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WO2016015653A1 - C-Met抑制剂结晶型游离碱或其结晶型酸式盐及其制备方法和应用 - Google Patents

C-Met抑制剂结晶型游离碱或其结晶型酸式盐及其制备方法和应用 Download PDF

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WO2016015653A1
WO2016015653A1 PCT/CN2015/085514 CN2015085514W WO2016015653A1 WO 2016015653 A1 WO2016015653 A1 WO 2016015653A1 CN 2015085514 W CN2015085514 W CN 2015085514W WO 2016015653 A1 WO2016015653 A1 WO 2016015653A1
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peak
methyl
diffraction
diffraction pattern
salt
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PCT/CN2015/085514
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English (en)
French (fr)
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李响
张磊
孙启明
吕爱锋
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江苏豪森药业股份有限公司
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Priority to KR1020177002561A priority Critical patent/KR102516745B1/ko
Priority to AU2015296117A priority patent/AU2015296117B2/en
Priority to BR112017001517-0A priority patent/BR112017001517B1/pt
Priority to CN201580025022.6A priority patent/CN106459091B/zh
Priority to CA2955547A priority patent/CA2955547C/en
Priority to JP2017501269A priority patent/JP6537591B2/ja
Priority to US15/328,795 priority patent/US10208065B2/en
Priority to EP15827529.7A priority patent/EP3176173B1/en
Publication of WO2016015653A1 publication Critical patent/WO2016015653A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous 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
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicines, and particularly relates to a C-Met inhibitor crystalline free base or a crystalline acid salt thereof, and a preparation method and application thereof.
  • the hepatocyte growth factor (HGF) receptor also known as C-Met
  • C-Met is a tyrosine kinase receptor. Abnormal activation of C-Met is associated with poor prognosis of cancer, and there is a problem of overexpression of C-Met.
  • C-Met abnormalities are also found in many types of tumors, such as liver cancer HCC, non-small cell lung cancer NSCLC, bladder cancer, liver cancer, kidney cancer, stomach cancer, breast cancer, squamous cell carcinoma, brain cancer, stomach cancer, colon cancer and the like.
  • C-Met abnormalities can be expressed as increased expression, gene amplification, gene mutation, or increased expression of HGF.
  • C-Met can be in an abnormal state of being activated, resulting in canceration and poor prognosis.
  • C-Met can cause tumor growth and new blood vessel formation (angiogenesis, which can provide nutrition for tumors) after abnormal activation, and help spread cancer to other organs (metastasis). Therefore, inhibition of C-Met signaling pathway is one of the important strategies for treating tumors.
  • Jiangsu Haosen Company describes a pharmacologically active C-Met inhibitor in the patent CN201310173581.4 and its PCT application (PCT/CN2014/072825), one of which is 9-((8-fluoro-6-(1-A) -1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)-4-methyl-2H-[1,4 Oxazido[3,2-c]quinoline-3(4H)-one (abbreviated as "compound of formula I").
  • the compound of formula I is a potent C-Met/HGFR (hepatocyte growth factor receptor) kinase inhibitor, and as a C-Met tyrosine kinase inhibitor, the compound of formula I is effective in blocking the HGF/C-Met signaling pathway.
  • C-Met/HGFR hepatocyte growth factor receptor
  • C-Met tyrosine kinase inhibitor the compound of formula I is effective in blocking the HGF/C-Met signaling pathway.
  • abnormal cell growth such as cancer
  • PCT/CN2014/072825 PCT/CN2014/072825
  • the amorphous form of a drug is an aggregate of drug molecules in a disordered state, and does not contain a distinct crystal lattice, has a higher thermodynamic state than a crystalline state, resulting in thermodynamic instability, and this thermodynamic Instability, will bring poor chemical stability, easy to absorb moisture and solid phase The shift has made the quality of the drug extremely unstable. Therefore, in drug development, amorphous form is difficult to use for drug development; in addition, in the preparation of drugs, the crystallization process of drugs is also an effective means of drug purification, and the resulting crystalline state also leads to easy further purification and easy The advantages of process operation such as filtration and drug drying.
  • the compound of the formula I discloses its amorphous free base in the patent CN 201310173581.4 and its PCT application (PCT/CN2014/072825), which has a low solubility in various solvents and is not conducive to dissolution of the drug in animals or humans. Therefore, it has become a very urgent task to develop a suitable salt-type compound to increase the dissolution rate and solubility of the compound of formula I.
  • the present invention provides 9-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[ 4,3-a]pyridin-3-yl)thio)-4-methyl-2H-[1,4]oxabi[3,2-c]quinolin-3(4H)-one ( Compounds of formula I) crystalline free bases, crystalline acid salts, and processes for their preparation and use.
  • the physicochemical properties of the compounds of formula I such as solubility, hygroscopicity and chemical stability, are greatly improved by in-depth study of different aggregation states.
  • One aspect of the invention provides a crystalline 9-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a Pyridin-3-yl)thio)-4-methyl-2H-[1,4]oxabi[3,2-c]quinoline-3(4H)-one (compound of formula I) free Alkali.
  • the free base polymorph contains a total of four crystal forms, which are designated as Form I, Form II, Form III, and Form IV, respectively.
  • the present invention provides a free base form I of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 13.0 ⁇ 0.2 °, 17.9 ⁇ 0.2 °, 21.2 ⁇ 0.2 ° and 31.4 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 15.7 ⁇ 0.2 °, 17.7 ⁇ 0.2 °, 26.8 ⁇ 0.2 °, 28.0 ⁇ 0.2 °, 31.7 ⁇ 0.2 °, and 32.8 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 1, and the X-ray powder diffraction data is as shown in Table 1:
  • the present invention provides a free base form II of a compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 8.6 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 14.1 ⁇ 0.2 ° and 19.8 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 5.8 ⁇ 0.2 °, 7.4 ⁇ 0.2 °, 20.9 ⁇ 0.2 °, 30.9 ⁇ 0.2 °, 31.4 ⁇ 0.2 °, and 37.9 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 4, and the X-ray powder diffraction data is as shown in Table 2:
  • the present invention provides a free base form III of a compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 12.8 ⁇ 0.2 °, 14.8 ⁇ 0.2 °, 18.0 ⁇ 0.2 ° and 20.5 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) of 5.3 ⁇ 0.2 °, 5.9 ⁇ 0.2 °, 12.0 ⁇ 0.2 °, 14.0 ⁇ 0.2 °, 17.3 ⁇ 0.2 °, and 19.9 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 5, and the X-ray powder diffraction data is as shown in Table 3:
  • the invention provides a free base crystalline form IV of a compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 8.9 ⁇ 0.2 °, 12.6 ⁇ 0.2 °, 17.0 ⁇ 0.2 ° and 17.9 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 7, and the X-ray powder diffraction data is as shown in Table 4:
  • Another aspect of the invention provides a crystalline 9-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3- a] Pyridin-3-yl)thio)-4-methyl-2H-[1,4]oxabi[3,2-c]quinolin-3(4H)-one acid salt.
  • the acid salt comprises a mineral acid salt or an organic acid salt; preferably the inorganic acid salt is from a hydrochloride, a sulfate, a hydrobromide, a hydrofluoride, a hydroiodide or a phosphate, more preferably a salt.
  • An acid salt, a sulfate or a phosphate is preferably selected from the group consisting of 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, acetate, dichloroacetate, trichloro Acetate, acetoacetate, adipate, besylate, 4-chlorobenzenesulfonate, benzoate, 4-acetamidobenzoate, 4-aminobenzoate, Citrate, hexanoate, octoate, cinnamate, citrate, cyclohexane sulfamate, camphor sulfonate, aspartate, camphorate, gluconate, glucuron Acid salt, glutamate, isoascorbate, lactate, aspartate, malate, mandelate, pyroglutamate, tartrate, lauryl sulfate, dibenzoyl Tartrate, ethane-1,2-disul
  • the present invention provides a hydrochloride polymorph of the compound of formula I, comprising a crystalline form designated as Form I, having a powder X-ray diffraction pattern comprising 8.1 ⁇ 0.2°, 19.2 ⁇ 0.2°, 24.1 ⁇ 0.2° and 26.2 ⁇ A peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 8, and the X-ray powder diffraction data is as shown in Table 5:
  • the present invention provides a sulfate polymorph of the compound of formula I, comprising a total of two crystal forms, designated as Form I, Form II, respectively.
  • the present invention provides a sulfate form I of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 18.4 ⁇ 0.2 °, 19.7 ⁇ 0.2 °, 23.8 ⁇ 0.2 ° and 24.5 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 8.7 ⁇ 0.2 °, 13.2 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 26.3 ⁇ 0.2 °, 26.6 ⁇ 0.2 °, and 29.0 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 9, and the X-ray powder diffraction data is as shown in Table 6:
  • the present invention provides a sulfate form II of a compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 6.3 ⁇ 0.2 °, 8.7 ⁇ 0.2 °, 12.7 ⁇ 0.2 ° and 18.4 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 9.1 ⁇ 0.2 °, 15.9 ⁇ 0.2 °, 16.8 ⁇ 0.2 °, 24.0 ⁇ 0.2 °, 25.2 ⁇ 0.2 °, and 28.4 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 10, and the X-ray powder diffraction data is as shown in Table 7:
  • the present invention provides a phosphate polymorph of the compound of formula I, comprising a total of four crystal forms, designated as Form I, Form II, Form III, Form IV, respectively.
  • the present invention provides a crystalline form I of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 7.9 ⁇ 0.2 °, 12.8 ⁇ 0.2 °, 15.9 ⁇ 0.2 ° and 18.3 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 16.5 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, 20.6 ⁇ 0.2 °, 21.8 ⁇ 0.2 °, 26.2 ⁇ 0.2 °, and 27.4 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 11, and the X-ray powder diffraction data is as shown in Table 8:
  • the present invention provides a crystalline form II of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 13.7 ⁇ 0.2 °, 16.1 ⁇ 0.2 °, 22.8 ⁇ 0.2 ° and 26.1 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 6.8 ⁇ 0.2 °, 17.0 ⁇ 0.2 °, 22.2 ⁇ 0.2 °, 26.6 ⁇ 0.2 °, 27.9 ⁇ 0.2 °, and 31.2 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 12, and the X-ray powder diffraction data is as shown in Table 9:
  • the present invention provides a crystalline form III of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 9.7 ⁇ 0.2 °, 15.6 ⁇ 0.2 °, 16.8 ⁇ 0.2 ° and 24.6 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 5.2 ⁇ 0.2 °, 12.8 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 18.0 ⁇ 0.2 °, 20.1 ⁇ 0.2 °, and 23.5 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 13, and the X-ray powder diffraction data is as shown in Table 10:
  • the present invention provides a crystalline form IV of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 7.8 ⁇ 0.2 °, 17.9 ⁇ 0.2 °, 25.0 ⁇ 0.2 ° and 27.7 ⁇ 0.2 °.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 5.2 ⁇ 0.2 °, 12.8 ⁇ 0.2 °, 20.9 ⁇ 0.2 °, 21.7 ⁇ 0.2 °, 22.3 ⁇ 0.2 °, and 26.8 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 14, and the X-ray powder diffraction data is as shown in Table 11:
  • the present invention provides a polymorphic form of the mesylate salt of the compound of formula I, comprising a total of five crystal forms, designated as Form I, Form II, Form III, Form IV, Form V, respectively.
  • the present invention provides a crystalline form I of the methanesulfonate salt of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 theta) at 15.6 ⁇ 0.2 °, 17.0 ⁇ 0.2 °, 25.6 ⁇ 0.2 ° and 26.0 ⁇ 0.2 °. .
  • it also includes peaks at diffraction angles (2 ⁇ ) at 6.6 ⁇ 0.2 °, 15.3 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 18.3 ⁇ 0.2 °, 19.7 ⁇ 0.2 °, and 26.4 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 15, and the X-ray powder diffraction data is as shown in Table 12:
  • the present invention provides a crystalline form II of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 9.4 ⁇ 0.2 °, 17.0 ⁇ 0.2 °, 18.9 ⁇ 0.2 ° and 27.3 ⁇ 0.2 °. .
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 16, and the X-ray powder diffraction data is as shown in Table 13:
  • the present invention provides a crystalline form III of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 16.7 ⁇ 0.2 °, 19.3 ⁇ 0.2 °, 23.2 ⁇ 0.2 ° and 26.5 ⁇ 0.2 °. .
  • it also includes peaks at diffraction angles (2 ⁇ ) at 11.7 ⁇ 0.2 °, 13.6 ⁇ 0.2 °, 14.1 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, and 27.2 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 17, and the X-ray powder diffraction data is as shown in Table 14:
  • the present invention provides a crystalline form IV of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) of 16.8 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 19.3 ⁇ 0.2 ° and 22.1 ⁇ 0.2 °. .
  • it also includes peaks at diffraction angles (2 ⁇ ) at 8.7 ⁇ 0.2 °, 13.4 ⁇ 0.2 °, 13.6 ⁇ 0.2 °, 19.6 ⁇ 0.2 °, 21.6 ⁇ 0.2 °, and 26.6 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 19, and the X-ray powder diffraction data is as shown in Table 15:
  • the present invention provides a crystalline form V of the compound of formula I, the powder X-ray diffraction pattern comprising peaks at diffraction angles (2 ⁇ ) at 25.2 ⁇ 0.2 °, 9.3 ⁇ 0.2 °, 16.6 ⁇ 0.2 ° and 19.1 ⁇ 0.2 °. .
  • it also includes peaks at diffraction angles (2 ⁇ ) at 23.7 ⁇ 0.2 °, 20.0 ⁇ 0.2 °, 15.9 ⁇ 0.2 °, 24.6 ⁇ 0.2 °, 28.6 ⁇ 0.2 °, and 25.5 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 20, and the X-ray powder diffraction data is as shown in Table 16:
  • the present invention provides a polymorphic form of the p-toluenesulfonate salt of the compound of formula I, which comprises three crystal forms, designated as Form I, Form II, and Form III, respectively.
  • the present invention provides a crystalline form I of a p-toluenesulfonate salt of the compound of formula I, the powder X-ray diffraction pattern comprising diffraction angles (2 ⁇ ) at 13.0 ⁇ 0.2°, 15.4 ⁇ 0.2°, 24.3 ⁇ 0.2° and 25.7 ⁇ 0.2°. peak.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 14.6 ⁇ 0.2 °, 16.9 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 25.3 ⁇ 0.2 °, and 29.3 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 21, and the X-ray powder diffraction data is as shown in Table 17:
  • the present invention provides a crystalline form II of p-toluenesulfonate salt of the compound of formula I, the powder X-ray diffraction pattern comprising diffraction angles (2 ⁇ ) at 13.7 ⁇ 0.2°, 16.1 ⁇ 0.2°, 25.7 ⁇ 0.2° and 26.1 ⁇ 0.2°. peak.
  • it also includes peaks at diffraction angles (2 ⁇ ) at 6.8 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 20.8 ⁇ 0.2 °, 22.2 ⁇ 0.2 °, 24.6 ⁇ 0.2 °, and 27.9 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 22, and the X-ray powder diffraction data is as shown in Table 18:
  • the present invention provides a crystalline form III of p-toluenesulfonate of the compound of formula I, the powder X-ray diffraction pattern comprising diffraction angles (2 ⁇ ) at 8.2 ⁇ 0.2 °, 14.4 ⁇ 0.2 °, 25.9 ⁇ 0.2 ° and 26.3 ⁇ 0.2 °. peak.
  • it also includes peaks at diffraction angles (2 ⁇ ) of 4.8 ⁇ 0.2 °, 13.2 ⁇ 0.2 °, 15.1 ⁇ 0.2 °, 19.3 ⁇ 0.2 °, 24.2 ⁇ 0.2 °, and 24.5 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 23, and the X-ray powder diffraction data is as shown in Table 19:
  • the present invention provides a polymorphic form of the compound 1,5-naphthalenedisulfonate of the formula I, which comprises three crystal forms, designated as Form I, Form II, Form III, respectively.
  • the present invention provides a crystalline form I of the compound 1,5-naphthalenedisulfonate of formula I, the powder X-ray diffraction pattern comprising diffraction angles at 10.8 ⁇ 0.2 °, 16.8 ⁇ 0.2 °, 21.8 ⁇ 0.2 ° and 25.8 ⁇ 0.2 ° ( The peak at 2 ⁇ ).
  • it also includes peaks at diffraction angles (2 ⁇ ) at 8.1 ⁇ 0.2 °, 13.6 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 18.7 ⁇ 0.2 °, 26.4 ⁇ 0.2 °, and 30.9 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 24, and the X-ray powder diffraction data is as shown in Table 20:
  • the present invention provides a crystalline form II of the compound 1,5-naphthalene disulfonate of the formula I, the powder X-ray diffraction pattern comprising diffraction angles at 4.2 ⁇ 0.2 °, 16.4 ⁇ 0.2 °, 22.8 ⁇ 0.2 ° and 27.3 ⁇ 0.2 ° ( The peak at 2 ⁇ ).
  • it also includes peaks at diffraction angles (2 ⁇ ) at 10.4 ⁇ 0.2 °, 13.5 ⁇ 0.2 °, 15.1 ⁇ 0.2 °, 21.2 ⁇ 0.2 °, 24.0 ⁇ 0.2 °, and 26.5 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 25, and the X-ray powder diffraction data is as shown in Table 21:
  • the present invention provides a crystalline form III of the compound 1,5-naphthalenedisulfonate of the formula I, the powder X-ray diffraction pattern comprising diffraction angles at 13.0 ⁇ 0.2 °, 22.7 ⁇ 0.2 °, 24.1 ⁇ 0.2 ° and 25.7 ⁇ 0.2 ° ( The peak at 2 ⁇ ).
  • it also includes peaks at diffraction angles (2 ⁇ ) at 12.6 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 16.9 ⁇ 0.2 °, 18.5 ⁇ 0.2 °, 20.0 ⁇ 0.2 °, and 21.4 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2 ⁇ ) shown in Fig. 26, and the X-ray powder diffraction data is as shown in Table 22:
  • substantially identical as used herein with respect to the position of the X-ray diffraction peak means to consider typical peak position and intensity variability. For example, those skilled in the art will appreciate that the peak position (2 theta) will vary depending on the XRPD instrument, sometimes varying up to as much as 0.2 degrees. In addition, those skilled in the art will appreciate that XRPD sample preparation methods, XRPD instruments, sample crystallinity, sample usage, and crystal orientation will result in changes in relative peak intensities in the XRPD diffraction pattern of the sample.
  • Another aspect of the invention provides a crystalline 9-((8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3- a]pyridin-3-yl)thio)-4-methyl-2H-[1,4]oxabi[3,2-c]quinoline-3(4H)-one (compound of formula I)
  • Method for preparing a free base including,
  • organic solvents include, but are not limited to, the solvent alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, rings listed below.
  • Alkane, benzene, amide, sulfoxide organic solvent or mixture thereof preferably from methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N , N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, n-heptane, n-hexane, isooctane, pentane, cyclohexane , cyclopentane, diethyl ether, methyl tert-butyl ether, diisopropyl ether, benzene, toluene, xylene or a combination thereof, supercritical fluid such as carbon dioxide liquid, ionic liquid, polymer
  • a suitable solvent including but not limited to isopropanol, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methoxyethanol or a mixture thereof.
  • a suitable solvent including but not limited to isopropanol, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methoxyethanol or a mixture thereof.
  • a suitable solvent including but not limited to methanol, ethanol, acetone, dichloromethane or a mixture thereof
  • a suitable solvent including but not limited to methanol, ethanol, acetone, dichloromethane or a mixture thereof
  • Acetonitrile is added to the free base of the compound of formula I to disperse it in acetonitrile to form a suspension having a content of 1-200 mg/mL.
  • the suspension is stirred at 40-60 ° C until completely converted to the free base form III, and then solid-liquid separation gives the compound free base form III.
  • the free base of the compound of formula I is heated to above 100 ° C (preferably above 120 ° C) to cause dissolution, and then slowly cooled to room temperature to give free base form IV.
  • One crystal form of the acid salt is converted to another crystal form of the salt by a method of crystal form conversion.
  • the method of crystal form conversion includes a method of heating or crystallizing a suspension in a suitable solvent.
  • the step 1) suitable organic solvent alcohols, chlorinated alkanes, ketones, ethers, cyclic ethers, esters, alkanes, cycloalkanes, benzenes, amides, sub-alloys described in the salt formation process.
  • a sulfone organic solvent or a mixture thereof preferably from methanol, ethanol, n-propanol, isopropanol, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, ethyl acetate , isopropyl acetate, 2-methoxyethyl ether or a mixture thereof;
  • the "acid salt” as used herein refers to a pharmaceutically acceptable salt formed by the compound of the present invention and an acidic substance, including a mineral acid salt or an organic acid salt; the acid salt includes inorganic salts.
  • An acid salt or an organic acid salt; preferably the inorganic acid salt is from a hydrochloride, a sulfate, a hydrobromide, a hydrofluoride, a hydroiodide or a phosphate, more preferably a hydrochloride, a sulfate or a phosphoric acid.
  • the organic acid salt is preferably selected from the group consisting of 2,5-dihydroxybenzoate, 1-hydroxy-2-naphthoate, acetate, dichloroacetate, trichloroacetate, acetoxyoxime Acid salt Diacid salt, besylate, 4-chlorobenzenesulfonate, benzoate, 4-acetamidobenzoate, 4-aminobenzoate, citrate, hexanoate, octoate , cinnamate, citrate, cyclohexane sulfamate, camphor sulfonate, aspartate, camphorate, gluconate, glucuronate, glutamate, isoascorbate , lactate, aspartate, malate, mandelate, pyroglutamate, tartrate, lauryl sulfate, dibenzoyl tartrate, ethane-1,2-di Sulfonate, ethanesulfon
  • a suitable solvent including but not limited to methanol, acetonitrile, acetone, ethyl acetate or a mixture thereof
  • hydrochloric acid including but not limited to methanol, acetonitrile, acetone, ethyl acetate or a mixture thereof
  • a suitable solvent including but not limited to acetonitrile, ethyl acetate, tetrahydrofuran or a mixture thereof
  • a suitable solvent including but not limited to acetonitrile, ethyl acetate, tetrahydrofuran or a mixture thereof
  • a suitable solvent including but not limited to acetone
  • a suitable solvent including but not limited to methanol
  • a suitable solvent including but not limited to acetone, tetrahydrofuran, isopropyl acetate, ethyl acetate, 2-methoxyethyl ether, 1,4-dioxane or a mixture thereof
  • a suitable solvent including but not limited to acetone, tetrahydrofuran, isopropyl acetate, ethyl acetate, 2-methoxyethyl ether, 1,4-dioxane or a mixture thereof
  • the mesylate salt form II is obtained by liquid separation.
  • the methanesulfonate salt form IV is dried under vacuum at 100-120 ° C, and the methanesulfonic acid form IV will be converted to the methanesulfonate salt.
  • Form III the methanesulfonic acid form IV will be converted to the methanesulfonate salt.
  • the methanesulfonate crystal form V is dispersed in a single or mixed anti-solvent, such as n-heptane/ethyl acetate solution, and stirred at room temperature or under heating to convert the methanesulfonate crystal form V to form III.
  • a single or mixed anti-solvent such as n-heptane/ethyl acetate solution
  • a suitable solvent including but not limited to methanol, acetonitrile, acetone or a mixture thereof
  • a suitable solvent including but not limited to methanol, acetonitrile, acetone or a mixture thereof
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a crystalline free base of the above formula I or a crystalline salt of the foregoing, or a pharmaceutically acceptable carrier or form Agent.
  • a crystalline free base of the above formula I a crystalline form of the above free base, a crystalline acid salt of the foregoing, a polymorph of the above acid salt, and a pharmaceutical composition as described above for the preparation of a therapeutic protein kinase Use in a medicament for a disease wherein the protein kinase is selected from the group consisting of c-Met and VEGFR receptor tyrosine kinases.
  • Another aspect of the present invention provides the use of the crystalline free base of the above formula I, the free base polymorph, the crystalline acid salt, the acid salt polymorph, and the pharmaceutical composition for preparing a protein kinase inhibitor, Wherein the protein kinase is selected from the group consisting of c-Met and VEGFR receptor tyrosine kinases.
  • Another aspect of the present invention provides a method for modulating catalytic activity of a protein kinase, comprising: the protein kinase and a crystalline free base of the compound of the above formula I, the above-described free base polymorph, the aforementioned crystalline acid salt, the foregoing
  • the acid salt polymorph, in contact with the aforementioned pharmaceutical composition is selected from the group consisting of c-met and VEGFR receptor tyrosine kinases.
  • the crystalline free base of the above formula I of the present invention, the above-mentioned free base polymorph, the above crystalline acid salt, the above acid salt polymorph, and the aforementioned pharmaceutical composition can also be used for the preparation of cancer and metastasis, including cancer.
  • cancer Solid tumors
  • lymphoid hematopoietic tumors hematopoietic tumors of the myeloid system
  • tumors of mesenchymal origin tumors of the central and peripheral nervous system, or other tumor drugs.
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, gastric cancer, lung cancer (non-small cell lung cancer) or skin cancer;
  • the lymphoid hematopoietic tumor is selected from leukemia, acute lymphocyte Leukemia or chronic lymphocytic leukemia;
  • the bone marrow system hematopoietic tumor is selected from acute or chronic myeloid leukemia, myelodysplastic syndrome or promyelocytic leukemia;
  • the mesenchymal origin of the tumor is selected from the group consisting of fibrosarcoma, rhabdomyosarcoma, soft tissue Sarcoma or osteosarcoma;
  • the tumor of the central and peripheral nervous system is selected from astrocytoma, neuroblastoma, glioma or nerve ending tumor;
  • the other tumor is selected from malignant melanoma, seminoma Teratogenic cancer, thyroid follicular carcinoma or Kaposi's s
  • It is preferably used in the preparation of a medicament for treating liver cancer, lung cancer, breast cancer, epidermal squamous cell carcinoma or gastric cancer.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components, or other components such as physiological/pharmaceutical Accepted carriers and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • Figure 1 is an X-ray powder diffraction pattern of the free base Form I of the compound of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 2 is a DSC diagram of the free base Form I of the compound of Formula I; the abscissa is temperature (degrees Celsius), the ordinate is heat flow (W/g), and the exothermic peak is downward; the peak area of the peak shown therein (Area): 121.2 J/g, Peak: 276.8 ° C, Onset: 274.4 ° C, End temperature: 278.7 ° C, Height: 6.716 mW/mg.
  • Figure 3 is a TGA diagram of the free base Form I of the compound of Formula I; the abscissa is temperature (degrees Celsius) and the ordinate is percent weight loss (%).
  • Figure 4 is an X-ray powder diffraction pattern of the free base Form II of the compound of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 5 is an X-ray powder diffraction pattern of the free base Form III of the compound of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 6 is a DSC/TGA overlay of the free base form III of the compound of formula I; the abscissa is temperature (degrees Celsius), the left ordinate is heat flow (W/g), the exothermic peak is upward; the right ordinate is the percentage of weight loss. (%).
  • Figure 7 is an X-ray powder diffraction pattern of the free base Form IV of the compound of Formula I; the abscissa is the angle 2? (?) and the ordinate is the intensity.
  • Figure 8 is an X-ray powder diffraction pattern of the salt form I of the salt of the compound of Formula I; the abscissa is the angle 2? (?) and the ordinate is the intensity.
  • Figure 9 is an X-ray powder diffraction pattern of the sulfate form I of the compound of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 10 is an X-ray powder diffraction pattern of the sulfate form II of the compound of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 11 is an X-ray powder diffraction pattern of the crystalline form I of the compound of formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 12 is an X-ray powder diffraction pattern of the crystalline form II of the compound of formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 13 is an X-ray powder diffraction pattern of the crystalline form III of the compound of formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 14 is an X-ray powder diffraction pattern of the crystalline form IV of the compound of formula I; the abscissa is the angle 2? (?) and the ordinate is the intensity.
  • Figure 15 is an X-ray powder diffraction pattern of the mesylate salt form I of the compound of Formula I; the abscissa is the angle 2? (?) and the ordinate is the intensity.
  • Figure 16 is an X-ray powder diffraction pattern of the mesylate salt form II of the compound of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 17 is an X-ray powder diffraction pattern of the methanesulfonate salt form III of the compound of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 18 is a DSC/TGA overlay of the methanesulfonate salt form III of the compound of Formula I; the abscissa is temperature (degrees Celsius), the right ordinate is heat flow (W/g), and the exothermic peak is upward; the left ordinate is Weight loss percentage (%).
  • Figure 19 is an X-ray powder diffraction pattern of the crystalline form IV of the compound of formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 20 is an X-ray powder diffraction pattern of the methanesulfonate Form V of the compound of Formula I; the abscissa is the angle 2? (?) and the ordinate is the intensity.
  • Figure 21 is an X-ray powder diffraction pattern of the crystalline form I of the p-toluenesulfonate salt of the compound of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 22 is an X-ray powder diffraction pattern of the compound of formula I p-toluenesulfonate Form II; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 23 is an X-ray powder diffraction pattern of the compound of formula I p-toluenesulfonate Form III; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 24 is an X-ray powder diffraction pattern of Form 1,5-naphthalenedisulfonate Form I of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 25 is an X-ray powder diffraction pattern of the crystalline form II of the compound 1,5-naphthalene disulfonate of Formula I; the abscissa is the angle 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 26 is an X-ray powder diffraction pattern of the crystalline form III of the compound 1,5-naphthalene disulfonate of the formula I; The angle is 2 ⁇ (°) and the ordinate is the intensity.
  • Figure 27 is a DSC chart of Form III of the compound 1,5-naphthalene disulfonate of Formula I.
  • the abscissa is the temperature (degrees Celsius)
  • the ordinate is the heat flow (W/g)
  • the exothermic peak is upward.
  • Figure 28 is a graph showing the plasma concentration-time curve for the crystalline form III of the compound of formula I and the crystalline form I of the free base.
  • the free base crystalline forms of the compounds of formula I and their salt crystal forms are characterized by their X-ray powder diffraction pattern. Therefore, in the presence of Cu K ⁇ radiation
  • the X-ray powder diffraction pattern of the salt was taken on a Bruker D8 Discover X-ray powder diffractometer of GADDS (General Area Diffraction Detector System) CS operating in a reflective manner.
  • the tube voltage and current quantities were set to 40kV and 40mA acquisition scans, respectively.
  • the sample was scanned for a period of 60 seconds in the range of 2 ⁇ from 3.0° to 40° or 45°.
  • the diffractometer was calibrated using a corundum standard for the peak position indicated by 2 ⁇ .
  • Measurement differences associated with such X-ray powder diffraction analysis results are produced by a variety of factors including: (a) errors in sample preparation (eg, sample height), (b) instrument error, (c) calibration differences, ( d) operator error (including those that occur when determining peak position), and (e) properties of the substance (eg, preferred orientation error). Calibration errors and sample height errors often result in displacement of all peaks in the same direction. In general, this calibration factor will align the measured peak position to the expected peak position and may be in the range of the expected 2 ⁇ value ⁇ 0.2°. The angle 2 ⁇ values (°) and intensity values (as % of the highest peak) of each polymorph obtained in the examples of the present invention are listed in Tables 1 to 22.
  • the amorphous form I compound free base is prepared according to the Chinese Patent CN201310173581.4 and its PCT application (PCT/CN2014/072825). The specific operation is as follows: 8-fluoro-6- is sequentially added to a 30 mL microwave tube.
  • Method of operation Weigh about 10mg of amorphous free base in 2-mL glass vial, add 1mL of simulated biological media (simulating artificial gastric juice, simulate artificial intestinal fluid - fasting, simulate artificial intestinal fluid - satiety), add magnetic stirrer Then, the vial was sealed, magnetically stirred at 37 ° C, and about 0.4 mL was sampled at different time points, and the mixture was filtered and centrifuged (filter pore size: 0.45 um), filtered, and the filtrate was taken, and the content of the compound I was analyzed by HPLC. The measurement results are shown in the following table:
  • a quantity of the free base of the compound of formula I (amorphous) is weighed into a container, and a solvent is added to disperse the free base of the compound of formula I in a solvent to form a suspension having a content of 1-200 mg/mL.
  • the suspension is stirred at room temperature (20-25 ° C) until the amorphous form I compound is converted into the free base form I.
  • the solid obtained by solid-liquid separation is the free base form I of the compound, and the X-ray powder diffraction pattern is as shown in the figure. 1 is shown.
  • the melting point of free base Form I was measured using a differential calorimeter (DSC, model Neszsch DSC 204F1). The measurement conditions were from room temperature to 300 ° C, a heating rate of 10 ° C per minute, and heating under a nitrogen atmosphere at a nitrogen flow rate of 20 mL per minute.
  • the DSC chart of free base form I is shown in Figure 2.
  • the melting point (starting temperature point) of free base form I is: 274.4 degrees Celsius.
  • the thermal weight loss of free base Form I was measured using a thermogravimetric analyzer (TGA, model TA Q500). The measurement conditions were from room temperature to 350 ° C, a heating rate of 10 ° C per minute, and heating under a nitrogen atmosphere at a nitrogen flow rate of 50 mL per minute.
  • the TGA chart of free base form I is shown in Figure 3. There is almost no weight loss within 100 degrees Celsius, so it can be judged that the compound free base crystal form I is an anhydrate.
  • Method of operation Weigh about 10 mg of the compound free base Form I in a 2-mL glass vial, plus 1mL simulated biological media (simulated artificial gastric juice, simulated artificial intestinal fluid - fasting, simulated artificial intestinal fluid - satiety), added magnetic stirrer and sealed the vial, magnetically stirred at 37 degrees Celsius, sampled about 0.4mL at different time points, filtered The tube was centrifuged (diameter of membrane 0.45 um), centrifuged by filtration, and the filtrate was taken, and the content of the compound I was analyzed by HPLC. The measurement results are shown in the following table:
  • a quantity of the free base of the compound of formula I (amorphous) is weighed into a container, and a solvent is added to disperse the free base of the compound of formula I in a solvent to form a suspension having a content of 1-200 mg/mL. Add the appropriate solvent. The suspension is stirred at room temperature (20-25 ° C) until the compound of the amorphous form I is converted into the free base crystal form II, and the solid obtained by solid-liquid separation is the free base crystal form II of the compound, and the X-ray powder diffraction pattern thereof is shown in the figure. 4 is shown.
  • the melting point of free base Form III was measured using a differential calorimeter (DSC, model TA Q2000). The measurement conditions were from room temperature to 300 ° C, a heating rate of 10 ° C per minute, and heating under a nitrogen atmosphere at a nitrogen flow rate of 20 mL per minute.
  • the DSC chart of free base form III is shown in Figure 5.
  • the melting point (starting temperature point) of the free base form III is: 275.5 degrees Celsius.
  • the thermal weight loss of free base Form III was measured using a thermogravimetric analyzer (TGA, model TA Q500). The measurement conditions were from room temperature to 350 ° C, a heating rate of 10 ° C per minute, and heating under a nitrogen atmosphere at a nitrogen flow rate of 50 mL per minute.
  • the TGA chart of free base Form III is shown in Figure 6. There is almost no weight loss within 100 degrees Celsius, so it can be judged that the compound free base III is an anhydrate.
  • Method of operation Weigh about 10 mg of the compound free base crystal form III in a 2-mL glass vial, and add 1 mL of simulated biological media (simulating artificial gastric juice, simulating artificial intestinal fluid - fasting, simulating artificial intestinal fluid - satiety), adding magnetic force After stirring, the vial was sealed, magnetically stirred at 37 ° C, and about 0.4 mL was sampled at different time points. The mixture was filtered and centrifuged (filter pore size 0.45 um), filtered and centrifuged, and the filtrate was taken for analysis of the compound I by HPLC. content. The measurement results are shown in the following table:
  • the salt crystal form I has an X-ray powder diffraction pattern as shown in FIG.
  • Method of operation Weigh about 10mg of compound phosphate crystal form I in a 2-mL glass vial, plus 1mL of simulated biological media (simulating artificial gastric juice, simulating artificial intestinal fluid - fasting, simulating artificial intestinal fluid - satiety), adding magnetic force After stirring, the vial was sealed, magnetically stirred at 37 ° C, and about 0.4 mL was sampled at different time points. The mixture was filtered and centrifuged (filter pore size 0.45 um), filtered and centrifuged, and the filtrate was taken for analysis of the compound I by HPLC. content. The measurement results are shown in the following table:
  • the solubility of the phosphate form I is much greater than the solubility of the free base, which increases the solubility of the compound of formula I and is beneficial for increasing bioavailability.
  • the salt crystal form IV has an X-ray powder diffraction pattern as shown in FIG.
  • the methane sulfonate crystal form I (hydrate) has an X-ray powder diffraction pattern as shown in FIG. E.g:
  • the mesylate salt form IV was dried under vacuum at 100 ° C overnight.
  • Form IV of methanesulfonic acid will be converted to the methanesulfonate Form III with an X-ray powder diffraction pattern consistent with Figure 17.
  • the melting point of the compound mesylate salt form III was measured by a differential calorimeter (DSC, model TA Q2000). The measurement conditions were from room temperature to 300 ° C, a heating rate of 10 ° C per minute, and heating under a nitrogen atmosphere at a nitrogen flow rate of 20 mL per minute.
  • the DSC chart of the mesylate salt form III is shown in FIG.
  • the melting point (starting temperature point) of the mesylate salt form III is: 252.4 degrees Celsius.
  • the thermal weight loss of the mesylate salt form III was measured using a thermogravimetric analyzer (TGA, model TA Q500).
  • the measurement conditions were from room temperature to 350 ° C, a heating rate of 10 ° C per minute, and heating under a nitrogen atmosphere at a nitrogen flow rate of 50 mL per minute.
  • the TGA pattern of the mesylate salt form III is shown in FIG. There is almost no weight loss within 100 degrees Celsius, so it can be judged that the compound mesylate salt form III is an anhydrate.
  • the method was as follows: weigh about 10 mg of Compound I mesylate salt form III in a 2-mL glass vial, and add 1 mL of simulated biological media (simulating artificial gastric juice, simulating artificial intestinal fluid - fasting, simulating artificial intestinal fluid - satiety After adding a magnetic stirrer and sealing the vial, magnetically stirring at 37 ° C, sampling about 0.4 mL at different time points, using a filter centrifuge tube (filter membrane pore size 0.45 um), filtering and centrifuging, taking the filtrate,
  • the solubility of the methanesulfonate crystal form III is much greater than the solubility of the free base, which improves the solubility of the compound of the formula I and is advantageous for improving bioavailability.
  • the mesylate salt form III accelerated stability test was used to investigate the physical and chemical stability of the mesylate salt form III.
  • the specific operation method is as follows: 100 mg of methanesulfonate is placed in an accelerated stabilization tank, and the experimental conditions in the following table are set. When the sample is placed in the following table for a sufficient time, the mobile phase is taken out and dissolved, and the purity is determined by HPLC. . Prior to the start of the accelerated stability test, the purity of the sample was determined by HPLC on the initial sample. The ratio of the purity of the accelerated stability test sample to the purity of the initial sample is used as the criterion for evaluating the stability of the compound. If the purity ratio is less than 95%, the sample is considered to be unstable.
  • the specific experimental conditions and experimental results are listed in the following table:
  • the mesylate salt form III can be increased in bioavailability by a factor of 5 compared to the free base form I.
  • the test conditions were as follows: the experimental animal was a dog, the dose was 5 mg/kg, and the stomach was administered in a single dose.
  • the salt form compound therefore has a greatly improved significance compared to the free base.
  • mesylate salt form V can also bring great convenience in unit operation, because the compound of the formula I can be dissolved in DMSO, easy to achieve on-line filtration, and the solution is transported through the pipeline to the GMP workshop, through The methanesulfonic acid is crystallized by reaction, precipitated from the solution, and filtered to obtain the methanesulfonate salt form V and purified.
  • Methanesulfonate crystal form VI is an important product of this advanced purification method and therefore has practical application value.
  • the melting point of the crystalline form III of the compound 1,5-naphthalene disulfonate was measured by a differential calorimeter (DSC, model TA Q2000). The measurement conditions were from room temperature to 300 ° C, a heating rate of 10 ° C per minute, and heating under a nitrogen atmosphere at a nitrogen flow rate of 20 mL per minute.
  • the DSC chart of 1,5-naphthalenedisulfonate III is shown in Fig. 26.
  • the melting point (starting temperature point) of the mesylate salt form III is: 321.2 degrees Celsius.
  • the method of operation is to weigh about 10 mg of compound I 1,5-naphthalene disulfonate crystal form III in a 2-mL glass vial, and add 1 mL of simulated biological media (simulating artificial gastric juice, simulating artificial intestinal fluid - fasting, simulation Artificial intestinal fluid - satiety), after adding magnetic stirrer and sealing the vial, magnetically stirring at 37 ° C, sampling about 0.4 mL at different time points, using a filter centrifuge tube (filter membrane pore size 0.45 um), filtering and centrifuging, taking the filtrate
  • the content of the compound I therein was analyzed by HPLC. The measurement results are shown in the following table:
  • the solubility of Form 1,5-naphthalene disulfonate Form III is much greater than the solubility of the free base, which improves the solubility of the compound of Formula I and is beneficial for increasing bioavailability.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

公开了C-Met抑制剂9-（（8-氟-6-（1-甲基-1H-吡唑-4-基）-[1,2,4]三唑并[4,3-a]吡啶-3-基）硫代）-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3（4H）-酮的结晶型游离碱或其结晶型酸式盐及其制备方法和应用。具体而言，公开了游离碱晶型I、II、III和IV，盐酸盐晶型I，硫酸盐晶型I和II，磷酸盐晶型I、II、III和IV，甲磺酸盐晶型I、II、III、IV和V，对甲苯磺酸盐晶型I、II和III，1,5-萘二磺酸盐晶型I、II和III，上述晶型的制备方法以及含有其的药物组合物，其制药用途以及调节蛋白激酶催化活性的方法。

Description

C-Met抑制剂结晶型游离碱或其结晶型酸式盐及其制备方法和应用 技术领域
本发明属于药物技术领域，具体涉及一种C-Met抑制剂结晶型游离碱或其结晶型酸式盐及其制备方法和应用。
背景技术
肝细胞生长因子(HGF)受体，也叫作C-Met，是一种酪氨酸激酶受体。C-Met异常激活与癌症的不良预后有关连，都存在C-Met过度表达的问题。C-Met异常也发现于多种类型的肿瘤，例如肝癌HCC，非小细胞肺癌NSCLC，膀胱癌，肝癌，肾癌，胃癌，乳腺癌，鳞状细胞癌，脑癌、胃癌，结肠癌等。C-Met异常可表现为表达量升高，基因扩增，基因突变，或者HGF表达量升高。在这些异常情况下，C-Met可处于一种被激活的异常状态，从而导致癌变和不良预后。C-Met在遇到异常激活后会引发肿瘤的生长与新血管的形成(血管再生，它可以为肿瘤提供营养)，帮助癌症扩散到其它器官(转移)。因此抑制C-Met信号通路是治疗肿瘤的重要策略之一。
江苏豪森公司在专利CN201310173581.4及其PCT申请(PCT/CN2014/072825)描述了具有药理活性的C-Met抑制剂，其中一个化合物为9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮(简称“式Ⅰ化合物”)。
Figure PCTCN2015085514-appb-000001
式Ⅰ化合物是有效的C-Met/HGFR(肝细胞生长因子受体)激酶抑制剂，作为C-Met酪氨酸激酶抑制剂，式Ⅰ化合物能够有效阻断HGF/C-Met信号传导途径达到治疗哺乳动物的异常细胞生长(如癌症)的目的。然而，在专利CN201310173581.4及其PCT申请(PCT/CN2014/072825)只描述了式I化合物的无定形物。众所周知，药物的无定形是药物分子处于无序状态的聚集体，且不含有明显的晶格，具有比结晶态更高的热力学能态，导致热力学上的不稳定性，而这种热力学上的不稳定性，将会给药物带来化学稳定性差、容易吸湿以及发生固相 转变，使得药物品质极其不稳定。因此，在药物开发中，无定形态很难用于药物开发；此外，在药物制备过程中，药物的结晶过程也是一个药物提纯的有效手段，得到的结晶态还会带来易于进一步提纯、易于过滤、药物干燥等工艺操作上的优势。因此，非常有必要进一步研究开发出结晶性好、粒度适中、溶解性好、稳定性高的新晶型以改善药物的生物利用度。式I化合物在专利CN201310173581.4及其PCT申请(PCT/CN2014/072825)公开了其无定型游离碱，所述的游离碱在各种溶剂中溶解度较低，不利于药物在动物或人体内溶出，因此，研究开发出合适的盐型化合物，从而提高式I化合物的溶出速度及溶解度成为一种非常紧迫的任务。
综上所述，相对于游离碱无定型物，无论从药物提纯、干燥、储备、制剂、和增加溶出等各方面，都需要做进一步的技术改进，从而提高药物生物利用度。
发明内容
为了解决现有技术存在的问题，本发明提供了9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮(式Ⅰ化合物)结晶型游离碱、结晶型酸式盐及其制备方法和应用。通过深入研究不同的聚集状态，大大改善了式Ⅰ化合物的理化性质，例如溶解性、吸湿性和化学稳定性。
本发明一方面提供了结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮(式Ⅰ化合物)游离碱。其游离碱多晶型共包含四种晶型，分别指定为晶型Ⅰ、晶型Ⅱ、晶型Ⅲ、晶型Ⅳ。
本发明提供式Ⅰ化合物游离碱晶型Ⅰ，其粉末X射线衍射图包括位于13.0±0.2°,17.9±0.2°,21.2±0.2°和31.4±0.2°的衍射角(2θ)处的峰。
优选还包括位于10.3±0.2°，11.1±0.2°，23.3±0.2°，23.8±0.2°和33.6±0.2°的衍射角(2θ)处的峰。
更优选还包括位于15.7±0.2°，17.7±0.2°，26.8±0.2°，28.0±0.2°，31.7±0.2°和32.8±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图1中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表1所示：
表1
2θ(°) 强度％ 2θ(°) 强度％
5.3 4.5 22.8 4.1
10.3 24.9 23.3 27.3
10.5 11.9 23.8 27.2
11.1 28.5 25.9 3.2
12.7 9.9 26.6 5.9
13.0 36.3 26.8 19.0
13.9 5.6 27.1 6.8
14.7 7.0 27.3 5.8
15.1 4.4 28.0 13.8
15.4 7.4 31.4 33.4
15.7 13.8 31.7 18.4
17.7 15.0 32.8 12.3
17.9 47.6 33.6 21.1
19.4 8.7 35.8 6.3
20.3 7.5 38.1 6.8
20.6 2.8 38.8 10.3
21.2 100.0    
本发明提供式Ⅰ化合物游离碱晶型Ⅱ，其粉末X射线衍射图包括位于8.6±0.2°，11.5±0.2°，14.1±0.2°和19.8±0.2°的衍射角(2θ)处的峰。
优选还包括位于11.9±0.2°，14.7±0.2°，15.2±0.2°，17.2±0.2°和18.9±0.2°的衍射角(2θ)处的峰。
更优选还包括位于5.8±0.2°，7.4±0.2°，20.9±0.2°，30.9±0.2°，31.4±0.2°和37.9±0.2°，的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图4中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表2所示：
表2
2θ(°) 强度％ 2θ(°) 强度％
5.8 2.1 17.2 7.8
7.4 2.8 18.9 5.1
8.6 100.0 19.8 9.6
11.5 13.3 20.9 2.0
11.9 5.6 30.9 3.5
14.1 10.5 31.4 4.0
14.7 6.2 37.9 2.2
15.2 4.7    
本发明提供式Ⅰ化合物游离碱晶型Ⅲ，其粉末X射线衍射图包括位于12.8±0.2°，14.8±0.2°，18.0±0.2°和20.5±0.2°的衍射角(2θ)处的峰。
优选还包括位于8.9±0.2°，9.2±0.2°，10.6±0.2°，15.8±0.2°和20.7±0.2°的衍射角(2θ)处的峰。
更优选还包括位于5.3±0.2°，5.9±0.2°，12.0±0.2°，14.0±0.2°，17.3±0.2°和19.9±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图5中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表3所示：
表3
2θ(°) 强度％ 2θ(°) 强度％
5.3 8.2 14.0 8.6
5.9 11.7 14.8 31.3
7.9 7.6 15.8 26.2
8.9 18.9 17.3 10.4
9.2 19.1 18.0 100.0
10.6 14.8 19.9 11.4
12.0 12.8 20.5 32.8
12.8 30.4 20.7 24.9
13.3 6.6    
发明提供式Ⅰ化合物游离碱晶型Ⅳ，其粉末X射线衍射图包括位于8.9±0.2°，12.6±0.2°，17.0±0.2°和17.9±0.2°的衍射角(2θ)处的峰。
优选还包括位于13.2±0.2°，14.5±0.2°，20.5±0.2°，23.9±0.2°和26.3±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图7中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表4所示：
表4
2θ(°) 强度％ 2θ(°) 强度％
8.9 100.0 17.9 15.1
12.6 34.5 20.5 11.1
13.2 14.6 23.9 6.7
14.5 13.8 26.3 13.9
17.0 16.1 29.0 6.5
本发明另一方面提供了结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐。
所述酸式盐包括无机酸盐或有机酸盐；所述无机酸盐优选自盐酸盐、硫酸盐、氢溴酸盐、氢氟酸盐、氢碘酸盐或磷酸盐，更优选自盐酸盐、硫酸盐或磷酸盐；所述有机酸盐优选自2,5-二羟基苯甲酸盐、1-羟基-2-萘甲酸盐、醋酸盐、二氯醋酸盐、三氯醋酸盐、乙酰氧肟酸盐、己二酸盐、苯磺酸盐、4-氯苯磺酸盐、苯甲酸盐、4-乙酰氨基苯甲酸盐、4-氨基苯甲酸盐、癸酸盐、己酸盐、辛酸盐、肉桂酸盐、柠檬酸盐、环己烷氨基磺酸盐、樟脑磺酸盐、天门冬氨酸盐、樟脑酸盐、葡萄糖酸盐、葡糖醛酸盐、谷氨酸盐、异抗坏血酸盐、乳酸盐、天门冬氨酸盐、苹果酸盐、扁桃酸盐、焦谷氨酸盐、酒石酸盐、十二烷基硫酸盐、二苯甲酰酒石酸盐、乙烷-1,2-二磺酸盐、乙磺酸盐、蚁酸盐、富马酸盐、半乳糖酸盐、龙胆酸盐、戊二酸盐、2-酮戊二酸盐、乙醇酸盐、马尿酸盐、羟乙基磺酸盐、乳糖酸盐、抗坏血酸盐、天冬氨酸盐、月桂酸盐、樟脑酸盐、马来酸盐、丙二酸盐、甲磺酸盐、1,5-萘二磺酸盐、萘-2-磺酸盐、烟酸盐、油酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、丙酸盐、水杨酸盐、4-氨基水杨酸盐、癸二酸盐、硬脂酸盐、丁二酸盐、、硫氰酸盐、十一碳烯酸盐、三氟乙酸盐、琥珀酸盐、对甲苯磺酸盐，更优选自甲磺酸盐、对甲苯磺酸盐或1，5-萘二磺酸盐。
本发明提供式Ⅰ化合物盐酸盐多晶型，包含一种晶型，指定为晶型Ⅰ，其粉末X射线衍射图包括位于8.1±0.2°，19.2±0.2°，24.1±0.2°和26.2±0.2°的衍射角(2θ)处的峰。
优选还包括位于9.1±0.2°，11.3±0.2°，13.4±0.2°，29.7±0.2°和23.4±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图8中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表5所示：
表5
2θ(°) 强度％ 2θ(°) 强度％
6.7 8.1 23.4 10.6
8.1 100.0 24.1 21.4
9.1 8.8 26.2 41.4
11.3 16.6 29.7 14.0
13.4 12.6 30.8 5.6
19.2 39.0 33.5 6.3
本发明提供式Ⅰ化合物硫酸盐多晶型，共包含两种晶型，分别指定为晶型Ⅰ、晶型Ⅱ。
本发明提供式Ⅰ化合物硫酸盐晶型Ⅰ，其粉末X射线衍射图包括位于18.4±0.2°，19.7±0.2°，23.8±0.2°和24.5±0.2°的衍射角(2θ)处的峰。
优选还包括位于12.8±0.2°，14.4±0.2°，17.0±0.2°，20.0±0.2°和21.0±0.2°的衍射角(2θ)处的峰。
更优选还包括位于8.7±0.2°，13.2±0.2°，19.1±0.2°，26.3±0.2°，26.6±0.2°和29.0±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图9中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表6所示：
表6
2θ(°) 强度％ 2θ(°) 强度％
5.7 19.7 19.7 84.5
6.6 14.9 20.0 49.4
8.7 37.2 21.0 58.7
9.9 13.6 21.6 32.0
11.0 33.6 22.7 25.3
12.8 45.8 23.8 89.8
13.2 40.1 24.5 83.2
14.4 78.3 24.9 28.3
17.0 75.6 26.3 45.2
17.4 27.5 26.6 41.1
18.4 100.0 29.0 41.6
19.1 38.8    
本发明提供式Ⅰ化合物硫酸盐晶型Ⅱ，其粉末X射线衍射图包括位于6.3±0.2°，8.7±0.2°，12.7±0.2°和18.4±0.2°的衍射角(2θ)处的峰。
优选还包括位于8.3±0.2°，17.5±0.2°，18.7±0.2°，20.4±0.2°和25.6±0.2°的衍射角(2θ)处的峰。
更优选还包括位于9.1±0.2°，15.9±0.2°，16.8±0.2°，24.0±0.2°，25.2±0.2°和28.4±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图10中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表7所示：
表7
2θ(°) 强度％ 2θ(°) 强度％
6.3 84.8 18.4 49.8
8.3 26.9 18.7 22.9
8.7 100.0 20.4 21.6
9.1 11.6 24.0 13.4
9.5 6.4 24.6 5.9
12.7 53.8 25.2 18.0
15.9 11.7 25.6 26.7
16.8 11.0 28.4 14.8
17.5 46.7    
本发明提供式Ⅰ化合物磷酸盐多晶型，共包含四种晶型，分别指定为晶型I、晶型Ⅱ、晶型Ⅲ、晶型Ⅳ。
本发明提供式Ⅰ化合物磷酸盐晶型I，其粉末X射线衍射图包括位于7.9±0.2°，12.8±0.2°，15.9±0.2°和18.3±0.2°的衍射角(2θ)处的峰。
优选还包括位于5.3±0.2°，10.6±0.2°，13.4±0.2°，20.9±0.2°和24.7±0.2°的衍射角(2θ)处的峰。
更优选还包括位于16.5±0.2°，18.7±0.2°，20.6±0.2°，21.8±0.2°，26.2±0.2°和27.4±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图11中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表8所示：
表8
2θ(°) 强度％ 2θ(°) 强度％
5.3 18.2 19.3 3.4
7.9 100.0 20.6 4.6
10.6 15.6 20.9 10.5
12.8 26.2 21.8 6.0
13.4 11.5 23.1 3.5
15.9 27.5 24.7 16.5
16.5 6.3 25.1 4.0
17.3 4.2 26.2 4.6
18.3 62.0 27.4 9.5
18.7 9.4    
本发明提供式Ⅰ化合物磷酸盐晶型II，其粉末X射线衍射图包括位于13.7±0.2°，16.1±0.2°，22.8±0.2°和26.1±0.2°的衍射角(2θ)处的峰。
优选还包括位于11.0±0.2°，14.6±0.2°，20.3±0.2°，20.8±0.2°和25.7±0.2°的衍射角(2θ)处的峰。
更优选还包括位于6.8±0.2°，17.0±0.2°，22.2±0.2°，26.6±0.2°，27.9±0.2°和31.2±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图12中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表9所示：
表9
2θ(°) 强度％ 2θ(°) 强度％
6.8 26.3 21.5 11.6
8.8 6.1 22.2 20.1
11.0 71.5 22.8 100.0
12.4 12.9 24.6 16.3
13.7 87.5 25.7 47.1
14.6 30.8 26.1 94.2
16.1 74.6 26.6 30.0
17.0 30.3 27.9 26.4
20.3 32.2 30.7 14.1
20.8 34.1 31.2 21.7
本发明提供式Ⅰ化合物磷酸盐晶型III，其粉末X射线衍射图包括位于9.7±0.2°，15.6±0.2°，16.8±0.2°和24.6±0.2°的衍射角(2θ)处的峰。
优选还包括位于4.8±0.2°，21.2±0.2°，25.0±0.2°，27.8±0.2°和28.1±0.2°的衍射角(2θ)处的峰。
更优选还包括位于5.2±0.2°，12.8±0.2°，14.5±0.2°，18.0±0.2°，20.1±0.2°和23.5±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图13中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表10所示：
表10
2θ(°) 强度％ 2θ(°) 强度％
4.8 26.0 19.2 11.7
5.2 20.8 20.1 16.5
7.8 5.2 21.2 36.9
9.7 49.4 22.6 12.2
10.7 6.1 23.5 12.5
12.4 10.1 24.6 86.0
12.8 21.4 25.0 39.2
14.5 14.7 26.8 11.3
15.6 41.0 27.8 29.3
16.8 100.0 28.1 24.0
18.0 21.0    
本发明提供式Ⅰ化合物磷酸盐晶型IV，其粉末X射线衍射图包括位于7.8±0.2°，17.9±0.2°，25.0±0.2°和27.7±0.2°的衍射角(2θ)处的峰。
优选还包括位于6.7±0.2°，10.8±0.2°，15.6±0.2°，23.4±0.2°和24.6±0.2°的衍射角(2θ)处的峰。
更优选还包括位于5.2±0.2°，12.8±0.2°，20.9±0.2°，21.7±0.2°，22.3±0.2°和26.8±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图14中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表11所示：
表11
2θ(°) 强度％ 2θ(°) 强度％
5.2 13.9 19.6 5.1
6.7 24.2 20.9 10.8
7.8 76.3 21.7 10.5
10.8 31.8 22.3 7.8
12.4 5.6 23.4 25.6
12.8 17.4 24.6 47.5
13.3 6.3 25.0 84.6
15.6 36.9 26.8 7.7
17.9 100.0 27.7 70.6
本发明提供式Ⅰ化合物甲磺酸盐多晶型，共包含五种晶型，分别指定为晶型I、晶型Ⅱ、晶型Ⅲ、晶型Ⅳ、晶型V。
本发明提供式Ⅰ化合物甲磺酸盐晶型I，其粉末X射线衍射图包括位于15.6±0.2°，17.0±0.2°，25.6±0.2°和26.0±0.2°的衍射角(2θ)处的峰。
优选还包括位于9.8±0.2°，21.8±0.2°，23.5±0.2°，23.8±0.2°和27.5±0.2°的衍射角(2θ)处的峰。
更优选还包括位于6.6±0.2°，15.3±0.2°，17.2±0.2°，18.3±0.2°，19.7±0.2°和26.4±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图15中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表12所示：
表12
2θ(°) 强度％ 2θ(°) 强度％
6.6 27.5 23.5 32.6
9.8 46.7 23.8 53.6
10.9 13.5 25.6 58.2
13.1 5.6 26.0 100.0
15.3 15.2 26.4 15.8
15.6 71.4 27.5 34.0
16.2 5.8 28.9 9.5
17.0 66.8 29.3 10.8
17.2 21.7 30.5 11.7
18.3 17.9 31.0 10.2
19.7 18.9 31.6 7.3
20.1 7.7 32.5 11.2
20.5 14.5 33.1 6.5
21.5 6.3 34.0 10.0
21.8 29.8    
本发明提供式Ⅰ化合物甲磺酸盐晶型II，其粉末X射线衍射图包括位于9.4±0.2°，17.0±0.2°，18.9±0.2°和27.3±0.2°的衍射角(2θ)处的峰。
优选还包括位于6.6±0.2°，14.9±0.2°，21.1±0.2°，26.1±0.2°和26.9±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图16中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表13所示：
表13
2θ(°) 强度％ 2θ(°) 强度％
6.6 33.4 21.1 22.5
9.4 66.5 23.7 19.8
14.9 42.7 26.1 46.3
17.0 100.0 26.9 34.7
18.9 61.2 27.3 61.6
19.5 20.1 36.1 15.3
本发明提供式Ⅰ化合物甲磺酸盐晶型III，其粉末X射线衍射图包括位于16.7±0.2°，19.3±0.2°，23.2±0.2°和26.5±0.2°的衍射角(2θ)处的峰。
优选还包括位于8.7±0.2°，19.5±0.2°，21.8±0.2°，23.6±0.2°和24.3±0.2°的衍射角(2θ)处的峰。
更优选还包括位于11.7±0.2°，13.6±0.2°，14.1±0.2°，17.2±0.2°，18.7±0.2°和27.2±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图17中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表14所示：
表14
2θ(°) 强度％ 2θ(°) 强度％
6.3 12.5 21.8 50.8
8.7 71.0 22.3 10.6
9.7 17.0 23.2 72.7
11.7 20.7 23.6 56.4
12.0 20.6 24.3 58.6
12.5 5.4 24.8 12.3
13.6 28.1 25.2 7.1
14.1 23.9 26.5 80.7
16.7 100.0 27.2 40.6
17.2 40.2 28.5 6.8
17.9 13.0 30.8 15.4
18.7 21.6 31.1 15.4
19.3 74.2 33.4 14.1
19.5 53.0 36.8 7.0
20.2 7.6 37.5 14.4
本发明提供式Ⅰ化合物甲磺酸盐晶型IV，其粉末X射线衍射图包括位于16.8±0.2°，19.1±0.2°，19.3±0.2°和22.1±0.2°的衍射角(2θ)处的峰。
优选还包括位于21.9±0.2°，23.2±0.2°，24.4±0.2°，26.0±0.2°和27.2±0.2°的衍射角(2θ)处的峰。
更优选还包括位于8.7±0.2°，13.4±0.2°，13.6±0.2°，19.6±0.2°，21.6±0.2°和26.6±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图19中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表15所示：
表15
2θ(°) 强度％ 2θ(°) 强度％
6.2 12.7 20.7 12.8
8.4 20.3 21.6 26.1
8.7 28.7 21.9 56.8
9.8 7.9 22.1 59.1
12.1 11.2 23.2 50.7
12.6 6.2 23.7 17.6
13.4 26.3 24.4 43.1
13.6 22.7 24.8 21.1
14.3 22.1 25.3 20.2
15.0 19.0 26.0 43.4
16.3 8.7 26.6 40.7
16.8 60.9 27.2 40.9
17.5 12.6 28.6 8.4
18.0 6.0 29.5 7.9
18.7 5.3 29.9 10.2
19.1 78.3 30.8 5.3
19.3 100.0 31.2 15.5
19.6 37.1 33.4 13.1
20.3 11.0 37.6 8.5
本发明提供式Ⅰ化合物甲磺酸盐晶型V，其粉末X射线衍射图包括位于25.2±0.2°，9.3±0.2°，16.6±0.2°和19.1±0.2°的衍射角(2θ)处的峰。
优选还包括位于22.7±0.2°，16.3±0.2°，21.2±0.2°，8.9±0.2°和12.3±0.2°的衍射角(2θ)处的峰。
更优选还包括位于23.7±0.2°，20.0±0.2°，15.9±0.2°，24.6±0.2°，28.6±0.2°和25.5±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图20中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表16所示：
表16
2θ(°) 强度％ 2θ(°) 强度％
5.4 19.9 20.0 25.9
8.9 35.8 21.2 37.3
9.3 96.9 22.7 54.1
10.9 15.0 23.7 28.9
12.3 34.9 24.6 23.1
15.9 23.4 25.2 100.0
16.3 42.9 25.5 20.1
16.6 62.2 28.6 20.9
17.8 19.8 30.5 13.7
19.1 61.6    
本发明提供式Ⅰ化合物对甲苯磺酸盐多晶型，共包含三种晶型，分别指定为晶型I、晶型Ⅱ、晶型Ⅲ。
本发明提供式Ⅰ化合物对甲苯磺酸盐晶型I，其粉末X射线衍射图包括位于13.0±0.2°，15.4±0.2°，24.3±0.2°和25.7±0.2°的衍射角(2θ)处的峰。
优选还包括位于5.3±0.2°，12.1±0.2°，18.4±0.2°，22.6±0.2°和23.2±0.2°的衍射角(2θ)处的峰。
更优选还包括位于14.6±0.2°，16.9±0.2°，18.8±0.2°，19.9±0.2°，25.3±0.2°和29.3±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图21中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表17所示：
表17
2θ(°) 强度％ 2θ(°) 强度％
5.3 37.0 22.6 40.5
8.6 12.9 23.2 40.5
12.1 27.0 23.4 13.1
12.5 20.9 24.3 79.4
13.0 100.0 25.3 22.6
14.1 7.0 25.7 56.9
14.6 23.5 26.5 21.1
15.4 55.0 28.1 10.8
16.9 22.9 29.3 23.1
17.2 11.7 30.1 7.0
18.4 26.3 30.9 13.4
18.8 22.8 33.0 9.0
19.6 16.0 33.2 8.2
19.9 25.4 37.3 8.6
20.5 13.9 38.4 6.0
21.3 21.9    
本发明提供式Ⅰ化合物对甲苯磺酸盐晶型II，其粉末X射线衍射图包括位于13.7±0.2°，16.1±0.2°，25.7±0.2°和26.1±0.2°的衍射角(2θ)处的峰。
优选还包括位于11.0±0.2°，14.6±0.2°，17.0±0.2°，22.8±0.2°和26.6±0.2°的衍射角(2θ)处的峰。
更优选还包括位于6.8±0.2°，20.3±0.2°，20.8±0.2°，22.2±0.2°，24.6±0.2°和27.9±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图22中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表18所示：
表18
2θ(°) 强度％ 2θ(°) 强度％
6.8 23.9 21.5 18.0
8.8 8.8 22.2 19.8
11.0 69.4 22.8 60.2
12.4 11.2 24.6 20.4
13.7 100.0 25.7 74.2
14.6 37.5 26.1 95.5
16.1 83.8 26.6 42.6
17.0 33.9 27.9 21.4
20.3 22.7 30.7 13.0
20.8 20.8 31.2 16.1
本发明提供式Ⅰ化合物对甲苯磺酸盐晶型III，其粉末X射线衍射图包括位于8.2±0.2°，14.4±0.2°，25.9±0.2°和26.3±0.2°的衍射角(2θ)处的峰。
优选还包括位于10.3±0.2°，12.8±0.2°，17.2±0.2°，18.0±0.2°和19.9±0.2°的衍射角(2θ)处的峰。
更优选还包括位于4.8±0.2°，13.2±0.2°，15.1±0.2°，19.3±0.2°，24.2±0.2°和24.5±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图23中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表19所示：
表19
2θ(°) 强度％ 2θ(°) 强度％
4.8 25.3 19.3 24.8
6.3 19.0 19.9 34.3
8.2 72.1 21.2 15.3
8.6 10.5 22.4 13.9
9.8 11.3 22.9 17.9
10.0 18.1 23.9 13.2
10.3 31.2 24.2 24.9
11.3 12.0 24.5 28.3
12.8 43.1 25.0 16.4
13.2 23.5 25.3 21.8
14.4 100.0 25.9 63.2
15.1 23.1 26.3 48.3
17.2 46.5 27.8 20.3
18.0 45.0 28.8 14.6
18.7 17.4 31.0 10.1
本发明提供式Ⅰ化合物1，5-萘二磺酸盐多晶型，共包含三种晶型，分别指定为晶型Ⅰ、晶型Ⅱ、晶型Ⅲ。
本发明提供式Ⅰ化合物1，5-萘二磺酸盐晶型I，其粉末X射线衍射图包括位于10.8±0.2°，16.8±0.2°，21.8±0.2°和25.8±0.2°的衍射角(2θ)处的峰。
优选还包括位于10.2±0.2°，16.0±0.2°，19.1±0.2°，20.8±0.2°和26.7±0.2°的衍射角(2θ)处的峰。
更优选还包括位于8.1±0.2°，13.6±0.2°，18.2±0.2°，18.7±0.2°，26.4±0.2°和30.9±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图24中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表20所示：
表20
2θ(°) 强度％ 2θ(°) 强度％
6.8 7.2 20.8 46.8
8.1 16.4 21.2 10.2
10.2 22.1 21.8 63.7
10.8 94.5 25.2 7.8
13.6 15.9 25.8 100.0
15.5 12.7 26.4 21.4
16.0 51.0 26.7 40.6
16.4 7.9 27.6 13.3
16.8 60.0 28.5 5.5
17.6 9.7 29.6 13.5
18.2 15.0 30.9 14.1
18.7 16.7 31.8 3.6
19.1 25.4 32.1 5.8
19.4 6.9 33.9 4.6
20.3 10.8 34.8 4.9
本发明提供式Ⅰ化合物1，5-萘二磺酸盐晶型II，其粉末X射线衍射图包括位于4.2±0.2°，16.4±0.2°，22.8±0.2°和27.3±0.2°的衍射角(2θ)处的峰。
优选还包括位于8.5±0.2°，17.8±0.2°，19.1±0.2°，22.3±0.2°和28.1±0.2°的衍射角(2θ)处的峰。
更优选还包括位于10.4±0.2°，13.5±0.2°，15.1±0.2°，21.2±0.2°，24.0±0.2°和26.5±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图25中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表21所示：
表21
2θ(°) 强度％ 2θ(°) 强度％
4.2 100.0 22.3 22.2
8.5 19.4 22.8 40.2
10.4 12.7 24.0 8.1
13.5 11.2 26.5 6.0
15.1 7.9 27.3 48.6
16.4 60.9 28.1 20.9
17.8 18.5 28.5 3.6
19.1 14.0 32.6 2.8
21.2 5.4    
本发明提供式Ⅰ化合物1，5-萘二磺酸盐晶型III，其粉末X射线衍射图包括位于13.0±0.2°，22.7±0.2°，24.1±0.2°和25.7±0.2°的衍射角(2θ)处的峰。
优选还包括位于15.4±0.2°，18.8±0.2°，23.2±0.2°，25.4±0.2°和26.5±0.2°的衍射角(2θ)处的峰。
更优选还包括位于12.6±0.2°，14.5±0.2°，16.9±0.2°，18.5±0.2°，20.0±0.2°和21.4±0.2°的衍射角(2θ)处的峰。
最优选其X射线粉末衍射图与图26中显示的衍射角(2θ)处的峰基本上相同，其X射线粉末衍射数据如表22所示：
表22
2θ(°) 强度％ 2θ(°) 强度％
5.3 20.4 20.5 12.9
11.2 12.2 21.1 16.3
12.0 20.7 21.4 23.3
12.6 21.4 22.7 48.7
13.0 72.2 23.2 34.9
13.9 12.8 24.1 100.0
14.5 22.4 25.4 27.7
15.4 43.7 25.7 49.9
16.3 12.3 26.2 20.3
16.9 23.6 26.5 36.5
17.2 12.5 28.0 13.1
18.5 22.5 29.3 20.0
18.8 25.6 30.8 11.7
19.7 14.1 33.0 10.8
20.0 23.0 37.3 8.7
本文所使用的关于X射线衍射峰位置的术语“基本上相同的”意指考虑典型的峰位置和强度可变性。例如，本领域技术人员将理解，峰位置(2θ)将由于XRPD仪器不同，而造成测量值有所变化，有时这种变化达有时多达0.2°。此外，本领域技术人员将理解，XRPD样品制样方法，XRPD仪器，样品结晶度，样品用量以及晶体择优取向等因素将导致样品XRPD衍射图中相对峰强度的改变。
本发明另一方面提供了结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮(式Ⅰ化合物)的游离碱的制备方法，包括，
通过将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮在含水溶剂、有机溶剂或溶剂混合物中通过升温溶解，然后降温析出或与反溶剂混合析出的方法获得；
或者通过快速或缓慢挥发9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮溶液或混悬液获得；
或者通过往9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮溶液中加入原化合物固体或其他固体颗粒添加剂作为异核晶种诱导结晶；
或者通过将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮分散在含水溶剂、有机溶剂或溶剂混合物中以及分散在这些媒介的气氛中得到晶体；
或者通过将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮加热，或升华，或研磨，或冷冻，或熔融-降温的方法处理化合物而得到化合物晶体；或者通过将上述方法的联合使用以获得晶体。
包括但不限定于以下所列举的方法，如有机溶剂是指包括但不限定于下列所列举的溶剂醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类、亚砜类有机溶剂或其混合物，优选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、乙腈、丙酮、甲乙酮、四氢呋喃、二氧六环、N，N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、二氯甲烷、三氯乙烷、四氯化碳、正庚烷、正己烷、异辛烷、戊烷、环己烷、环戊烷、乙醚、甲基叔丁基醚、异丙醚、苯、甲苯、二甲苯或其组合物，超临界流体如二氧化碳液体、离子液体，高分子溶液等。
例如：
1)游离碱晶型I制备
在式Ⅰ化合物游离碱中加入适当的溶剂(包括但不限于异丙醇、乙酸异丙酯、乙腈、四氢呋喃、2-甲氧基乙醇或其混合物)，使其分散在溶剂中形成含量为1-200mg/mL的混悬液。搅拌混悬液至完全转化成游离碱晶型I后，固液分离得到化合物游离碱晶型I。
2)游离碱晶型II制备
在式Ⅰ化合物游离碱中加入适当的溶剂(包括但不限于甲醇、乙醇、丙酮、二氯甲烷或其混合物)使其分散在溶剂中形成含量为1-200mg/mL的混悬液，搅拌混悬液至完全转化成游离碱晶型II后，固液分离得到化合物游离碱晶型II。
3)游离碱晶型III制备
在式Ⅰ化合物游离碱中加入乙腈使其分散在乙腈中形成含量为1-200mg/mL的混悬液。在40-60℃下搅拌搅拌混悬液至完全转化成游离碱晶型III后，固液分离得到化合物游离碱晶型III。
4)游离碱晶型IV制备
将式Ⅰ化合物游离碱加热至100℃以上(优选120℃以上)使其熔解，然后缓慢降温至室温，得到游离碱晶型IV。
本发明再一方面提供了一种结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐的制备方法，包括，
1)将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱溶解或分散在含水溶剂或适合的有机溶剂中，在上述体系中加入无机酸或有机酸的液体或固体或者酸的溶液，制备9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐；
或者将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱固体加入酸的溶液中，制备9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐；
2)收集上述成盐反应过程中析出的固体产物、或者通过创造成盐体系中的过饱合度来得到固体产物，创造过饱合度的方法包括：挥发溶剂、或者加入反溶剂、或者通过降温的方法得到结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐；
和/或，
通过晶型转化的方法，将酸式盐的一种晶型转化为该盐的另外一种晶型。晶型转化的方法包括：加热或在合适的溶剂中混悬液转晶的方法。
所述步骤1)成盐过程中所述的适合的有机溶剂醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类、亚砜类有机溶剂或其混合物，优选自甲醇、乙醇、正丙醇、异丙醇、乙腈、丙酮、1,4-二氧六环、四氢呋喃、N，N-二甲基甲酰胺、乙酸乙酯、乙酸异丙酯、2-甲氧基乙醚或其混合物；
所述的“酸式盐”本文所述的“酸式盐”指本发明化合物与酸性物所形成的适合于药用的盐，包括无机酸盐或有机酸盐；所述酸式盐包括无机酸盐或有机酸盐；所述无机酸盐优选自盐酸盐、硫酸盐、氢溴酸盐、氢氟酸盐、氢碘酸盐或磷酸盐，更优选自盐酸盐、硫酸盐或磷酸盐；所述有机酸盐优选自2,5-二羟基苯甲酸盐、1-羟基-2-萘甲酸盐、醋酸盐、二氯醋酸盐、三氯醋酸盐、乙酰氧肟酸盐、己 二酸盐、苯磺酸盐、4-氯苯磺酸盐、苯甲酸盐、4-乙酰氨基苯甲酸盐、4-氨基苯甲酸盐、癸酸盐、己酸盐、辛酸盐、肉桂酸盐、柠檬酸盐、环己烷氨基磺酸盐、樟脑磺酸盐、天门冬氨酸盐、樟脑酸盐、葡萄糖酸盐、葡糖醛酸盐、谷氨酸盐、异抗坏血酸盐、乳酸盐、天门冬氨酸盐、苹果酸盐、扁桃酸盐、焦谷氨酸盐、酒石酸盐、十二烷基硫酸盐、二苯甲酰酒石酸盐、乙烷-1,2-二磺酸盐、乙磺酸盐、蚁酸盐、富马酸盐、半乳糖酸盐、龙胆酸盐、戊二酸盐、2-酮戊二酸盐、乙醇酸盐、马尿酸盐、羟乙基磺酸盐、乳糖酸盐、抗坏血酸盐、天冬氨酸盐、月桂酸盐、樟脑酸盐、马来酸盐、丙二酸盐、甲磺酸盐、1,5-萘二磺酸盐、萘-2-磺酸盐、烟酸盐、油酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、丙酸盐、水杨酸盐、4-氨基水杨酸盐、癸二酸盐、硬脂酸盐、丁二酸盐、、硫氰酸盐、十一碳烯酸盐、三氟乙酸盐、琥珀酸盐、对甲苯磺酸盐，更优选自甲磺酸盐、对甲苯磺酸盐或1，5-萘二磺酸盐。
例如：
1)盐酸盐晶型I制备
在式Ⅰ化合物游离碱中加入适当的溶剂(包括但不限于甲醇、乙腈、丙酮、乙酸乙酯或其混合物)，再加入同等或过量摩尔当量的盐酸，混合搅拌，待成盐反应完全后，进行固液分离即得到盐酸盐晶型I。
2)硫酸盐晶型I制备
在式Ⅰ化合物游离碱中加入适当的溶剂(包括但不限于乙腈、丙酮或其混合物)，再加入同等或过量摩尔当量的硫酸，混合搅拌，待成盐反应完全后，进行固液分离即得到硫酸盐晶型I。
3)硫酸盐晶型II制备
在式Ⅰ化合物游离碱中加入体积比为5-95％乙醇水溶液，再加入同等或过量摩尔当量的硫酸，混合搅拌，待成盐反应完全后，进行固液分离即得到硫酸盐晶型II。
4)磷酸盐晶型I制备
在式Ⅰ化合物游离碱中加入甲醇或体积比为5-95％乙醇水溶液，再加入同等或过量摩尔当量的磷酸，混合搅拌，待成盐反应完全后，进行固液分离即得到磷酸盐晶型I。
5)磷酸盐晶型II制备
在式Ⅰ化合物游离碱中加入适当的溶剂(包括但不限于乙腈、乙酸乙酯、四氢呋喃或其混合物)，再加入同等或过量摩尔当量的磷酸，混合搅拌，待成盐反应完全后，进行固液分离即得到磷酸盐晶型II。
6)磷酸盐晶型III制备
在式Ⅰ化合物游离碱中加入适当的溶剂(包括但不限于丙酮)，再加入同等或过量摩尔当量的磷酸，混合搅拌，待成盐反应完全后，进行固液分离即得到磷酸盐晶型III。
7)磷酸盐晶型IV制备
式Ⅰ化合物游离碱中加入适当的溶剂(包括但不限于甲醇)，再加入同等或过量摩尔当量的磷酸，混合搅拌，待成盐反应完全后，进行固液分离，得到磷酸盐晶型IV。
8)甲磺酸盐晶型I制备
在式Ⅰ化合物游离碱中加入适当的溶剂(包括但不限于丙酮、四氢呋喃、乙酸异丙酯、乙酸乙酯、2-甲氧基乙醚、1,4-二氧六环或其混合物)，再加入同等或过量摩尔当量的甲磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得到甲磺酸盐晶型I。
9)甲磺酸盐晶型II制备
在式Ⅰ化合物游离碱中加入体积比为5％-95％的甲醇水溶液，混合搅拌，再加入等量或过量摩尔当量的甲磺酸至溶液澄清，待成甲磺酸盐析出后，进行固液分离即得到甲磺酸盐晶型II。
10)甲磺酸盐晶型III制备
在式Ⅰ化合物游离碱中加入甲醇，再缓慢滴加入同等或过量摩尔当量的甲磺酸，至化合物溶解后，立即加入甲磺酸晶型III的晶种，混合搅拌，待成盐反应完全后，进行固液分离即得到甲磺酸盐晶型III。
或者在不加晶种的情况下，先得到甲磺酸盐晶型IV，将甲磺酸盐晶型IV在100-120℃下真空干燥，甲磺酸晶型IV将转化为甲磺酸盐晶型III。
或将甲磺酸盐晶型V分散在单一或混合反溶剂中，如正庚烷/乙酸乙酯溶液，在室温或加热条件下搅拌，将甲磺酸盐晶型V转化成晶型III。
11)甲磺酸盐晶型IV制备
在式Ⅰ化合物游离碱中加入甲醇，再缓慢滴加入同等或过量摩尔当量的甲磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得甲磺酸盐晶型IV。
12)甲磺酸盐晶型V制备
在式Ⅰ化合物游离碱中加入二甲基亚砜(DMSO)，再缓慢滴加入同等或过量摩尔当量的甲磺酸，混合搅拌，待成盐反应完全后，加入适量乙酸乙酯，继续搅拌，然后进行固液分离即得甲磺酸盐晶型V。
13)对甲苯磺酸盐晶型I制备
在式Ⅰ化合物游离碱中加入适当溶剂(包括但不限于甲醇、乙腈、丙酮或其混合物)，再加入同等或过量摩尔当量的对甲苯磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得到对甲苯磺酸盐晶型I。
14)对甲苯磺酸盐晶型II制备
在式Ⅰ化合物游离碱中加入适当溶剂(包括但不限于乙酸乙酯)，再加入同等或过量摩尔当量的对甲苯磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得到对甲苯磺酸盐晶型II。
15)对甲苯磺酸盐晶型III制备
在式Ⅰ化合物游离碱中加入体积比为5％-95％乙醇水溶液，再加入同等或过量摩尔当量的对甲苯磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得到对甲苯磺酸盐晶型III。
16)1，5-萘二磺酸盐晶型I制备
在式Ⅰ化合物游离碱中加入适当溶剂(包括但不限于甲醇、乙腈、丙酮或其混合物)，再加入同等或过量摩尔当量的1，5-萘二磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得到1，5-萘二磺酸盐晶型I。
17)1，5-萘二磺酸盐晶型II制备
在式Ⅰ化合物游离碱中加入适当溶剂(包括但不限于乙酸乙酯)，再加入同等或过量摩尔当量的1，5-萘二磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得到1，5-萘二磺酸盐晶型II。
18)1，5-萘二磺酸盐晶型III制备
在式Ⅰ化合物游离碱中加入适当溶剂(包括但不限于甲醇)，再加入同等或过量摩尔当量的1，5-萘二磺酸，混合搅拌，待成盐反应完全后，进行固液分离，得到1，5-萘二磺酸盐晶型III。
应当说明的是，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换，例如，采用本发明前述部分所例举的一些有机溶剂，也包含了本发明技术方案的精神和范围，其均应涵盖在本发明的发明内容之内。
本发明的另一个方面提供了一种药物组合物，所述药物组合物含有治疗有效剂量的前述式Ⅰ化合物结晶型游离碱或前述结晶型酸式盐，或药学上可接受的载体或赋形剂。
本发明另一个方面提供了前述式Ⅰ化合物结晶型游离碱、前述游离碱多晶型、前述结晶型酸式盐、前述酸式盐多晶型、前述药物组合物在制备治疗与蛋白质激酶有关的疾病的药物中的用途，其中所述蛋白激酶选自c-Met和VEGFR受体酪氨酸激酶。
本发明另一个方面提供了前述式Ⅰ化合物结晶型游离碱、前述游离碱多晶型、前述结晶型酸式盐、前述酸式盐多晶型、前述药物组合物制备蛋白激酶抑制剂的用途，其中所述蛋白激酶选自c-Met和VEGFR受体酪氨酸激酶。
本发明的另一个方面提供了一种调节蛋白激酶催化活性的方法，其中包括将所述蛋白激酶与前述式Ⅰ化合物结晶型游离碱、前述游离碱多晶型、前述结晶型酸式盐、前述酸式盐多晶型、前述药物组合物相接触，所述蛋白激酶选自c-met和VEGFR受体酪氨酸激酶。
本发明前述式Ⅰ化合物结晶型游离碱、前述游离碱多晶型、前述结晶型酸式盐、前述酸式盐多晶型、前述药物组合物还可以用于在制备治疗癌症和转移，包括癌症(实体瘤)、淋巴系统造血肿瘤、骨髓系统造血瘤、间充质起因的肿瘤、中枢和外周神经系统的肿瘤或其他肿瘤药物中的用途。包括但不限于：所述癌症选自膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、胃癌、肺癌(非小细胞肺癌)或皮肤癌；所述淋巴系统造血肿瘤选自白血病、急性淋巴细胞白血病或慢性淋巴细胞白血病；所述骨髓系统造血瘤选自急性或慢性骨髓性白血病、骨髓发育不良综合征或前髓细胞白血病；所述间充质起因的肿瘤选自纤维肉瘤、横纹肌肉瘤、软组织肉瘤或骨肉瘤；所述中枢和外周神经系统的肿瘤选自星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经末梢瘤；所述其他肿瘤选自恶性黑素瘤、精原细胞瘤、畸胎癌、甲状腺滤泡癌或卡波西肉瘤。
优选在制备治疗肝癌、肺癌、乳腺癌、表皮鳞癌或胃癌的药物中的用途。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/药学上可接受的盐或前体药物与其他化学组分的混合物，以或其他组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
附图说明
图1为式Ⅰ化合物游离碱晶型I的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图2为式Ⅰ化合物游离碱晶型I的DSC图；横坐标为温度(摄氏度)，纵坐标为热流(W/g),放热峰向下；其中所示峰的峰面积(Area)：121.2J/g，熔点(Peak)：276.8℃，起始温度(Onset)：274.4℃，终止温度(End)：278.7℃，峰高(Height)：6.716mW/mg。
图3为式Ⅰ化合物游离碱晶型I的TGA图；横坐标为温度(摄氏度)，纵坐标为失重百分比(％)。
图4为式Ⅰ化合物游离碱晶型II的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图5为式Ⅰ化合物游离碱晶型III的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图6为式Ⅰ化合物游离碱晶型III的DSC/TGA叠加图；横坐标为温度(摄氏度)，左侧纵坐标为热流(W/g),放热峰向上；右侧纵坐标为失重百分比(％)。
图7为式Ⅰ化合物游离碱晶型IV的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图8为式Ⅰ化合物盐酸盐晶型I的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图9为式Ⅰ化合物硫酸盐晶型I的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图10为式Ⅰ化合物硫酸盐晶型II的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图11为式Ⅰ化合物磷酸盐晶型I的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图12为式Ⅰ化合物磷酸盐晶型II的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图13为式Ⅰ化合物磷酸盐晶型III的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图14为式Ⅰ化合物磷酸盐晶型IV的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图15为式Ⅰ化合物甲磺酸盐晶型I的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图16为式Ⅰ化合物甲磺酸盐晶型II的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图17为式Ⅰ化合物甲磺酸盐晶型III的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图18为式Ⅰ化合物甲磺酸盐晶型III的DSC/TGA叠加图；横坐标为温度(摄氏度)，右侧纵坐标为热流(W/g),放热峰向上；左侧纵坐标为失重百分比(％)。
图19为式Ⅰ化合物甲磺酸盐晶型IV的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图20为式Ⅰ化合物甲磺酸盐晶型V的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图21为式Ⅰ化合物对甲苯磺酸盐晶型I的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图22为式Ⅰ化合物对甲苯磺酸盐晶型II的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图23为式Ⅰ化合物对甲苯磺酸盐晶型III的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图24为式Ⅰ化合物1，5-萘二磺酸盐晶型I的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图25为式Ⅰ化合物1，5-萘二磺酸盐晶型II的X射线粉末衍射图；横坐标为角度2θ(°)，纵坐标为强度。
图26为式Ⅰ化合物1，5-萘二磺酸盐晶型III的X射线粉末衍射图；横坐标 为角度2θ(°)，纵坐标为强度。
图27为式Ⅰ化合物1，5-萘二磺酸盐晶型III的DSC图。横坐标为温度(摄氏度)，纵坐标为热流(W/g),放热峰向上。
图28为式Ⅰ化合物甲磺酸盐晶型III与游离碱晶型I的血药浓度-时间曲线。
具体实施方式
以下提供的具体实施例以及制备方法例将进一步举例说明本发明实施方案的特定方面。下列实施例的范围将不以任何方式限制本发明的范围。
方法和材料
式Ⅰ化合物的游离碱晶型及其盐晶型由它们的X射线粉末衍射图表征。因此，在具有使用Cu Kα辐射
Figure PCTCN2015085514-appb-000002
以反射方式操作的GADDS(一般面积衍射检测器系统)CS的Bruker D8Discover X射线粉末衍射仪上采集所述盐的X射线粉末衍射图。管电压和电流量分别设置为40kV和40mA采集扫描。在3.0°至40°或45°的2θ范围内扫描样品60秒的时期。针对2θ表示的峰位置，使用刚玉标准品校准衍射仪。在通常是20℃-30℃的室温下实施所有分析。使用用于4.1.14T版WNT软件的GADDS，采集和积分数据。使用2003年发行的具有9.0.0.2版Eva的DiffracPlus软件，分析衍射图。XRPD样品的制备，通过是将样品至于单晶硅片上，用玻璃片或等效物压样品粉末以确保样品的表面平坦并有适当的高度。然后将样品支架放入Bruker XRPD仪器，并使用上文描述的仪器参数采集X射线粉末衍射图。由包括以下的多种因素产生与这类X射线粉末衍射分析结果相关的测量差异：(a)样品制备物(例如样品高度)中的误差，(b)仪器误差，(c)校准差异，(d)操作人员误差(包括在测定峰位置时出现的那些误差)，和(e)物质的性质(例如优选的定向误差)。校准误差和样品高度误差经常导致所有峰在相同方向中的位移。一般地说，这个校准因子将使测量的峰位置与预期的峰位置一致并且可以在预期的2θ值±0.2°的范围中。本发明实施例所得各多晶型的角度2θ值(°)和强度值(作为最高峰值的％)已列入表1-表22中。
无定形游离碱的制备
无定形式Ⅰ化合物游离碱是根据中国专利CN201310173581.4及其PCT申请(PCT/CN2014/072825)实施例二十二制备而得，具体操作为：30mL微波管中依次加入8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-硫醇(93mg,0.375mmol),9-溴-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮(100mg,0.341mmol)，三(二亚苄基丙酮)二钯(20mg,0.034mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(40mg,0.068mmol)，叔丁醇钠(40mg,0.409mmol)和无水N,N二甲基甲酰胺(5mL)。氮气扫吹，微波加热至120℃反应4个小时。反应结束后，旋干N,N二甲基甲酰胺，反相柱层析分离，得到36mg白色无定型9-((8-氟-6-(1-甲基- 1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮22。
无定形游离碱在不同模拟生物媒介中的溶解度
操作方法：称取约10mg的无定形游离碱置于2-mL玻璃小瓶中，再加1mL模拟生物媒介(模拟人工胃液，模拟人工肠液-空腹，模拟人工肠液-饱腹)，加入磁力搅拌子后并密封小瓶，在37摄氏度下磁力搅拌，在不同时间点取样约0.4mL，用过滤离心管(滤膜孔径0.45um)，过滤离心，取过滤液，用HPLC分析其中的化合物I的含量。测量结果见下表：
Figure PCTCN2015085514-appb-000003
实施例1游离碱晶型I制备
称取一定量的式Ⅰ化合物游离碱(无定形)置于容器中，加入溶剂使式Ⅰ化合物游离碱分散在溶剂中形成含量为1-200mg/mL的混悬液。室温下(20-25℃)搅拌混悬液至无定形式Ⅰ化合物转化成游离碱晶型I后，固液分离得到的固体即为化合物游离碱晶型I，其X射线粉末衍射图如图1所示。
用差示量热扫描仪(DSC,型号Neszsch DSC 204F1)测量游离碱晶型I的熔点。测量条件为从室温加热到300摄氏度，升温速率为10摄氏度每分钟，加热在氮气气氛下进行，氮气流量为20mL每分钟。游离碱晶型I的DSC图如图2所示。游离碱晶型I的熔点(起始温度点)为：274.4摄氏度。用热重分析仪(TGA，型号TA Q500)测量游离碱晶型I的热失重情况。测量条件为从室温加热到350摄氏度，升温速率为10摄氏度每分钟，加热在氮气气氛下进行，氮气流量为50mL每分钟。游离碱晶型I的TGA图如图3所示。在100摄氏度以内几乎不失重，因此可以判定化合物游离碱晶型I为无水合物。
Figure PCTCN2015085514-appb-000004
化合物游离碱晶型I在不同模拟生物媒介中的溶解度
操作方法：称取约10mg的化合物游离碱晶型I置于2-mL玻璃小瓶中，再加 1mL模拟生物媒介(模拟人工胃液，模拟人工肠液-空腹，模拟人工肠液-饱腹)，加入磁力搅拌子后并密封小瓶，在37摄氏度下磁力搅拌，在不同时间点取样约0.4mL，用过滤离心管(滤膜孔径0.45um)，过滤离心，取过滤液，用HPLC分析其中的化合物I的含量。测量结果见下表：
Figure PCTCN2015085514-appb-000005
实施例2游离碱晶型II制备
称取一定量的式Ⅰ化合物游离碱(无定形)置于容器中，加入溶剂使式Ⅰ化合物游离碱分散在溶剂中形成含量为1-200mg/mL的混悬液。加入的适当的溶剂。室温下(20-25℃)搅拌混悬液至无定形式Ⅰ化合物转化成游离碱晶型II后，固液分离得到的固体即为化合物游离碱晶型II，其X射线粉末衍射图如图4所示。
Figure PCTCN2015085514-appb-000006
实施例3游离碱晶型III制备
称取约20mg的式Ⅰ化合物游离碱晶型II置于2-mL HPLC小瓶中，然后加入1.0mL的乙腈，50℃下磁力搅拌约1天，使其充分结晶得到固体，即为化合物游离碱晶型III，其X射线粉末衍射图如图5所示。
用差示量热扫描仪(DSC,型号TA Q2000)测量有游离碱晶型III的熔点。测量条件为从室温加热到300摄氏度，升温速率为10摄氏度每分钟，加热在氮气气氛下进行，氮气流量为20mL每分钟。游离碱晶型III的DSC图如图5所示。游离碱晶型III的熔点(起始温度点)为：275.5摄氏度。用热重分析仪(TGA，型号TA Q500)测量游离碱晶型III的热失重情况。测量条件为从室温加热到350摄氏度，升温速率为10摄氏度每分钟，加热在氮气气氛下进行，氮气流量为50mL每分钟。游离碱晶型III的TGA图如图6所示。在100摄氏度以内几乎不失重，因此可以判定化合物游离碱III为无水合物。
化合物游离碱晶型III在不同模拟生物媒介中的溶解度
操作方法：称取约10mg的化合物游离碱晶型III置于2-mL玻璃小瓶中，再加1mL模拟生物媒介(模拟人工胃液，模拟人工肠液-空腹，模拟人工肠液-饱腹)，加入磁力搅拌子后并密封小瓶，在37摄氏度下磁力搅拌，在不同时间点取样约0.4mL，用过滤离心管(滤膜孔径0.45um)，过滤离心，取过滤液，用HPLC分析其中的化合物I的含量。测量结果见下表：
Figure PCTCN2015085514-appb-000007
实施例4游离碱晶型IV制备
称取约10mg的式Ⅰ化合物游离碱晶型II置于TGA(热重分析仪中，型号TA Q500)中，加热至从室温25℃以10℃/min速率加热至120摄氏度脱去溶剂后缓慢降至室温(10℃/min)得到固体。其X射线粉末衍射图如图7所示。
实施例5盐酸盐晶型I制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的甲醇，再加入4.8μL 37％盐酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到盐酸盐晶型I，其X射线粉末衍射图如图8所示。
Figure PCTCN2015085514-appb-000008
实施例6硫酸盐晶型I制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的乙腈或丙酮，再加入4.9μL 98％浓硫酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到硫酸盐晶型I，其X射线粉末衍射图如图9所示。
Figure PCTCN2015085514-appb-000009
Figure PCTCN2015085514-appb-000010
实施例7硫酸盐晶型II制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的50％乙醇溶液，再加入4.9μL 98％浓硫酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到硫酸盐，得到硫酸盐晶型II，其X射线粉末衍射图如图10所示。
实施例8磷酸盐晶型I制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的甲醇或50％乙醇，再加入7.5μL 85％磷酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到磷酸盐晶型I，其X射线粉末衍射图如图11所示。
式Ⅰ化合物起始状态 无定形 无定形
式Ⅰ化合物投料量 20mg 20mg
溶剂名称 甲醇 50％乙醇/水
溶剂量 1mL 1mL
浓度 20mg/mL 20mg/mL
85％磷酸溶液 7.5uL 7.5uL
实验温度 室温 室温
实验结果 磷酸盐晶型I 磷酸盐晶型I
化合物磷酸盐晶型I在不同模拟生物媒介中的溶解度
操作方法：称取约10mg的化合物磷酸盐晶型I置于2-mL玻璃小瓶中，再加1mL模拟生物媒介(模拟人工胃液，模拟人工肠液-空腹，模拟人工肠液-饱腹)，加入磁力搅拌子后并密封小瓶，在37摄氏度下磁力搅拌，在不同时间点取样约0.4mL，用过滤离心管(滤膜孔径0.45um)，过滤离心，取过滤液，用HPLC分析其中的化合物I的含量。测量结果见下表：
Figure PCTCN2015085514-appb-000011
磷酸盐晶型I的溶解度，远大于游离碱的溶解度，提高了式I化合物的溶解性，有利于增加生物利用度。
实施例9磷酸盐晶型II制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的乙腈、乙酸乙酯或四氢呋喃，再加入7.5μL 85％磷酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到磷酸盐晶型II，其X射线粉末衍射图如图12所示。
Figure PCTCN2015085514-appb-000012
实施例10磷酸盐晶型III制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的丙酮，再加入7.5μL 85％磷酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到磷酸盐晶型III，其X射线粉末衍射图如图13所示。
实施例11磷酸盐晶型IV制备
称取约100mg的式Ⅰ化合物游离碱置于20-mL玻璃瓶中，然后加入5.0mL的甲醇，再加入37.5μL 85％磷酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到磷酸盐晶型IV，其X射线粉末衍射图如图14所示。
实施例12甲磺酸盐晶型I制备
称取一定质量的式Ⅰ化合物的游离碱置于容器中，然后加入适当的溶剂，再加入同等或过量摩尔当量的甲磺酸，混合搅拌，待成盐反应完全后，进行固液分离，得到甲磺酸盐晶型I(水合物)，其X射线粉末衍射图如图15所示。例如：
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的丙酮，再加入6.2μL 98％甲磺酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到甲磺酸盐晶型I。
Figure PCTCN2015085514-appb-000013
Figure PCTCN2015085514-appb-000014
实施例13甲磺酸盐晶型II制备
称取约为一定质量的式Ⅰ化合物的游离碱置于容器中，然后加入甲醇/水混合溶剂(甲醇/水比例5％-95％体积/体积)，混合搅拌，再加入等量或过量摩尔当量的甲磺酸至溶液澄清，待成甲磺酸盐析出后，进行固液分离，得到甲磺酸盐晶型II(水合物)，其X射线粉末衍射图如图16所示。
实施例14甲磺酸盐晶型III制备
方法一：
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的甲醇，再加入6.2μL 98％甲磺酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到甲磺酸盐，然后在100摄氏度的真空干燥箱中干燥1天，得到甲磺酸盐晶型III，其X射线粉末衍射图如图17所示。
方法二：
将甲磺酸盐晶型IV在100℃下真空干燥，过夜。甲磺酸晶型IV将转化为甲磺酸盐晶型III，其X射线粉末衍射图与如图17一致。
方法三：
称取约300mg甲磺酸盐晶型V置于20mL玻璃瓶中，加入15mL 25％乙酸乙酯/正庚烷溶液(v/v)，40℃下搅拌24小时，过滤得到甲磺酸盐晶型III，其X射线粉末衍射图与如图17一致。
用差示量热扫描仪(DSC,型号TA Q2000)测量有化合物甲磺酸盐晶型III的熔点。测量条件为从室温加热到300摄氏度，升温速率为10摄氏度每分钟，加热在氮气气氛下进行，氮气流量为20mL每分钟。甲磺酸盐晶型III的DSC图如图18所示。甲磺酸盐晶型III的熔点(起始温度点)为：252.4摄氏度。用热重分析仪(TGA，型号TA Q500)测量甲磺酸盐晶型III的热失重情况。测量条件为从室温加热到350摄氏度，升温速率为10摄氏度每分钟，加热在氮气气氛下进行，氮气流量为50mL每分钟。甲磺酸盐晶型III的TGA图如图18所示。在100摄氏度以内几乎不失重，因此可以判定化合物甲磺酸盐晶型III为无水合物。
化合物I甲磺酸盐晶型III在不同模拟生物媒介中的溶解度
操作方法为，称取约10mg的化合物I甲磺酸盐晶型III置于2-mL玻璃小瓶中，再加1mL模拟生物媒介(模拟人工胃液，模拟人工肠液-空腹，模拟人工肠液-饱腹)，加入磁力搅拌子后并密封小瓶，在37摄氏度下磁力搅拌，在不同时间点取样约0.4mL，用过滤离心管(滤膜孔径0.45um)，过滤离心，取过滤液，
用HPLC分析其中的化合物I的含量。测量结果见下表：
Figure PCTCN2015085514-appb-000015
甲磺酸盐晶型III的溶解度，远大于游离碱的溶解度，提高了式I化合物的溶解性，有利于提高生物利用度。
甲磺酸盐晶型III加速稳定性试验用于考察甲磺酸盐晶型III的物理和化学稳定性。具体操作方法为，取100mg甲磺酸盐置于加速稳定箱中，设定好下表中的实验条件，当样品放置下表中的足够时间后，取出用流动相溶解，用HPLC测定其纯度。加速稳定性试验开始前，初始样品用HPLC测定样品的纯度。用加速稳定性试验样品纯度与初始样品纯度的比值，作为化合物稳定性评判标准，若纯度比值小于95％，则认为样品不稳定，具体实验条件和实验结果列于下表：
Figure PCTCN2015085514-appb-000016
从上表结果可知，甲磺酸酸盐晶型III在上述条件下物理稳定性和化学稳定性良好。
从图28可见，甲磺酸盐晶型III与游离碱晶型I相比，生物利用度可以提高5倍。试验条件为：实验动物为狗，剂量为5mg/kg，灌胃，单次给药。因此盐型化合物相对于游离碱相比具有极大改进意义。
实施例15甲磺酸盐晶型IV制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的甲醇，再加入6.2μL 98％甲磺酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到甲磺酸盐晶型IV(甲醇溶剂合物)，其X射线粉末衍射图如图19所示。
实施例16甲磺酸盐晶型V制备
称取约100mg的式Ⅰ化合物游离碱置于10-mL玻璃瓶中，然后加入2.0mL的DMSO，再加入31.2μL98％甲磺酸溶液，室温搅拌至澄清，过滤。向所得滤液中加入3-mL的乙酸乙酯溶液，搅拌平衡24小时后，过滤得到甲磺酸盐晶型V(DMSO溶剂合物)。其X射线粉末衍射图如图20所示。
甲磺酸盐晶型V，DMSO溶剂合物的形成，起到了对式I化合物的提纯和精制的作用。
晶型 纯度
式I游离碱 95.0％
制成甲磺酸盐DMSO溶剂合物 99.7％
此外，形成甲磺酸盐晶型V，在单元操作上也可以带来极大便利，因为式I化合物可以溶解于DMSO，易于实现在线过滤，并通过管道将溶液输送到GMP车间中，通过与甲磺酸成盐反应结晶，从溶液中析出，过滤得到甲磺酸盐晶型V而提纯。甲磺酸盐晶型VI作为这种先进的提纯方法的重要产物，因此具有实际的应用价值。
实施例17对甲苯磺酸盐晶型I制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的甲醇，再加入8.6uL 98％对甲苯磺酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到对甲苯磺酸盐晶型I，其X射线粉末衍射图如表17所示。
Figure PCTCN2015085514-appb-000017
实施例18对甲苯磺酸盐晶型II制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的乙酸乙酯，再加入8.6uL 98％对甲苯磺酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到对甲苯磺酸盐晶型II，其X射线粉末衍射图如表18所示。
实施例19对甲苯磺酸盐晶型III制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的50％乙醇溶液，再加入8.6uL 98％对甲苯磺酸溶液，室温下磁力搅拌约2天，使其充分反应结晶得到对甲苯磺酸盐晶型III，其X射线粉末衍射图如表19所示。
实施例201，5-二萘磺酸盐晶型I制备
称取一定质量的式Ⅰ化合物游离碱置于容器中，然后加入甲醇、乙腈或丙酮，再加入同等或过量摩尔当量的1，5-萘二磺酸，混合搅拌，待成盐反应完全后，进行固液分离，得到1，5-萘二磺酸盐晶型I。例如：
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的丙酮，再加入23.8mg的1,5-萘二磺酸，室温下磁力搅拌约2天，使其充分反应结晶得到1,5-萘二磺酸盐晶型I，其X射线粉末衍射图如表20所示。
Figure PCTCN2015085514-appb-000018
实施例211，5-萘二磺酸盐晶型II制备
称取约20mg的式Ⅰ化合物游离碱置于2-mL HPLC小瓶中，然后加入1.0mL的乙酸乙酯，再加入23.8mg的1,5-萘二磺酸，室温下磁力搅拌约2天，使其充分反应结晶得到1,5-萘二磺酸盐晶型II，其X射线粉末衍射图如图20所示。
实施例221，5-萘二磺酸盐晶型III制备
称取约100mg的式Ⅰ化合物游离碱置于20-mL HPLC小瓶中，然后加入5.0mL的甲醇，再加入119mg的1,5-萘二磺酸，室温下磁力搅拌约2天，使其充分反应结晶得到1,5-萘二磺酸盐晶型III，其X射线粉末衍射图如图27所示。
用差示量热扫描仪(DSC,型号TA Q2000)测量有化合物1,5-萘二磺酸盐晶型III的熔点。测量条件为从室温加热到300摄氏度，升温速率为10摄氏度每分钟，加热在氮气气氛下进行，氮气流量为20mL每分钟。1,5-萘二磺酸盐III的DSC图如图26所示。甲磺酸盐晶型III的熔点(起始温度点)为：321.2摄氏度。
化合物I的1,5-萘二磺酸盐晶型III在不同模拟生物媒介中的溶解度
操作方法为，称取约10mg的化合物I 1,5-萘二磺酸盐晶型III置于2-mL玻璃小瓶中，再加1mL模拟生物媒介(模拟人工胃液，模拟人工肠液-空腹，模拟人工肠液-饱腹)，加入磁力搅拌子后并密封小瓶，在37摄氏度下磁力搅拌，在不同时间点取样约0.4mL，用过滤离心管(滤膜孔径0.45um)，过滤离心，取过滤液，用HPLC分析其中的化合物I的含量。测量结果见下表：
Figure PCTCN2015085514-appb-000019
1,5-萘二磺酸盐晶型III的溶解度，远大于游离碱的溶解度，提高了式I化合物的溶解性，有利于增加生物利用度。
最后应当说明的是，以上实施例仅用以说明本发明的技术方案而非限制本发明，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围内。

Claims (19)

  1. 一种结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱，所述结晶型游离碱选自晶型I、晶型II、晶型III或晶型IV，所述游离碱晶型Ⅰ，其粉末X射线衍射图包括位于13.0±0.2°,17.9±0.2°,21.2±0.2°和31.4±0.2°的衍射角(2θ)处的峰，优选还包括位于10.3±0.2°，11.1±0.2°，23.3±0.2°，23.8±0.2°和33.6±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于15.7±0.2°，17.7±0.2°，26.8±0.2°，28.0±0.2°，31.7±0.2°和32.8±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图1中显示的衍射角(2θ)处的峰基本上相同；所述游离碱晶型Ⅱ，其粉末X射线衍射图包括位于8.6±0.2°，11.5±0.2°，14.1±0.2°和19.8±0.2°的衍射角(2θ)处的峰，优选还包括位于11.9±0.2°，14.7±0.2°，15.2±0.2°，17.2±0.2°和18.9±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于5.8±0.2°，7.4±0.2°，20.9±0.2°，30.9±0.2°，31.4±0.2°和37.9±0.2°，的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图4中显示的衍射角(2θ)处的峰基本上相同；所述游离碱晶型Ⅲ，其粉末X射线衍射图包括位于12.8±0.2°，14.8±0.2°，18.0±0.2°和20.5±0.2°的衍射角(2θ)处的峰，优选还包括位于8.9±0.2°，9.2±0.2°，10.6±0.2°，15.8±0.2°和20.7±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于5.3±0.2°，5.9±0.2°，12.0±0.2°，14.0±0.2°，17.3±0.2°和19.9±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图5中显示的衍射角(2θ)处的峰基本上相同；所述游离碱晶型Ⅳ，其粉末X射线衍射图包括位于8.9±0.2°，12.6±0.2°，17.0±0.2°和17.9±0.2°的衍射角(2θ)处的峰，优选还包括位于13.2±0.2°，14.5±0.2°，20.5±0.2°，23.9±0.2°和26.3±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图7中显示的衍射角(2θ)处的峰基本上相同。
  2. 一种结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐，所述酸式盐包括无机酸盐或有机酸盐；所述无机酸盐优选自盐酸盐、硫酸盐、氢溴酸盐、氢氟酸盐、氢碘酸盐或磷酸盐，更优选自盐酸盐、硫酸盐或磷酸盐；所述有机酸盐优选自2,5-二羟基苯甲酸盐、1-羟基-2-萘甲酸盐、醋酸盐、二氯醋酸盐、三氯醋酸盐、乙酰氧肟酸盐、己二酸盐、苯磺酸盐、4-氯苯磺酸盐、苯甲酸盐、4-乙酰氨基苯甲酸盐、4-氨基苯甲酸盐、癸酸盐、己酸盐、辛酸盐、肉桂酸盐、柠檬酸盐、环己烷氨基磺酸盐、樟脑磺酸盐、天门冬氨酸盐、樟脑酸盐、葡萄糖酸盐、葡糖醛酸盐、谷氨酸盐、异抗坏血酸盐、乳酸盐、天门冬氨酸盐、苹果酸盐、扁桃酸盐、焦谷氨酸盐、酒石酸盐、十二烷基硫酸盐、二苯甲酰酒石酸盐、乙烷-1,2-二磺酸盐、乙磺酸盐、蚁酸盐、富马酸盐、半乳糖酸盐、龙胆酸盐、戊二酸 盐、2-酮戊二酸盐、乙醇酸盐、马尿酸盐、羟乙基磺酸盐、乳糖酸盐、抗坏血酸盐、天冬氨酸盐、月桂酸盐、樟脑酸盐、马来酸盐、丙二酸盐、甲磺酸盐、1,5-萘二磺酸盐、萘-2-磺酸盐、烟酸盐、油酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、丙酸盐、水杨酸盐、4-氨基水杨酸盐、癸二酸盐、硬脂酸盐、丁二酸盐、硫氰酸盐、十一碳烯酸盐、三氟乙酸盐、琥珀酸盐、对甲苯磺酸盐，更优选自甲磺酸盐、对甲苯磺酸盐或1，5-萘二磺酸盐。
  3. 根据权利要求2所述的结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐，其特征在于，所述酸式盐选自盐酸盐晶型Ⅰ，其粉末X射线衍射图包括位于8.1±0.2°，19.2±0.2°，24.1±0.2°和26.2±0.2°的衍射角(2θ)处的峰，优选还包括位于9.1±0.2°，11.3±0.2°，13.4±0.2°，29.7±0.2°和23.4±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图8中显示的衍射角(2θ)处的峰基本上相同。
  4. 根据权利要求2所述的结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐，其特征在于，所述酸式盐选自硫酸盐，优选自硫酸盐晶型I或硫酸盐晶型II，所述硫酸盐晶型Ⅰ，其粉末X射线衍射图包括位于18.4±0.2°，19.7±0.2°，23.8±0.2°和24.5±0.2°的衍射角(2θ)处的峰，优选还包括位于12.8±0.2°，14.4±0.2°，17.0±0.2°，20.0±0.2°和21.0±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于8.7±0.2°，13.2±0.2°，19.1±0.2°，26.3±0.2°，26.6±0.2°和29.0±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图9中显示的衍射角(2θ)处的峰基本上相同；所述硫酸盐晶型Ⅱ，其粉末X射线衍射图包括位于6.3±0.2°，8.7±0.2°，12.7±0.2°和18.4±0.2°的衍射角(2θ)处的峰，优选还包括位于8.3±0.2°，17.5±0.2°，18.7±0.2°，20.4±0.2°和25.6±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于9.1±0.2°，15.9±0.2°，16.8±0.2°，24.0±0.2°，25.2±0.2°和28.4±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图10中显示的衍射角(2θ)处的峰基本上相同。
  5. 根据权利要求2所述的结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐，其特征在于，所述酸式盐选自磷酸盐，优选自磷酸盐晶型I、磷酸盐晶型II、磷酸盐晶型III或磷酸盐晶型IV，所述磷酸盐晶型I，其粉末X射线衍射图包括位于7.9±0.2°，12.8±0.2°，15.9±0.2°和18.3±0.2°的衍射角(2θ)处的峰，优选还包括位于5.3±0.2°，10.6±0.2°，13.4±0.2°，20.9±0.2°和24.7±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于16.5±0.2°，18.7±0.2°，20.6±0.2°， 21.8±0.2°，26.2±0.2°和27.4±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图11中显示的衍射角(2θ)处的峰基本上相同；所述磷酸盐晶型II，其粉末X射线衍射图包括位于13.7±0.2°，16.1±0.2°，22.8±0.2°和26.1±0.2°的衍射角(2θ)处的峰，优选还包括位于11.0±0.2°，14.6±0.2°，20.3±0.2°，20.8±0.2°和25.7±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于6.8±0.2°，17.0±0.2°，22.2±0.2°，26.6±0.2°，27.9±0.2°和31.2±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图12中显示的衍射角(2θ)处的峰基本上相同；所述磷酸盐晶型III，其粉末X射线衍射图包括位于9.7±0.2°，15.6±0.2°，16.8±0.2°和24.6±0.2°的衍射角(2θ)处的峰，优选还包括位于4.8±0.2°，21.2±0.2°，25.0±0.2°，27.8±0.2°和28.1±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于5.2±0.2°，12.8±0.2°，14.5±0.2°，18.0±0.2°，20.1±0.2°和23.5±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图13中显示的衍射角(2θ)处的峰基本上相同；所述磷酸盐晶型IV，其粉末X射线衍射图包括位于7.8±0.2°，17.9±0.2°，25.0±0.2°和27.7±0.2°的衍射角(2θ)处的峰，优选还包括位于6.7±0.2°，10.8±0.2°，15.6±0.2°，23.4±0.2°和24.6±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于5.2±0.2°，12.8±0.2°，20.9±0.2°，21.7±0.2°，22.3±0.2°和26.8±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图14中显示的衍射角(2θ)处的峰基本上相同。
  6. 根据权利要求2所述的结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐，其特征在于，所述酸式盐选自甲磺酸盐，优选自甲磺酸盐晶型I、甲磺酸盐晶型II、甲磺酸盐III、甲磺酸盐晶型IV或甲磺酸盐晶型V，所述甲磺酸盐晶型I，其粉末X射线衍射图包括位于15.6±0.2°，17.0±0.2°，25.6±0.2°和26.0±0.2°的衍射角(2θ)处的峰，优选还包括位于9.8±0.2°，21.8±0.2°，23.5±0.2°，23.8±0.2°和27.5±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于6.6±0.2°，15.3±0.2°，17.2±0.2°，18.3±0.2°，19.7±0.2°和26.4±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图15中显示的衍射角(2θ)处的峰基本上相同；所述甲磺酸盐晶型II，其粉末X射线衍射图包括位于9.4±0.2°，17.0±0.2°，18.9±0.2°和27.3±0.2°的衍射角(2θ)处的峰，优选还包括位于6.6±0.2°，14.9±0.2°，21.1±0.2°，26.1±0.2°和26.9±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图16中显示的衍射角(2θ)处的峰基本上相同；所述甲磺酸盐晶型III，其粉末X射线衍射图包括位于16.7±0.2°，19.3±0.2°，23.2±0.2°和26.5±0.2°的衍射角(2θ)处的峰，优选还包括位于8.7±0.2°，19.5±0.2°，21.8±0.2°，23.6±0.2°和24.3±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于11.7±0.2°，13.6±0.2°，14.1±0.2°，17.2±0.2°，18.7±0.2°和27.2±0.2° 的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图17中显示的衍射角(2θ)处的峰基本上相同；所述甲磺酸盐晶型IV，其粉末X射线衍射图包括位于16.8±0.2°，19.1±0.2°，19.3±0.2°和22.1±0.2°的衍射角(2θ)处的峰，优选还包括位于21.9±0.2°，23.2±0.2°，24.4±0.2°，26.0±0.2°和27.2±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于8.7±0.2°，13.4±0.2°，13.6±0.2°，19.6±0.2°，21.6±0.2°和26.6±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图19中显示的衍射角(2θ)处的峰基本上相同；所述甲磺酸盐晶型V，其粉末X射线衍射图包括位于25.2±0.2°，9.3±0.2°，16.6±0.2°和19.1±0.2°的衍射角(2θ)处的峰，优选还包括位于22.7±0.2°，16.3±0.2°，21.2±0.2°，8.9±0.2°和12.3±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于23.7±0.2°，20.0±0.2°，15.9±0.2°，24.6±0.2°，28.6±0.2°和25.5±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图20中显示的衍射角(2θ)处的峰基本上相同。
  7. 根据权利要求2所述的结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐，其特征在于，所述酸式盐选自对甲苯磺酸盐，优选自对甲苯磺酸盐晶型I、对甲苯磺酸盐晶型II或对甲苯磺酸盐晶型III，所述对甲苯磺酸盐晶型I，其粉末X射线衍射图包括位于13.0±0.2°，15.4±0.2°，24.3±0.2°和25.7±0.2°的衍射角(2θ)处的峰，优选还包括位于5.3±0.2°，12.1±0.2°，18.4±0.2°，22.6±0.2°和23.2±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于14.6±0.2°，16.9±0.2°，18.8±0.2°，19.9±0.2°，25.3±0.2°和29.3±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图21中显示的衍射角(2θ)处的峰基本上相同；所述对甲苯磺酸盐晶型II，其粉末X射线衍射图包括位于13.7±0.2°，16.1±0.2°，25.7±0.2°和26.1±0.2°的衍射角(2θ)处的峰，优选还包括位于11.0±0.2°，14.6±0.2°，17.0±0.2°，22.8±0.2°和26.6±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于6.8±0.2°，20.3±0.2°，20.8±0.2°，22.2±0.2°，24.6±0.2°和27.9±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图22中显示的衍射角(2θ)处的峰基本上相同；所述对甲苯磺酸盐晶型III，其粉末X射线衍射图包括位于8.2±0.2°，14.4±0.2°，25.9±0.2°和26.3±0.2°的衍射角(2θ)处的峰，优选还包括位于10.3±0.2°，12.8±0.2°，17.2±0.2°，18.0±0.2°和19.9±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于4.8±0.2°，13.2±0.2°，15.1±0.2°，19.3±0.2°，24.2±0.2°和24.5±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图23中显示的衍射角(2θ)处的峰基本上相同。
  8. 根据权利要求2所述的结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式 盐，其特征在于，所述酸式盐选自1，5-萘二磺酸盐，优选自1，5-萘二磺酸盐晶型I、1，5-萘二磺酸盐晶型II或1，5-萘二磺酸盐晶型III，所述1，5-萘二磺酸盐晶型I，其粉末X射线衍射图包括位于10.8±0.2°，16.8±0.2°，21.8±0.2°和25.8±0.2°的衍射角(2θ)处的峰，优选还包括位于10.2±0.2°，16.0±0.2°，19.1±0.2°，20.8±0.2°和26.7±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于8.1±0.2°，13.6±0.2°，18.2±0.2°，18.7±0.2°，26.4±0.2°和30.9±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图24中显示的衍射角(2θ)处的峰基本上相同；所述1，5-萘二磺酸盐晶型II，其粉末X射线衍射图包括位于4.2±0.2°，16.4±0.2°，22.8±0.2°和27.3±0.2°的衍射角(2θ)处的峰，优选还包括位于8.5±0.2°，17.8±0.2°，19.1±0.2°，22.3±0.2°和28.1±0.2°的衍射角(2θ)处的峰，更优选进一步还优选还包括位于10.4±0.2°，13.5±0.2°，15.1±0.2°，21.2±0.2°，24.0±0.2°和26.5±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图25中显示的衍射角(2θ)处的峰基本上相同；所述1，5-萘二磺酸盐晶型III，其粉末X射线衍射图包括位于13.0±0.2°，22.7±0.2°，24.1±0.2°和25.7±0.2°的衍射角(2θ)处的峰，优选还包括位于15.4±0.2°18.8±0.2°，23.2±0.2°，25.4±0.2°和26.5±0.2°的衍射角(2θ)处的峰，更优选进一步还包括位于12.6±0.2°，14.5±0.2°，16.9±0.2°，18.5±0.2°，20.0±0.2°和21.4±0.2°的衍射角(2θ)处的峰，最优选其X射线粉末衍射图与图26中显示的衍射角(2θ)处的峰基本上相同。
  9. 一种结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱的制备方法，包括，
    通过将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮在含水溶剂、有机溶剂或溶剂混合物中通过升温溶解，然后降温析出或与反溶剂混合析出的方法获得；
    或者通过快速或缓慢挥发9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮溶液或混悬液获得；
    或者通过往9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮溶液中加入原化合物固体或其他固体颗粒添加剂作为异核晶种诱导结晶；
    或者通过将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮分散在含水溶剂、有机溶剂或溶剂混合物中以及分散在这些媒介的气氛中得到晶体；
    或者通过将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮加热，或升华，或研磨，或冷冻，或熔融-降温的方法处理化合物而得到化合物晶体；
    或者通过将上述方法的联合使用以获得晶体；
    优选的，所述有机溶剂选自醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类、亚砜类有机溶剂或其混合物，更优选甲醇、乙醇、正丙醇、异丙醇、正丁醇、乙腈、丙酮、甲乙酮、四氢呋喃、二氧六环、N，N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、二氯甲烷、三氯乙烷、四氯化碳、正庚烷、正己烷、异辛烷、戊烷、环己烷、环戊烷、乙醚、甲基叔丁基醚、异丙醚、苯、甲苯、二甲苯或其混合物。
  10. 一种结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐的制备方法，包括，
    1)将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱溶解或分散在含水溶剂或适合的有机溶剂中，在上述体系中加入无机酸或有机酸的液体或固体酸的溶液，制备9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐；
    或者将9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱固体加入酸的溶液中，制备9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐；
    2)收集上述成盐反应过程中析出的固体产物、或者通过创造成盐体系中的过饱合度来得到固体产物，创造过饱合度的方法包括：挥发溶剂、或者加入反溶剂、或者通过降温的方法得到结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮酸式盐；
    和/或，
    通过晶型转化的方法，将酸式盐的一种晶型转化为该盐的另外一种晶型,晶型转化的方法包括：加热或在合适的溶剂中混悬液转晶的方法；
    所述步骤1)成盐过程中所述的适合的有机溶剂选自醇类、氯代烷烃、酮类、醚类、环醚类、酯类、烷烃类、环烷烃类、苯类、酰胺类、亚砜类有机溶剂或其混合物，优选甲醇、乙醇、正丙醇、异丙醇、乙腈、丙酮、1,4-二氧六环、四氢呋喃、N，N-二甲基甲酰胺、乙酸乙酯、乙酸异丙酯、2-甲氧基乙醚或其混合物；
    所述的“酸式盐”包括无机酸盐或有机酸盐；所述酸式盐包括无机酸盐或有机酸盐；所述无机酸盐优选自盐酸盐、硫酸盐、氢溴酸盐、氢氟酸盐、氢碘酸盐或磷酸盐，更优选自盐酸盐、硫酸盐或磷酸盐；所述有机酸盐优选自2,5-二羟基苯甲酸盐、1-羟基-2-萘甲酸盐、醋酸盐、二氯醋酸盐、三氯醋酸盐、乙酰氧肟酸盐、己二酸盐、苯磺酸盐、4-氯苯磺酸盐、苯甲酸盐、4-乙酰氨基苯甲酸盐、4-氨基苯甲酸盐、癸酸盐、己酸盐、辛酸盐、肉桂酸盐、柠檬酸盐、环己烷氨基磺酸盐、樟脑磺酸盐、天门冬氨酸盐、樟脑酸盐、葡萄糖酸盐、葡糖醛酸盐、谷氨酸盐、异抗坏血酸盐、乳酸盐、天门冬氨酸盐、苹果酸盐、扁桃酸盐、焦谷氨酸盐、酒石酸盐、十二烷基硫酸盐、二苯甲酰酒石酸盐、乙烷-1,2-二磺酸盐、乙磺酸盐、蚁酸盐、富马酸盐、半乳糖酸盐、龙胆酸盐、戊二酸盐、2-酮戊二酸盐、乙醇酸盐、马尿酸盐、羟乙基磺酸盐、乳糖酸盐、抗坏血酸盐、天冬氨酸盐、月桂酸盐、樟脑酸盐、马来酸盐、丙二酸盐、甲磺酸盐、1,5-萘二磺酸盐、萘-2-磺酸盐、烟酸盐、油酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、丙酸盐、水杨酸盐、4-氨基水杨酸盐、癸二酸盐、硬脂酸盐、丁二酸盐、、硫氰酸盐、十一碳烯酸盐、三氟乙酸盐、琥珀酸盐、对甲苯磺酸盐，更优选自甲磺酸盐、对甲苯磺酸盐或1，5-萘二磺酸盐。
  11. 根据权利要求10所述的制备方法，其特征在于，在9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱中加入适当的溶剂，再加入同等或过量摩尔当量的甲磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得到甲磺酸盐晶型I，所述适当的溶剂选自丙酮、四氢呋喃、乙酸异丙酯、乙酸乙酯、2-甲氧基乙醚、1,4-二氧六环或其混合物。
  12. 根据权利要求10所述的制备方法，其特征在于，在9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱中加入体积比为5％-95％的甲醇水溶液，混合搅拌，再加入等量或过量摩尔当量的甲磺酸至溶液澄清，待成甲磺酸盐析出后，进行固液分离即得到甲磺酸盐晶型II。
  13. 根据权利要求10所述的制备方法，其特征在于，在9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱中加入甲醇，再缓慢滴加入同等或过量摩尔当量的甲磺酸，至化合物溶解后，立即加入甲磺酸晶型III的晶种，混合搅拌，待成盐反应完全后，进行固液分离即得到甲磺酸盐晶型III；
    或者在不加晶种的情况下，先得到甲磺酸盐晶型IV，将甲磺酸盐晶型IV在100-120℃下真空干燥，过夜，甲磺酸晶型IV将转化为甲磺酸盐晶型III；
    或者将甲磺酸盐晶型V分散在单一或混合反溶剂中，在室温或加热条件下搅拌，将甲磺酸盐晶型V转化成晶型III。
  14. 根据权利要求10所述的制备方法，其特征在于，在9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱中加入甲醇，再缓慢滴加入同等或过量摩尔当量的甲磺酸，混合搅拌，待成盐反应完全后，进行固液分离即得甲磺酸盐晶型IV。
  15. 根据权利要求10所述的制备方法，其特征在于，在9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱中加入二甲基亚砜，再缓慢滴加入同等或过量摩尔当量的甲磺酸，混合搅拌，待成盐反应完全后，加入适量乙酸乙酯，继续搅拌，然后进行固液分离即得甲磺酸盐晶型V。
  16. 药物组合物，其特征在于，所述药物组合物包含有效量的权利要求1所述的结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱或权利要求2-8任意一项所述的结晶型酸式盐或其多晶型，或药学上可接受的载体或赋形剂。
  17. 权利要求1所述结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱或其多晶型、权利要求2-8任一所述的结晶型酸式盐或其多晶型、权利要求16所述药物组合物在制备蛋白激酶抑制剂或治疗与蛋白质激酶有关的疾病的药物中的用途，其中所述蛋白激酶选自c-Met和VEGFR受体酪氨酸激酶。
  18. 一种调节蛋白激酶催化活性的方法，所述方法包括将所述蛋白激酶与其权利要求1所述结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱或其多晶型、权利要求2-8任意一项所述的结晶型酸式盐或其多晶型、权利要求16所述药物组合物相接触，所述蛋白激酶选自C-met和VEGFR受体酪氨酸激酶。
  19. 权利要求1所述结晶型9-((8-氟-6-(1-甲基-1H-吡唑-4-基)-[1,2,4]三唑并[4,3-a]吡啶-3-基)硫代)-4-甲基-2H-[1,4]氧杂联氮基[3,2-c]喹啉-3(4H)-酮游离碱或其多晶型、权利要求2-8任意一项所述的结晶型酸式盐或其多晶型、权利要求16所述药物组合物在制备治疗癌症和转移，包括癌症、淋巴系统造血肿瘤、骨髓系统 造血瘤、间充质起因的肿瘤、中枢和外周神经系统的肿瘤或其他肿瘤药物中的用途；
    优选的，所述癌症选自膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌、胃癌或皮肤癌；所述淋巴系统造血肿瘤选自白血病、急性淋巴细胞白血病或慢性淋巴细胞白血病；所述骨髓系统造血瘤选自急性或慢性骨髓性白血病、骨髓发育不良综合征或前髓细胞白血病；所述间充质起因的肿瘤选自纤维肉瘤、横纹肌肉瘤、软组织肉瘤或骨肉瘤；所述中枢和外周神经系统的肿瘤选自星形细胞瘤、神经母细胞瘤、神经胶质瘤或神经末梢瘤；所述其他肿瘤选自恶性黑素瘤、精原细胞瘤、畸胎癌、甲状腺滤泡癌或卡波西肉瘤；优选肝癌、肺癌、乳腺癌、表皮鳞癌或胃癌。
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CN106459091A (zh) 2017-02-22
CA2955547C (en) 2022-08-23
KR102516745B1 (ko) 2023-03-31
TW201605869A (zh) 2016-02-16

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