、14.35、15.49、15.75、16.34、17.84、18.28、18.73、19.43、20.02、20.65、20.96、21.88、22.42、23.03、24.17、25.27、25.99、26.16和29.24度处有衍射峰。
进一步地，本申请的式I化合物的B型结晶的使用Cu Kα辐射的粉末X-射线衍射图谱中，衍射峰的峰位置及相对强度由表2表示：
表2 B型结晶的X射线粉末衍射图谱的衍射峰的峰位置及相对强度
编号 2θ(度) 相对强度(I/I 0) 编号 2θ(度) 相对强度(I/I 0)
1 7.44 100.0 16 17.84 49.2
2 8.93 26.6 17 18.28 17.4
3 9.48 3.0 18 18.73 19.4
4 10.26 22.8 19 19.43 5.3
5 10.44 31.0 20 20.02 5.0
6 10.70 17.3 21 20.65 4.5
7 11.17 8.4 22 20.96 12.8
8 11.85 3.9 23 21.88 163
9 12.65 5.8 24 22.42 7.7
10 12.96 18.6 25 23.03 11.9
11 13.57 5.0 26 24.17 6.9
12 14.35 13.5 27 25.27 8.8
13 15.49 8.7 28 25.99 6.8
14 15.75 3.9 29 26.16 10.8
15 16.34 21.8 30 29.24 5.9
在一具体实施方案中，本申请的式I化合物的B型结晶的XRPD图谱如图4所示。
非限制性地，本申请的式I化合物的B型结晶的差示扫描量热(DSC)在约125.70℃和174.07℃处有吸热峰，具体而言，式I化合物的B型结晶的差示扫描量热(DSC)图谱如图5所示。
非限制性地，本申请的式I化合物的B型结晶的热重分析(TGA)图谱如图6所示。
另一方面，本申请提供了式I化合物的C型结晶，其使用Cu Kα辐射的X-射线粉末衍射图中，以2θ角度表示在约7.38、10.33和17.84度处有衍射峰，优选在约7.38、8.80、10.33、11.15、15.30、17.84、18.18、19.76、21.03和21.86度处有衍射峰，最优选在约7.38、8.80、10.33、11.15、11.71、12.33、12.58、12.88、13.50、14.28、15.30、16.04、16.33、16.55、17.84、18.18、18.43、19.76、21.03、21.86、22.83、25.34和25.86度处有衍射峰。
进一步地，本申请的式I化合物的C型结晶的使用Cu Kα辐射的粉末X-射线衍射图谱中，衍射峰的峰位置及相对强度由表3表示：
表3 C型结晶的X射线粉末衍射图谱的衍射峰的峰位置及相对强度
编号 2θ(度) 相对强度(I/I 0) 编号 2θ(度) 相对强度(I/I 0)
1 7.38 100 13 16.33 6.9
2 8.80 18.5 14 16.55 7.8
3 10.33 37.3 15 17.84 34.1
4 11.15 11.9 16 18.18 19.7
5 11.71 2.9 17 18.43 9.0
6 12.33 10.6 18 19.76 15.3
7 12.58 6.5 19 21.03 16.2
8 12.88 8.5 20 21.86 22.5
9 13.50 5.4 21 22.83 2.8
10 14.28 7.4 22 25.34 5.3
11 15.30 24.9 23 25.86 4.6
12 16.04 7.5
在一具体实施方案中，本申请的式I化合物的C型结晶的XRPD图谱如图7所示。
在本申请的一些实施方案中，在式I化合物的C型结晶中，式I化合物以式I化合物二氧六环合物的形式存在；具体地，所述式I化合物二氧六环合物中，式I化合物与二氧六环的摩尔比为1～10:1，优选为2～8:1，更优选为2～3:1，最优选约为2.33:1。
非限制性地，本申请的式I化合物的C型结晶的差示扫描量热(DSC)在约174.16℃处有吸热峰，具体而言，式I化合物的C型结晶的差示扫描量热(DSC)图谱如图8所示。
非限制性地，本申请的式I化合物的C型结晶的热重分析(TGA)图谱如图9所示。
再一方面，本申请提供了式I化合物的D型结晶，其使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约7.44、13.38、16.43、20.14、20.88和21.45度处有衍射峰，优选在约7.07、7.44、8.92、9.23、10.46、13.38、14.06、15.76、16.43、17.21、17.84、18.17、18.47、19.82、20.14、20.88、21.45、21.82、22.49、23.44、24.87、25.44和29.09度处有衍射峰，最优选在约7.07、7.44、8.05、8.92、9.23、9.64、10.46、11.24、12.63、13.38、14.06、15.76、16.43、17.21、17.84、18.17、18.47、18.77、19.82、20.14、20.88、21.45、21.82、22.49、23.44、24.26、24.87、25.44、26.06、26.48、26.80、29.09、33.00、34.64和36.02度处有衍射峰。
进一步地，本申请的式I化合物的D型结晶的使用Cu Kα辐射的粉末X-射线衍射图谱中，衍射峰的峰位置及相对强度由表4表示：
表4 D型结晶的X射线粉末衍射图谱的衍射峰的峰位置及相对强度
编号 2θ(度) 相对强度(I/I 0) 编号 2θ(度) 相对强度(I/I 0)
1 7.07 26.0 19 19.82 32.7
2 7.44 61.7 20 20.14 83.9
3 8.05 5.8 21 20.88 68.5
4 8.92 11.9 22 21.45 100.0
5 9.23 12.6 23 21.82 19.6
6 9.64 8.5 24 22.49 26.7
7 10.46 40.4 25 23.44 22.1
8 11.24 11.3 26 24.26 8.0
9 12.63 5.6 27 24.87 46.0
10 13.38 84.4 28 25.44 15.7
11 14.06 16.6 29 26.06 6.0
12 15.76 29.2 30 26.48 7.5
13 16.43 49.4 31 26.80 7.1
14 17.21 36.2 32 29.09 24.0
15 17.84 39.7 33 33.00 4.3
16 18.17 27.8 34 34.64 5.7
17 18.47 35.0 35 36.02 4.5
18 18.77 8.5
在一具体实施方案中，本申请的式I化合物的D型结晶的XRPD图谱如图10所示。
非限制性地，本申请的式I化合物的D型结晶的差示扫描量热(DSC)在约176.14℃处有吸热峰，具体而言，式I化合物的D型结晶的差示扫描量热(DSC)图谱如图11所示。
非限制性地，本申请的式I化合物的D型结晶的热重分析(TGA)图谱如图12所示。
再一方面，本申请提供了式I化合物的E型结晶，其使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约4.51、6.64和10.66度处有衍射峰，优选在约4.51、6.64、9.03、9.64、10.66、16.69和17.12度处有衍射峰，更优选在约4.51、6.64、9.03、9.64、10.66、13.26、13.59、15.20、15.85、16.69、17.12、19.33、20.49、22.12和22.50度处有衍射峰，最优选在约4.51、6.64、9.03、9.64、10.66、13.26、13.59、14.40、15.20、15.85、16.69、17.12、17.36、18.10、19.33、20.49、21.38、22.12和22.50度处有衍射峰。
进一步地，本申请的式I化合物的E型结晶的使用Cu Kα辐射的粉末X-射线衍射图谱中，衍射峰的峰位置及相对强度由表5表示：
表5 E型结晶的X射线粉末衍射图谱的衍射峰的峰位置及相对强度
编号 2θ(度) 相对强度(I/I 0) 编号 2θ(度) 相对强度(I/I 0)
1 4.51 55.6 11 16.69 53.9
2 6.64 68.8 12 17.12 44.9
3 9.03 48.7 13 17.36 17.6
4 9.64 44.7 14 18.10 9.4
5 10.66 100.0 15 19.33 12.2
6 13.26 25.3 16 20.49 12.1
7 13.59 19.6 17 21.38 8.7
8 14.40 9.3 18 22.12 24.7
9 15.20 12.1 19 22.50 16.2
10 15.85 15.8
在一具体实施方案中，本申请的式I化合物的E型结晶的XRPD图谱如图13所示。
非限制性地，本申请的式I化合物的E型结晶的差示扫描量热(DSC)在约136.34℃处有吸热峰，具体而言，式I化合物的E型结晶的差示扫描量热(DSC)图谱如图14所示。
非限制性地，本申请的式I化合物的E型结晶的热重分析(TGA)图谱如图15所示。
本申请中，X-射线粉末衍射光谱测定的仪器型号为Bruker D2 X射线衍射仪，条件及方法：30kv 10mA，狭缝：0.6/3/Ni/8，2theta：4-40°,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：30-300℃范围内10℃/min升温。
本申请中，TGA光谱测定的仪器型号为PerKinElmerPyris 1型热重分析仪，条件及方法：25-700℃范围内20℃/min升温，。
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峰或熔点时，这是指该DSC峰或熔点±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峰或熔点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I化合物的A型结晶的制备方法，所述方法包括如下步骤：
(1)将式I化合物和溶剂A混合，得到式I化合物的溶液；
(2)析出固体；
其中所述步骤(1)中的溶剂A选自甲苯、丁酮、乙腈、乙腈和水的混合溶剂或者乙酸乙酯，优选为甲苯。
在本申请的一些实施方式中，溶剂A选自乙腈和水的混合溶剂，其中所述混合溶剂中乙腈的体积分数为65％-95％。
在本申请的一些实施方式中，以式I化合物为1g计，则溶剂A的体积为1-50mL，优选为2-15mL。
在本申请的一些实施方式中，以式I化合物为1g计，则溶剂A的体积为5mL。
在本申请的一些实施方式中，所述步骤(1)在0℃至混合后溶剂***的沸点的温度范围内进行，优选步骤(1)在混合后溶剂***的沸点温度下进行。
在本申请的一些实施方式中，所述步骤(2)在静置、振摇或搅拌状态下析出固体，优选为在搅拌下进行步骤(2)。可以在室温下进行步骤(2)。
在本申请的一些实施方式中，所述A型结晶的制备方法还包括将步骤(2)析出的固体进行分离，例如通过过滤进行分离；在本申请的一些实施方式中，还包括将分离的固体进行干燥，所述干燥温度可以是60℃。
又一方面，本申请提供式I化合物的B型结晶的制备方法，所述方法包括如下步骤：
(1)将式I化合物和溶剂B混合，得到式I化合物的溶液；
(2)析出固体；
其中所述步骤(1)中的溶剂B选自甲醇、乙醇、丙酮、甲醇和水的混合溶剂、乙醇和水的混合溶剂、丙酮和水的混合溶剂或者乙醇和丁酮的混合溶剂，优选为乙醇；其中所述甲醇和水的混合溶剂中甲醇的体积分数为95％；其中所述乙醇和水的混合溶剂中乙醇的体积分数为65％-95％；其中所述丙酮和水的混合溶剂中丙酮的体积分数为65％-95％；其中所述乙醇和丁酮的混合溶剂中丁酮的体积分数为不超过30％。
在本申请的一些实施方式中，以式I化合物为1g计，则溶剂B的体积为1-50mL，优选为5-20mL。
在本申请的一些具体实施方式中，以式I化合物为1g计，则溶剂B的体积为8.75mL。
在本申请的一些实施方式中，所述步骤(1)在0℃至混合后溶剂***的沸点的温度范围内进行，优选步骤(1)在混合后溶剂***的沸点温度下进行。
在本申请的一些实施方式中，所述步骤(2)在静置、振摇或搅拌状态下析出固体，优选为在搅拌下进行步骤(2)。可以在室温下进行步骤(2)。
在本申请的一些实施方式中，所述B型结晶的制备方法还包括将步骤(2)析出的固体进行分离，例如通过过滤进行分离；在本申请的一些实施方式中，还包括将分离的固体进行干燥，所述干燥温度可以是60℃；所述干燥可以在减压条件下进行。
再一方面，本申请提供式I化合物的C型结晶的制备方法，所述方法包括如下步骤：
(1)将式I化合物和溶剂C混合，得到式I化合物的溶液；
(2)析出固体；
其中所述步骤(1)中的溶剂C为二氧六环。
在本申请的一些实施方式中，以式I化合物为1g计，则溶剂C的体积为1-100mL，优选为5-20mL。
在本申请的一些具体实施方式中，以式I化合物为1g计，则溶剂C的体积为7.5mL。
在本申请的一些实施方式中，所述步骤(1)在0℃至混合后溶剂***的沸点的温度范围内进行，优选步骤(1)在混合后溶剂***的沸点温度下进行。
在本申请的一些实施方式中，所述步骤(2)在静置、振摇或搅拌状态下析出固体，优选为在搅拌下进行步骤(2)。可以在室温下进行步骤(2)。
在本申请的一些实施方式中，所述C型结晶的制备方法还包括将步骤(2)析出的固体进行分离，例如通过过滤进行分离；在本申请的一些实施方式中，还包括将分离的固体进行干燥，所述干燥温度可以是60℃。
再一方面，本申请提供式I化合物的D型结晶的制备方法，所述方法包括如下步骤：
(1)将式I化合物和溶剂D混合，得到式I化合物的溶液；
(2)析出固体；
其中所述步骤(1)中的溶剂D为乙醇和水的混合溶剂；其中所述乙醇和水的混合溶剂中乙醇的体积分数为55％。
在本申请的一些实施方式中，以式I化合物为1g计，则溶剂D的体积为1-50mL，优选为5-20mL。
在本申请的一些具体实施方式中，以式I化合物为1g计，则溶剂D的体积为10mL。
在本申请的一些实施方式中，所述步骤(1)在0℃至混合后溶剂***的沸点的温度范围内进行，优选步骤(1)在混合后溶剂***的沸点温度下进行。
在本申请的一些实施方式中，所述步骤(2)在静置、振摇或搅拌状态下析出固体的状态，优选为在搅拌下进行步骤(2)。可以在室温下进行步骤(2)。
在本申请的一些实施方式中，所述D型结晶的制备方法还包括将步骤(2)析出的固体进 行分离，例如通过过滤进行分离；在本申请的一些实施方式中，还包括将分离的固体进行干燥，所述干燥温度可以是45℃；所述干燥可以在减压条件下进行。
再一方面，本申请提供式I化合物的E型结晶的制备方法，所述方法包括如下步骤：
(1)将式I化合物和溶剂E混合，得到式I化合物的溶液；
(2)析出固体；
其中所述步骤(1)中的溶剂E为甲醇和水的混合溶剂；其中所述甲醇和水的混合溶剂中甲醇的体积分数为75％-85％。
在本申请的一些实施方式中，以式I化合物为1g计，则溶剂E的体积为1-50mL，最优选为5-20mL。
在本申请的一些具体实施方式中，以式I化合物为1g计，则溶剂E的体积为10mL。
在本申请的一些实施方式中，所述步骤(1)在0℃至混合后溶剂***的沸点的温度范围内进行，优选步骤(1)在混合后溶剂***的沸点温度下进行。
在本申请的一些实施方式中，所述步骤(2)在静置、振摇或搅拌状态下析出固体，优选为在搅拌下进行步骤(2)。可以在室温下进行步骤(2)。
在本申请的一些实施方式中，所述E型结晶的制备方法还包括将步骤(2)析出的固体进行分离，例如通过过滤进行分离；在本申请的一些实施方式中，还包括将分离的固体进行干燥。
又一方面，本申请提供包含所述式I化合物的结晶的结晶组合物，其中，所述式I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，其中所述的式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
再一方面，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化合物的结晶、或上述结晶组合物，其中所述的式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。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。
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。
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、***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。
还一方面，本申请提供了式I化合物的结晶、或上述结晶组合物、或上述药物组合物在制备用于治疗和/或预防c-Met激酶介导的疾病的药物中的用途，其中所述的式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
还一方面，本申请提供了式I化合物的结晶、或上述结晶组合物、或上述药物组合物在治疗和/或预防c-Met激酶介导的疾病中的用途，其中所述的式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
还一方面，本申请提供了治疗c-Met激酶介导的疾病的方法，所述方法包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式I化合物的结晶、或上述结晶组合物、或上述药物组合物，其中所述的式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
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。
还一方面，本申请提供了预防或者治疗c-Met激酶介导的疾病的式I化合物的结晶、或上述结晶组合物、或上述药物组合物，其中所述的式I化合物的结晶为式I化合物的A型结晶、式I化合物的B型结晶、式I化合物的C型结晶、式I化合物的D型结晶或式I化合物的E型结晶，或它们的混合物。
在本申请的一些实施方案中，上述c-Met激酶介导的疾病为癌症，例如肺癌。
以下结合附图及实施例详细说明本申请的技术方案，但本申请的保护范围包括但是不限于此。本申请的式I化合物参照WO2012034055公开的方法进行制备。
实施例1式I化合物A型结晶的制备
取20g的式I化合物溶于甲苯(100mL)中，回流溶清后，过滤，滤液室温搅拌析晶，过滤，60℃常压鼓风干燥，得A型结晶，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，热重分析(TGA)图如图3所示。
实施例2式I化合物B型结晶的制备
取20g的式I化合物溶于乙醇(175mL)中，回流溶清后，过滤，滤液室温搅拌析晶，过滤，60℃减压干燥，得B型结晶，其使用Cu Kα辐射的X-射线粉末衍图如图4所示，差示扫描量热(DSC)图如图5所示，热重分析(TGA)图如图6所示。
实施例3式I化合物C型结晶的制备
取20g的式I化合物溶于二氧六环(150mL)中，回流溶清后，过滤，滤液室温搅拌析晶，过滤，60℃常压鼓风干燥，得C型结晶，其使用Cu Kα辐射的X-射线粉末衍图如图7所示，差示扫描量热(DSC)图如图8所示，热重分析(TGA)图如图9所示。
实施例4式I化合物D型结晶的制备
取20g的式I化合物溶于55％乙醇水溶液(200mL)中，回流至恰好溶清后，过滤，滤液室温搅拌析晶，过滤，45℃减压干燥，得D型结晶，其使用Cu Kα辐射的X-射线粉末衍图如图10所示，差示扫描量热(DSC)图如图11所示，热重分析(TGA)图如图12所示。
实施例5式I化合物E型结晶的制备
取20g的式I化合物溶于85％甲醇水溶液(200mL)中，回流溶清后，过滤，滤液室温搅拌析晶，过滤，室温放置10天，得E型结晶，其使用Cu Kα辐射的X-射线粉末衍图如图13所示，差示扫描量热(DSC)图如图14所示，热重分析(TGA)图如图15所示。
实施例6引湿性实验
取式I化合物的A型结晶、B型结晶、D型结晶以及E型结晶，按照《中国药典》2015年版第四部通则9103的《药物引湿性试验指导原则》进行试验，分别计算样品引湿增重，结果如表6所示。
表6 引湿性试验结果
化合物 引湿增重(％)
实施例1 小于0.2
实施例2 小于0.2
实施例4 小于0.2
实施例5 小于0.2
实施例7固有溶出速率测定
取式I化合物的A型结晶、B型结晶、D型结晶以及E型结晶各约80mg，高压下直接压制成片(片芯直径4mm，压力150kg，维持时间2min，重复三次)。取700ml的0.01mol/L盐酸溶液作为介质，测定原料药的固有溶出速率。结果见表7。
表7 式I化合物固有溶出速率
Figure PCTCN2019076683-appb-000003
实施例8大鼠药代动力学试验
1.1试验目的
SD大鼠灌胃式I化合物的A型结晶、B型结晶、D型结晶和E型结晶后体内式I化合物的相对生物利用度评价。
1.2试验材料
SD大鼠：购自上海西普尔必凯实验动物有限公司
受试样品：式I化合物的A型结晶、B型结晶、D型结晶和E型结晶，分别填充于9号灌胃胶囊
1.3试验方法
a)分组给药
SD大鼠，体重180～200g，适应3-5天后，随机分为4组，每组4只，按20mg/kg剂量分别灌胃给予式I化合物的A型结晶、B型结晶、D型结晶和E型结晶。大鼠给药前禁食12h，给药后4h给食物，实验前后和实验过程中均自由饮水。
b)取样
给药后采集时间点为0.167h(10min)、0.5h、1h、2h、4h、6h、8h、10h、24h，分别于眼眶静脉丛采血约0.3mL置于含EDTA-K2离心管中，4℃保存，于1h内在4℃，4000rpm，10min条件下离心，-20℃保存待测。
吸取50μL待测血浆样品，加入300μL含内标的乙腈溶液，振荡混匀5min，13000rpm离心10min，取上清30μL，加入150μL50％乙腈水溶液，吸取1μL用于LC/MS/MS分析测定。
c)检测方法
利用液相色谱-串联质谱法(LC-MS/MS)，使用***作为内标(IS)，采用蛋白沉淀法从血浆中提取待测物和内标，采用反相色谱柱来分离化合物和内标，使用串联四极杆质谱仪的电喷雾离子化方式(ESI)对分析物进行定量分析。
表8 色谱检测条件
Figure PCTCN2019076683-appb-000004
表9 化合物及内标(式I化合物及***)的质谱检测条件
Figure PCTCN2019076683-appb-000005
Figure PCTCN2019076683-appb-000006
表10 母离子、碎片离子、碰撞电压和碰撞能量(CE)
Figure PCTCN2019076683-appb-000007
1.4试验结果
表11 受试化合物药代动力学参数
Figure PCTCN2019076683-appb-000008

Claims (15)

  1. 式I化合物的A型结晶，
    Figure PCTCN2019076683-appb-100001
    所述A型结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约13.38、15.71、16.47、20.15、20.86和21.43度处有衍射峰；优选在约9.25、10.45、13.38、14.03、15.71、16.47、17.20、17.85、18.16、18.48、19.80、20.15、20.86、21.43、22.53、23.43和24.87度处有衍射峰；更优选在约9.25、10.45、12.48、13.38、14.03、15.71、16.47、17.20、17.85、18.16、18.48、18.85、19.80、20.15、20.86、21.43、21.79、22.53、23.43、24.87、25.47和29.07度处有衍射峰；最优选在约9.25、9.64、10.45、11.27、12.48、13.38、14.03、15.71、16.47、17.20、17.85、18.16、18.48、18.85、19.80、20.15、20.86、21.43、21.79、22.53、23.43、24.25、24.87、25.47、26.54、26.76、27.78、29.07、30.51、31.99、33.01、34.65、35.10和36.00度处有衍射峰。
  2. 权利要求1所述的A型结晶的制备方法，所述方法包括如下步骤：
    (1)将式I化合物和溶剂A混合，得到式I化合物的溶液；
    (2)析出固体；
    其中所述步骤(1)中的溶剂A选自甲苯、丁酮、乙腈、乙腈和水的混合溶剂或者乙酸乙酯，优选甲苯。
  3. 式I化合物的B型结晶，
    Figure PCTCN2019076683-appb-100002
    所述B型结晶的使用Cu Kα辐射的X-射线粉末衍射图中，以2θ角度表示在约7.44、8.93、10.44和17.84度处有衍射峰；优选在约7.44、8.93、10.26、10.44、10.70、11.17、12.65、12.96、14.35、15.49、16.34、17.84、18.28、18.73、20.96、21.88、22.42、23.03、24.17、25.27和26.16度处有衍射峰；最优选在约7.44、8.93、9.48、10.26、10.44、10.70、11.17、11.85、12.65、12.96、13.57、14.35、15.49、15.75、16.34、17.84、18.28、18.73、19.43、20.02、20.65、20.96、21.88、22.42、23.03、24.17、25.27、25.99、26.16和29.24度处有衍射峰。
  4. 权利要求3所述的B型结晶的制备方法，所述方法包括如下步骤：
    (1)将式I化合物和溶剂B混合，得到式I化合物的溶液；
    (2)析出固体；
    其中所述步骤(1)中的溶剂B选自甲醇、乙醇、丙酮、甲醇和水的混合溶剂、乙醇 和水的混合溶剂、丙酮和水的混合溶剂或者乙醇和丁酮的混合溶剂，优选乙醇；其中所述甲醇和水的混合溶剂中甲醇的体积分数为95％；其中所述乙醇和水的混合溶剂中乙醇的体积分数为65％-95％；其中所述丙酮和水的混合溶剂中丙酮的体积分数为65％-95％；其中所述乙醇和丁酮的混合溶剂中丁酮的体积分数为不超过30％。
  5. 式I化合物的C型结晶，
    Figure PCTCN2019076683-appb-100003
    所述C型结晶的使用Cu Kα辐射的X-射线粉末衍射图中，以2θ角度表示在约7.38、10.33和17.84度处有衍射峰；优选在约7.38、8.80、10.33、11.15、15.30、17.84、18.18、19.76、21.03和21.86度处有衍射峰；最优选在约7.38、8.80、10.33、11.15、11.71、12.33、12.58、12.88、13.50、14.28、15.30、16.04、16.33、16.55、17.84、18.18、18.43、19.76、21.03、21.86、22.83、25.34和25.86度处有衍射峰。
  6. 权利要求5所述的C型结晶的制备方法，所述方法包括如下步骤：
    (1)将式I化合物和溶剂C混合，得到式I化合物的溶液；
    (2)析出固体；
    其中所述步骤(1)中的溶剂C为二氧六环。
  7. 式I化合物的D型结晶，
    Figure PCTCN2019076683-appb-100004
    所述D型结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约7.44、13.38、16.43、20.14、20.88和21.45度处有衍射峰；优选在约7.07、7.44、8.92、9.23、10.46、13.38、14.06、15.76、16.43、17.21、17.84、18.17、18.47、19.82、20.14、20.88、21.45、21.82、22.49、23.44、24.87、25.44和29.09度处有衍射峰；最优选在7.07、7.44、8.05、8.92、9.23、9.64、10.46、11.24、12.63、13.38、14.06、15.76、16.43、17.21、17.84、18.17、18.47、18.77、19.82、20.14、20.88、21.45、21.82、22.49、23.44、24.26、24.87、25.44、26.06、26.48、26.80、29.09、33.00、34.64和36.02度处有衍射峰。
  8. 权利要求7所述的D型结晶的制备方法，所述方法包括如下步骤：
    (1)将式I化合物和溶剂D混合，得到式I化合物的溶液；
    (2)析出固体；
    其中所述步骤(1)中的溶剂D为乙醇和水的混合溶剂；其中所述乙醇和水的混合溶剂中乙醇的体积分数为55％。
  9. 式I化合物的E型结晶，
    Figure PCTCN2019076683-appb-100005
    所述E型结晶的使用Cu Kα辐射的X-射线粉末衍射图谱中，以2θ角度表示在约4.51、6.64和10.66度处有衍射峰；优选在约4.51、6.64、9.03、9.64、10.66、16.69和17.12度处有衍射峰；更优选在约4.51、6.64、9.03、9.64、10.66、13.26、13.59、15.20、15.85、16.69、17.12、19.33、20.49、22.12和22.50度处有衍射峰；最优选在约4.51、6.64、9.03、9.64、10.66、13.26、13.59、14.40、15.20、15.85、16.69、17.12、17.36、18.10、19.33、20.49、21.38、22.12和22.50度处有衍射峰。
  10. 权利要求9所述的E型结晶的制备方法，所述方法包括如下步骤：
    (1)将式I化合物和溶剂E混合，得到式I化合物的溶液；
    (2)析出固体；
    其中所述步骤(1)中的溶剂E为甲醇和水的混合溶剂；其中所述甲醇和水的混合溶剂中甲醇的体积分数为75％-85％。
  11. 包含式I化合物的结晶的结晶组合物，
    Figure PCTCN2019076683-appb-100006
    其中所述式I化合物的结晶占所述结晶组合物重量的50％以上，较好是80％以上，更好是90％以上，最好是95％以上，并且所述式I化合物的结晶为权利要求1所述的式I化合物的A型结晶、权利要求3所述的式I化合物的B型结晶、权利要求5所述的式I化合物的C型结晶、权利要求7所述的式I化合物的D型结晶或权利要求9所述的式I化合物的E型结晶，或它们的混合物。
  12. 药物组合物，其包含治疗有效量的式I化合物的结晶或者权利要求11所述的结晶组合物，
    Figure PCTCN2019076683-appb-100007
    其中所述式I化合物的结晶为权利要求1所述的式I化合物的A型结晶、权利要求3所述的式I化合物的B型结晶、权利要求5所述的式I化合物的C型结晶、权利要求7所述的式I化合物的D型结晶或权利要求9所述的式I化合物的E型结晶，或它们的混合物。
  13. 式I化合物的结晶或权利要求11所述的结晶组合物或权利要求12所述的药物组合物在制备用于治疗和/或预防c-Met激酶介导的疾病的药物中的用途，
    Figure PCTCN2019076683-appb-100008
    其中所述式I化合物的结晶为权利要求1所述的式I化合物的A型结晶、权利要求3所述的式I化合物的B型结晶、权利要求5所述的式I化合物的C型结晶、权利要求7所述的式I化合物的D型结晶或权利要求9所述的式I化合物的E型结晶，或它们的混合物；优选地，其中c-Met激酶介导的疾病为癌症；更优选地，其中c-Met激酶介导的疾病为肺癌。
  14. 治疗c-Met激酶介导的疾病的方法，所述方法包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式I化合物的结晶或权利要求11所述的结晶组合物或权利要求12所述的药物组合物，
    Figure PCTCN2019076683-appb-100009
    其中所述式I化合物的结晶为权利要求1所述的式I化合物的A型结晶、权利要求3所述的式I化合物的B型结晶、权利要求5所述的式I化合物的C型结晶、权利要求7所述的式I化合物的D型结晶或权利要求9所述的式I化合物的E型结晶，或它们的混合物；优选地，其中c-Met激酶介导的疾病为癌症；更优选地，其中c-Met激酶介导的疾病为肺癌。
  15. 用于预防和/或治疗c-Met激酶介导的疾病的式I化合物的结晶或权利要求11所述的结晶组合物或权利要求12所述的药物组合物，
    Figure PCTCN2019076683-appb-100010
    其中所述式I化合物的结晶为权利要求1所述的式I化合物的A型结晶、权利要求3所述的式I化合物的B型结晶、权利要求5所述的式I化合物的C型结晶、权利要求7所述的式I化合物的D型结晶或权利要求9所述的式I化合物的E型结晶，或它们的混合物；优选地，其中c-Met激酶介导的疾病为癌症；更优选地，其中c-Met激酶介导的疾病为肺癌。
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