WO2018113592A1 - 4'-硫代-2'-氟代核苷磷酰胺化合物的固体形式及其制备方法和用途 - Google Patents

4'-硫代-2'-氟代核苷磷酰胺化合物的固体形式及其制备方法和用途 Download PDF

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WO2018113592A1
WO2018113592A1 PCT/CN2017/116396 CN2017116396W WO2018113592A1 WO 2018113592 A1 WO2018113592 A1 WO 2018113592A1 CN 2017116396 W CN2017116396 W CN 2017116396W WO 2018113592 A1 WO2018113592 A1 WO 2018113592A1
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crystal
compound
formula
diffraction angles
characteristic peaks
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PCT/CN2017/116396
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English (en)
French (fr)
Inventor
杨成喜
梁玉峰
周江峰
葛建华
田强
赵明亮
曾宏
赵富录
韩剑锋
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN201780065200.7A priority Critical patent/CN109952307B/zh
Priority to AU2017383598A priority patent/AU2017383598B2/en
Priority to EA201990780A priority patent/EA201990780A1/ru
Priority to US16/343,846 priority patent/US10787477B2/en
Priority to JP2019521416A priority patent/JP2020502043A/ja
Priority to EP17885123.4A priority patent/EP3560944A4/en
Priority to CA3041420A priority patent/CA3041420A1/en
Publication of WO2018113592A1 publication Critical patent/WO2018113592A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to (S)-isopropyl 2-(((S)-(((2R,3S,4S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)) Solid of 4-fluoro-3-hydroxy-tetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate (hereinafter referred to as "the compound of formula (I)”) Form, a method of preparing the solid form, a pharmaceutical composition comprising the solid form, and the use of the solid form for treating a cell proliferative disorder or a viral infectious disease.
  • Synthetic nucleoside analogues are an important class of tumor chemotherapy drugs, often referred to as antimetabolites, such as the marketed gemcitabine, azacytidine, decitabine, cytarabine, fludarabine. , cladribine, 6-azide uridine, thiazofurin and clofibrate. Its mechanism of action mainly inhibits the synthesis of DNA and RNA by affecting the enzyme system of tumor cells.
  • the 4'-thionucleoside refers to a nucleoside analog in which the oxygen atom in the furanose ring is substituted by a sulfur atom.
  • the synthetic route is long and the synthesis is difficult, which greatly restricts the research of such compounds.
  • US6147058 discloses a 4'-thionucleoside compound which inhibits colon cancer on a nude mouse model. This compound is superior to gemcitabine in tumor growth inhibition and is less toxic (Cancer Let. 1999, 144, 177-182). This compound also has an inhibitory effect on pancreatic cancer and ovarian cancer in a nude mouse model, and its inhibitory activity and safety are superior to gemcitabine (Int. J. Cancer, 2005, 114, 1002 - 1009).
  • One aspect of the present invention provides a compound of the formula (I) as shown below ((S)-isopropyl 2-(((S)-(((2),4S,4S,5R)-5-(4-amino) -2-oxo pyrimidine-1(2H)-yl)-4-fluoro-3-hydroxy-tetrahydrothiophen-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionate) Crystal:
  • the preferred crystal of the present invention not only has an excellent effect in preventing or treating a cell proliferation abnormal disease or a viral infectious disease, but also has other advantages.
  • preferred crystals of the compound of formula (I) of the present invention have excellent physical properties (including solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, fluidity, etc.), and are Preferred crystal forms of the present invention may have more excellent properties in terms of bioavailability, physical and/or chemical stability, and ease of preparation.
  • the preferred crystalline form of the present invention has good powder properties, is more suitable and convenient for mass production and is used to form a formulation, reduces irritation and enhances absorption, solves problems in metabolic rate, and significantly reduces drug accumulation. Toxicity improves safety and ensures the quality and efficacy of pharmaceutical products.
  • Preferred crystals of the compound of formula (I) of the present invention exhibit good chemical and thermal stability, and thus are more advantageous for adequate dissolution upon administration and formulation, and which retain sufficient biological activity. Further, preferred crystallinity of the compound of the formula (I) of the present invention With high bioavailability, an effective therapeutic dose of a compound of formula (I) can be provided in vivo.
  • differential scanning calorimetry of the crystals of the preferred compounds of formula (I) of the present invention is preferred because the crystals of the preferred compounds of formula (I) of the present invention are minimally or less degraded when stored or transported at ambient temperatures.
  • (DSC) analysis showed melting or desolvation at greater than 50 °C. This property indicates that the preferred crystals of the present invention are more suitable for use in standard formulation manufacturing processes.
  • the crystal of the compound of the formula (I) of the present invention is more stable in the aqueous pharmaceutical preparation, and therefore, the preferred crystal of the present invention is more advantageous to be developed into a controlled release preparation or a sustained release preparation.
  • the crystal of the compound of the formula (I) of the present invention preferably has good photostability, ensures the reliability of the crystal (for example, crystal A) during storage and transportation, thereby ensuring the safety of the drug, and the crystal (For example, crystal A) does not require special packaging treatment to prevent exposure to light, thereby reducing costs.
  • the crystal (for example, crystal A) does not undergo degradation due to the influence of light, and improves the safety of the drug and the effectiveness after long-term storage.
  • a patient taking the crystal eg, crystal A
  • Preferred crystals of the compound of formula (I) of the present invention have good flowability and particle shape, as well as significantly improved stickiness, which can significantly reduce filtration time, shorten production cycle, and save cost during formulation.
  • Another aspect of the present invention provides a method of preparing the crystal of the present invention, which is selected from the group consisting of a gas-liquid permeation method, a room temperature slow volatilization method, a polymer induced crystallization method, a gas-solid osmosis method, a slow cooling method, and an anti-solvent addition method. , room temperature suspension stirring method and high temperature suspension stirring method.
  • Another aspect of the invention provides a pharmaceutical composition comprising any one or more of the crystals of the invention, and one or more pharmaceutically acceptable carriers.
  • Another aspect of the present invention provides the use of the crystal of the present invention for the preparation of a medicament for preventing or treating a cell proliferative disorder or a viral infectious disease.
  • the invention provides crystal A of a compound of formula (I), the XRPD pattern of said crystal A comprising diffraction angles (2 ⁇ ) at about 10.5 ⁇ 0.2°, 13.5 ⁇ 0.2°, and 17.9 ⁇ 0.2° Characteristic peak.
  • the XRPD pattern of Crystal A of the compound of Formula (I) is comprised at about 10.5 ⁇ 0.2°, 13.5 ⁇ 0.2°, 15.8 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.3 ⁇ 0.2°, and 21.3 ⁇ Characteristic peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the XRPD pattern of crystal A of the compound of formula (I) is comprised at about 10.5 ⁇ 0.2°, 13.5 ⁇ 0.2°, 15.8 ⁇ 0.2°, 17.9 ⁇ 0.2°, 18.3 ⁇ 0.2°, 21.3. Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 22.3 ⁇ 0.2°, 24.2 ⁇ 0.2°, and 26.8 ⁇ 0.2°.
  • the XRPD pattern of crystal A of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal A of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal A of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal A of the compound of formula (I) comprises a peak at substantially the same diffraction angle (2 theta) as shown in FIG.
  • the XRPD peak position of crystal A of the compound of formula (I) is substantially the same as that shown in FIG.
  • the DSC profile of Crystal A of the compound of Formula (I) of the present invention comprises a characteristic peak at about 155.7 ⁇ 0.2 ° C (starting temperature).
  • the DSC profile of Crystal A of the compound of Formula (I) includes characteristic peaks at substantially the same temperature as shown in Figure 2.
  • the characteristic peak position of the DSC pattern of crystal A of the compound of formula (I) is substantially the same as that shown in FIG.
  • the crystal A of the compound of the formula (I) of the present invention is an unsolvate. In a more preferred embodiment, the crystal A of the compound of the formula (I) of the present invention is an amorphous form.
  • the invention provides crystal B of a compound of formula (I), the XRPD pattern of said crystal B comprising diffraction angles (2 theta) at about 7.0 ⁇ 0.2 °, 14.0 ⁇ 0.2 °, and 21.1 ⁇ 0.2 ° Characteristic peak at the place.
  • the XRPD pattern of crystal B of the compound of formula (I) is comprised at about 6.2 ⁇ 0.2 °, 7.0 ⁇ 0.2 °, 13.2 ⁇ 0.2 °, 14.0 ⁇ 0.2 °, 21.1 ⁇ 0.2 °, and 26.2 ⁇ Characteristic peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the XRPD pattern of the crystal B of the compound of formula (I) is comprised at about 6.2 ⁇ 0.2 °, 7.0 ⁇ 0.2 °, 9.3 ⁇ 0.2 °, 13.2 ⁇ 0.2 °, 14.0 ⁇ 0.2 °, 15.5. Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 18.7 ⁇ 0.2°, 21.1 ⁇ 0.2°, and 26.2 ⁇ 0.2°.
  • the XRPD pattern of crystal B of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal B of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal B of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal B of the compound of formula (I) comprises a peak at substantially the same diffraction angle (2 theta) as shown in FIG.
  • the XRPD peak position of crystal B of the compound of formula (I) is substantially the same as that shown in FIG.
  • the DSC profile of crystal B of the compound of formula (I) of the present invention comprises a characteristic peak at about 125.3 ⁇ 0.2 ° C (starting temperature).
  • the DSC spectrum of crystal B of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG.
  • the characteristic peak position of the DSC pattern of the crystal B of the compound of formula (I) is substantially the same as that shown in FIG.
  • the crystal B of the compound of formula (I) of the invention is an unsolvate. In a more preferred embodiment, the crystal B of the compound of formula (I) of the present invention is amorphous.
  • the invention provides crystal C of a compound of formula (I), the XRPD pattern of said crystal C comprising diffraction angles (2 theta) at about 8.6 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, and 21.0 ⁇ 0.2 ° Characteristic peak at the place.
  • the XRPD pattern of the crystalline C of the compound of formula (I) is comprised at about 8.6 ⁇ 0.2°, 10.1 ⁇ 0.2°, 14.4 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.0 ⁇ 0.2°, and 21.0 ⁇ Characteristic peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the XRPD pattern of the crystal C of the compound of formula (I) is comprised at about 8.6 ⁇ 0.2°, 10.1 ⁇ 0.2°, 14.4 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.0 ⁇ 0.2°, 18.6. Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 21.0 ⁇ 0.2°, 24.9 ⁇ 0.2°, and 26.0 ⁇ 0.2°.
  • the XRPD pattern of crystal C of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal C of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal C of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal C of the compound of formula (I) comprises a peak at substantially the same diffraction angle (2 theta) as shown in FIG.
  • the XRPD peak position of Crystal C of the compound of Formula (I) is substantially the same as that shown in Figure 5.
  • the invention provides crystal D of a compound of formula (I), the XRPD pattern of said crystal D comprising diffraction angles (2 theta) at about 10.2 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, and 20.4 ⁇ 0.2 ° Characteristic peak at the place.
  • the XRPD pattern of the crystal D of the compound of formula (I) is comprised at about 10.2 ⁇ 0.2 °, 15.4 ⁇ 0.2 °, 16.9 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, and 20.4 ⁇ Characteristic peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the XRPD pattern of the crystal D of the compound of formula (I) is comprised at about 10.2 ⁇ 0.2 °, 14.3 ⁇ 0.2 °, 15.4 ⁇ 0.2 °, 16.9 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 18.8. Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 20.4 ⁇ 0.2°, 25.0 ⁇ 0.2°, and 28.6 ⁇ 0.2°.
  • the XRPD pattern of the crystal D of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the crystal D of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the crystal D of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal D of the compound of formula (I) comprises a peak at substantially the same diffraction angle (2 theta) as shown in FIG.
  • the XRPD peak position of crystal D of the compound of formula (I) is substantially the same as that shown in FIG.
  • the DSC profile of crystal D of the compound of formula (I) of the present invention comprises a characteristic peak at about 144.2 ⁇ 0.2 ° C (starting temperature).
  • the DSC pattern of the crystal D of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG. In a most preferred embodiment, the characteristic peak position of the DSC pattern of the crystal D of the compound of formula (I) is substantially the same as that shown in FIG.
  • the crystal D of the compound of formula (I) of the invention is an unsolvate. In a more preferred embodiment, the crystal D of the compound of formula (I) of the invention is amorphous.
  • the invention provides crystal E of a compound of formula (I), the XRPD pattern of said crystal E comprising diffraction angles (2 theta) at about 4.0 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, and 8.0 ⁇ 0.2 ° Characteristic peak at the place.
  • the XRPD pattern of the crystal E of the compound of formula (I) is comprised at about 4.0 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 8.0 ⁇ 0.2 °, 11.6 ⁇ 0.2 °, 18.6 ⁇ 0.2 °, and 19.8 ⁇ Characteristic peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the XRPD pattern of the crystal E of the compound of formula (I) is comprised at about 4.0 ⁇ 0.2 °, 6.8 ⁇ 0.2 °, 8.0 ⁇ 0.2 °, 11.6 ⁇ 0.2 °, 18.6 ⁇ 0.2 °, 19.8. Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 23.8 ⁇ 0.2°, 29.6 ⁇ 0.2°, and 33.9 ⁇ 0.2°.
  • the XRPD pattern of crystal E of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal E of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of crystal E of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the crystal E of the compound of formula (I) comprises a peak at substantially the same diffraction angle (2 ⁇ ) as shown in FIG.
  • the XRPD peak position of the crystal E of the compound of formula (I) is substantially the same as that shown in FIG.
  • the DSC profile of Crystal E of the compound of Formula (I) of the present invention comprises a characteristic peak at about 96.6 ⁇ 0.2 ° C (starting temperature).
  • the DSC profile of crystal E of the compound of formula (I) comprises a characteristic peak at substantially the same temperature as shown in FIG.
  • the characteristic peak position of the DSC pattern of the crystal E of the compound of formula (I) is substantially the same as that shown in FIG.
  • the crystal E of the compound of formula (I) of the present application is a solvate of a compound of formula (I) with tetrahydrofuran.
  • the invention provides crystal F of a compound of formula (I), the XRPD pattern of said crystal F comprising diffraction angles (2 theta) at about 6.7 ⁇ 0.2 °, 13.5 ⁇ 0.2 °, and 20.4 ⁇ 0.2 ° Characteristic peak at the place.
  • the XRPD pattern of the crystalline F of the compound of formula (I) is comprised at about 5.8 ⁇ 0.2 °, 6.7 ⁇ 0.2 °, 13.5 ⁇ 0.2 °, 14.2 ⁇ 0.2 °, 17.8 ⁇ 0.2 °, and 20.4 ⁇ Characteristic peak at a diffraction angle (2 ⁇ ) of 0.2°.
  • the XRPD pattern of the crystalline F of the compound of formula (I) is comprised at about 5.8 ⁇ 0.2 °, 6.7 ⁇ 0.2 °, 9.4 ⁇ 0.2 °, 11.7 ⁇ 0.2 °, 13.5 ⁇ 0.2 °, 14.2. Characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 17.8 ⁇ 0.2°, 20.4 ⁇ 0.2°, and 27.3 ⁇ 0.2°.
  • the XRPD pattern of the crystal F of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the crystal F of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the crystal F of the compound of formula (I) comprises a peak at the following diffraction angle (2 ⁇ ):
  • the XRPD pattern of the crystal F of the compound of formula (I) includes a peak at substantially the same diffraction angle (2 ⁇ ) as shown in FIG.
  • the XRPD peak position of the crystal F of the compound of formula (I) is substantially the same as that shown in FIG.
  • the DSC profile of the crystalline form F of the compound of formula (I) of the present invention is comprised at about 121.9 ⁇ 0.2 ° C (starting temperature) Characteristic peak at degree).
  • the DSC spectrum of the crystal F of the compound of formula (I) includes characteristic peaks at substantially the same temperature as shown in FIG.
  • the characteristic peak position of the DSC pattern of the crystal F of the compound of formula (I) is substantially the same as that shown in FIG.
  • the crystal F of the compound of formula (I) of the invention is a solvate of a compound of formula (I) with tetrahydrofuran.
  • the present invention also provides a method of preparing any one of the above-mentioned crystalline AFs, including but not limited to a gas-liquid permeation method, a room temperature slow volatilization method, a polymer induced crystallization method, a gas-solid permeation method. Method, slow cooling method, anti-solvent addition method, room temperature suspension stirring method and high temperature suspension stirring method.
  • crystals are prepared by gas-liquid permeation, which comprises dissolving a compound of formula (I) in a good solvent in a first vessel to form a clear solution (the solution may be filtered as needed) A clear solution is obtained, an anti-solvent is charged into the second container, the first container is opened and placed in the second container, the second container is sealed and allowed to stand, and the precipitated solid is filtered to obtain crystals.
  • the good solvent includes, but is not limited to, an organic solvent, such as an alcohol having from 1 to 10 carbon atoms, a ketone, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes, and Aromatic hydrocarbons, ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane) and organic acids, etc., such as acetone, acetic acid, methanol, ethanol, tetrahydrofuran Or chloroform, or a mixed solvent formed of two or more of the above solvents.
  • an organic solvent such as an alcohol having from 1 to 10 carbon atoms, a ketone, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes, and Aromatic hydrocarbons, ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydro
  • the anti-solvent includes, but is not limited to, an organic solvent, such as a ketone having from 1 to 10 carbon atoms, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics) , ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), esters and nitriles, such as dichloromethane, chloroform, methyl Tert-butyl ether, toluene, n-hexane, acetonitrile, 2-methyltetrahydrofuran, ethyl acetate, methyl ethyl ketone or the like, or a mixed solvent formed of two or more of the above solvents.
  • an organic solvent such as a ketone having from 1 to 10 carbon atoms, a hydrocarbon (including alkanes, halogenated alkanes, alken
  • the weight to volume ratio (mg/mL) of the compound of Formula (I) to the good solvent is about (10-50):1. In some embodiments, the volume ratio of the good solvent to the anti-solvent is 1: (2-10). In some embodiments, the sealing and standing of the second container can be carried out at room temperature. In some embodiments of the present invention, the crystal preparation method and results of the present invention are exemplified as follows:
  • crystals are prepared using a room temperature slow volatilization process comprising dissolving a compound of formula (I) in a solvent in a vessel to form a clear solution (the solution may be filtered as needed to provide a clear solution)
  • the container is sealed (for example, using a parafilm), small holes or slits are left in the seal, and the clear solution is placed to volatilize the solvent to obtain crystals.
  • the solvent includes, but is not limited to, an organic solvent, such as an alcohol having from 1 to 10 carbon atoms, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics), Ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), ketones, nitriles or esters, such as methanol, ethanol, isopropanol, Trichloromethane (chloroform), tetrahydrofuran, acetone, methyl tert-butyl ether, ethyl acetate or acetonitrile, or a mixed solvent formed of two or more of the above solvents.
  • an organic solvent such as an alcohol having from 1 to 10 carbon atoms, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics), Ethers (including
  • the weight to volume ratio (mg/mL) of the compound of formula (I) to solvent is (5-20):1.
  • the placement can be performed at room temperature.
  • the crystal preparation method and results of the present invention are exemplified as follows:
  • the preparation of crystals by high polymer induced crystallization comprises forming a clear solution of the compound of formula (I) in a solvent of the vessel (the solution may be filtered as needed to obtain a clear solution)
  • the polymer is added, the container is sealed, and small holes or slits are left in the seal, and the clear solution is placed to volatilize the solvent to obtain crystals.
  • the solvent includes, but is not limited to, an organic solvent, such as an alcohol having from 1 to 10 carbon atoms, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics), Ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), ketones, nitriles or esters, such as methanol, ethanol, isopropanol, Trichloromethane (chloroform), tetrahydrofuran, acetone, methyl tert-butyl ether, ethyl acetate, acetonitrile, or a mixed solvent formed of two or more of the above solvents.
  • an organic solvent such as an alcohol having from 1 to 10 carbon atoms, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics), Ethers (including
  • the high polymer may be a mixture of a plurality of high polymers (mixed high polymers), which may be mixed in any ratio, provided that the crystals can be used to prepare crystals.
  • the mixed high polymer is, for example, a mixed polymer A: polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, and methylcellulose. mixture.
  • the mixed high polymer is, for example, a mixture of mixed high polymer B: polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, and hydroxyethyl cellulose.
  • the placing is performed at room temperature.
  • the mixed high polymer is mixed by weight of each component.
  • the weight ratio of the compound of formula (I) to the mixed polymer is (5-10):1.
  • the weight to volume ratio (mg/mL) of the compound of formula (I) to solvent is (5-20):1.
  • the crystal preparation method and results of the present invention are exemplified as follows:
  • the crystals are prepared by a gas-solid permeation process, the method comprising placing a first container containing a compound of formula (I) in a second container containing a solvent, wherein the solid form The compound of formula (I) is not in direct contact with the solvent, the second container is sealed, and crystals are obtained after standing.
  • the solvent includes, but is not limited to, an inorganic solvent (eg, water) and an organic solvent, such as a ketone having from 1 to 10 carbon atoms, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes) Hydrocarbons and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), nitriles and esters, such as dichloromethane, acetonitrile , tetrahydrofuran, acetone, ethyl acetate, methyl tert-butyl ether, toluene or chloroform.
  • an inorganic solvent eg, water
  • an organic solvent such as a ketone having from 1 to 10 carbon atoms, a hydrocarbon (including alkanes, halogenated alkanes, alkenes, alkynes) Hydrocarbons and
  • the weight to volume ratio (mg/mL) of the compound of Formula (I) to the solvent is about (1-10):1.
  • the crystal preparation method and results of the present invention are exemplified as follows:
  • the crystals are prepared by a slow cooling process comprising adding a compound of formula (I) to a solvent, heating to stir to dissolve, and obtaining a clear solution (filtering the solution as needed) To obtain a clear solution), it was slowly cooled to obtain crystals.
  • the solvent includes, but is not limited to, an inorganic solvent (eg, water) and an organic solvent, such as an alcohol having from 1 to 10 carbon atoms, a ketone, a hydrocarbon (including an alkane, a halogenated alkane, an olefin) Classes, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), nitriles and esters, specifically Propylene alcohol, acetone, chloroform, acetonitrile, tetrahydrofuran, methanol, n-hexane or ethyl acetate, or a mixed solvent formed of two or more of the above solvents.
  • an inorganic solvent eg, water
  • an organic solvent such as an alcohol having from 1 to 10 carbon atoms, a ketone, a hydrocarbon (including an alkane, a halogenated alkan
  • the slow cooling refers to, for example, a rate of temperature drop of from 0.1 to 0.5 ° C/minute, such as from 0.1 to 0.3 ° C/minute, preferably 0.1 ° C/minute.
  • the heating temperature is, for example, 30-80 ° C, such as 50 ° C.
  • the temperature at the end of the temperature drop is room temperature or 0-10 °C, such as 5 °C.
  • the weight to volume ratio (mg/mL) of the compound of formula (I) to solvent is (10-50):1.
  • the crystal preparation method and results of the present invention are exemplified as follows:
  • the crystals are prepared using an anti-solvent addition process, including, but not limited to, dissolving the compound of formula (I) in a good solvent to form a clear solution (the solution can be filtered as needed to obtain Clarifying the solution), then adding an anti-solvent to the clear solution, and crystallizing under stirring (the stirring can be carried out at room temperature or under heating conditions (for example, heating to 30-60 ° C, preferably 50 ° C)), or standing still (For example, it is left at room temperature) (preferably, the solvent is slowly volatilized at the same time) to precipitate crystals.
  • an anti-solvent addition process including, but not limited to, dissolving the compound of formula (I) in a good solvent to form a clear solution (the solution can be filtered as needed to obtain Clarifying the solution), then adding an anti-solvent to the clear solution, and crystallizing under stirring (the stirring can be carried out at room temperature or under heating conditions (for example, heating to 30-60 ° C, preferably 50 ° C)), or standing still
  • the good solvent includes, but is not limited to, an organic solvent such as an alcohol having 1 to 10 carbon atoms, a ketone, a hydrocarbon (including an alkane, a halogenated alkane, an alkene, an alkyne, and Aromatic hydrocarbons, ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), sulfones, amides and organic acids, such as methanol, ethanol, Acetone, tetrahydrofuran, acetic acid, chloroform, dimethyl sulfoxide or dimethyl acetamide.
  • an organic solvent such as an alcohol having 1 to 10 carbon atoms, a ketone, a hydrocarbon (including an alkane, a halogenated alkane, an alkene, an alkyne, and Aromatic hydrocarbons, ethers (including chain ethers and cyclic ethers (such as furans
  • the anti-solvent includes, but is not limited to, inorganic solvents (eg, water) and organic solvents (eg, ketones having from 1 to 10 carbon atoms, hydrocarbons (including alkanes, halogenated alkanes, alkenes) Classes, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), esters and nitriles), such as Alkane, n-heptane, cyclopentyl methyl ether, acetonitrile, methyl isobutyl ketone, 2-methyltetrahydrofuran, dioxane, isopropyl acetate, dichloromethane, toluene, acetonitrile, butanone, methyl uncle Butyl ether, ethyl isopropylate, dimethyl carbonate and ethyl acetate.
  • the volume ratio of the good solvent to the anti-solvent is (0.2-1): (1-20). In some embodiments, the weight to volume ratio (mg/mL) of the compound of formula (I) to the good solvent is (10-80):1. In some embodiments of the present invention, the crystal preparation method and results of the present invention are exemplified as follows:
  • the crystals are prepared by a room temperature suspension agitation process including, but not limited to, adding a compound of formula (I) to a solvent to obtain a suspension, stirring, and then separating to obtain crystals.
  • the solvent includes, but is not limited to, an inorganic solvent (eg, water) and an organic solvent (eg, an alcohol having from 1 to 10 carbon atoms, a ketone, a hydrocarbon (including an alkane, a halogenated alkane, an olefin) Classes, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), esters, nitriles and organic acids
  • an inorganic solvent eg, water
  • an organic solvent eg, an alcohol having from 1 to 10 carbon atoms, a ketone, a hydrocarbon (including an alkane, a halogenated alkane, an olefin) Classes, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), esters, n
  • the weight to volume ratio (mg/mL) of the compound of formula (I) to solvent is (20-250):1, preferably (20-200):1, more preferably (20-150) : 1, most preferably (20-100): 1.
  • the crystal preparation method and results of the present invention are exemplified as follows:
  • the crystals are prepared using a high temperature suspension agitation process, including, but not limited to, adding a compound of formula (I) to a solvent to provide a suspension, which is heated (eg, heated to Stirring is carried out at 30-100 ° C, preferably 50 ° C or 80 ° C, and then the crystals are separated.
  • a high temperature suspension agitation process including, but not limited to, adding a compound of formula (I) to a solvent to provide a suspension, which is heated (eg, heated to Stirring is carried out at 30-100 ° C, preferably 50 ° C or 80 ° C, and then the crystals are separated.
  • the solvent includes, but is not limited to, an inorganic solvent (eg, water) and an organic solvent (eg, an alcohol having from 1 to 10 carbon atoms, a ketone, a hydrocarbon (including an alkane, a halogenated alkane, an olefin) Classes, alkynes and aromatics), ethers (including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxane), esters, nitriles and nitrogen heterocycles Classes such as acetone, methyl isobutyl ketone, isopropyl acetate, dimethyl carbonate, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, n-hexane, dioxane, N-methyl Pyrrolidone, cyclopentyl methyl ether, toluene and anisole).
  • the weight to volume ratio (mg/mL) of the compound of formula (I) to solvent is (15-100):1, preferably (20-100):1.
  • the heating temperature is 50-80 °C.
  • the crystal preparation method and results of the present invention are exemplified as follows:
  • solid form includes all solid forms of the compounds of formula (I), such as crystalline or amorphous forms.
  • amorphous refers to any solid material that is not ordered in three dimensions.
  • amorphous solids can be characterized by known techniques, including XRPD crystallography, solid state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As explained below, amorphous solids produce a diffuse XRPD pattern that typically includes one or two broad peaks (i.e., peaks having a base width of about 5 ° 2 ⁇ or greater).
  • crystal form or “crystal” as used herein refers to any solid material that exhibits a three-dimensional order, as opposed to an amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern refers to a diffraction pattern experimentally observed or a parameter derived therefrom.
  • the XRPD pattern is usually characterized by a peak position (abscissa) and/or a peak intensity (ordinate).
  • the XRPD pattern in the present application is preferably collected on a PANalytacal Empyrean and X'Pert3 X-ray powder diffraction analyzer, and the transmission mode is preferably collected on a PANalytacal Empyrean X-ray powder diffraction analyzer.
  • 2 ⁇ refers to a peak position expressed in degrees based on experimental settings of an X-ray diffraction experiment, and is usually an abscissa unit in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle ⁇ with a certain lattice plane, the experimental setup requires that the reflected beam be recorded at a 2 theta angle. It will be understood that the particular 2 theta value of a particular crystal form referred to herein is intended to mean a 2 theta value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-K ⁇ (K ⁇ 1) 1.540598 and K ⁇ 2 1.544426) as a source of radiation.
  • DSC differential scanning calorimetry
  • the term "substantially the same" for an X-ray diffraction peak position means taking into account representative peak position and intensity variations. For example, those skilled in the art will appreciate that the peak position (2 theta) will show some variation, typically as much as 0.1-0.2 degrees, and the instrument used to measure the diffraction will also show some variation. Additionally, those skilled in the art will appreciate that relative peak intensities will show variations between instruments and variations in the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered as only For qualitative measurements. Similarly, as used herein, “substantially the same” for a DSC map is also intended to encompass variations known to those skilled in the art that are relevant to these analytical techniques. For example, for a well-defined peak, the differential scanning calorimetry typically has a variation of up to ⁇ 0.2 °C, and even greater for broad peaks (eg, up to ⁇ 1 °C).
  • liquid NMR spectrum in this application is preferably collected on a Bruker 400M NMR spectrometer, with DMSO-d6 as the solvent unless otherwise stated.
  • the polarized microscopy data in this application is preferably collected at room temperature by an Axio Lab. A1 upright microscope.
  • hydrocarbon as used herein preferably means a hydrocarbon having from 1 to 10 carbon atoms, including alkanes, halogenated alkanes, alkenes, alkynes, and aromatics, including but not limited to dichloride. Methane, chloroform (chloroform), n-hexane, n-heptane and toluene.
  • alcohol as used herein preferably means an alcohol having from 1 to 10 carbon atoms including, but not limited to, methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropyl) Alcohol), 1-butanol, 2-butanol and tert-butanol.
  • ether as used herein preferably means an ether having 2 to 6 carbon atoms, including chain ethers and cyclic ethers (eg, furans (including tetrahydrofurans) and dioxane). Specific, including but not limited to diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole and dimethoxy Ethane.
  • nitrile as used herein preferably refers to a nitrile having from 2 to 6 carbon atoms including, but not limited to, acetonitrile and propionitrile.
  • ketone solvent preferably means a ketone having 2 to 6 carbon atoms including, but not limited to, acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl Ketone.
  • ester as used herein preferably means an ester having from 3 to 10 carbon atoms including, but not limited to, ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropylate, carbonic acid Methyl ester and butyl acetate.
  • organic acid as used herein preferably means an organic acid having from 1 to 10 carbon atoms including, but not limited to, formic acid and acetic acid.
  • sulfone as used herein preferably means a sulfone or sulfoxide having from 2 to 10 carbon atoms including, but not limited to, dimethyl sulfoxide.
  • amide as used herein preferably means an amide having from 1 to 10 carbon atoms including, but not limited to, dimethylformamide or dimethylacetamide.
  • nitrogenheterocycle as used herein preferably means a nitrogen-containing heterocycle having from 3 to 10 carbon atoms and at least one nitrogen atom, including but not limited to N-methylpyrrolidone.
  • the prepared salt or its crystalline form can be recovered by a method including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for solids recovery under pressure or under reduced pressure.
  • the recovered solids can optionally be dried.
  • "Drying" in the present invention is carried out under reduced pressure (preferably vacuum) until the residual solvent content is lowered to the limits given in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines. Within the scope.
  • the residual solvent content depends on the type of solvent, but does not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm.
  • the drying may be in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a quick dryer, and the like. get on.
  • the drying may be at atmospheric pressure or reduced pressure at a temperature below about 100 ° C, below about 80 ° C, below about 60 ° C, below about 50 ° C, below about 30 ° C, or at any other suitable temperature. It is preferably carried out under vacuum) in any desired time (e.g., about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) to achieve the desired result, as long as the quality of the salt does not deteriorate.
  • the drying can be carried out any desired number of times until the desired product quality is achieved.
  • the dried product can optionally undergo a comminution operation to produce the desired particle size. Grinding or micronizing may be carried out before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roll milling and hammer milling, as well as jet milling.
  • anagen free as used herein preferably means a crystalline form in which no water molecules are contained as structural elements.
  • the present invention provides a pharmaceutical composition comprising any one or more of crystals A, B, C, D, E or F of a compound of formula (I) of the present invention, and a Or a plurality of pharmaceutically acceptable carriers.
  • the invention provides crystals A, B, C, D, E or F of a compound of formula (I) of the invention for use in the manufacture of a medicament for the prevention or treatment of a cell proliferative disorder or a viral infectious disorder. Use in medicine.
  • the invention provides crystals A, B, C, D, E or F of a compound of formula (I) of the invention for use in preventing or treating a cell proliferative disorder or a viral infectious disorder.
  • the invention provides a method of preventing or treating a cell proliferative disorder or a viral infectious disease comprising administering to a subject in need thereof, preferably a mammal, a prophylactically or therapeutically effective amount of a formula of the invention Any one or more of the crystals A, B, C, D, E or F of the compound of (I).
  • the cell proliferation abnormality disease includes esophagus, stomach, intestine, rectum, mouth, pharynx, larynx, lung, colon, breast, uterus, endometrium, ovary, prostate, testis, bladder, kidney , liver, pancreas, bone, connective tissue, skin, eye, brain and central nervous system, etc., tumors and / or cancer and related diseases, as well as thyroid cancer, leukemia, Hodgkin's disease, lymphoma and myeloma, etc. .
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contact within the scope of sound medical judgment. Tissues of humans and/or other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage form may be a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation, and specifically includes, but not limited to, a tablet, a capsule, a powder, a granule, a lozenge, a hard candy, a powder, a spray, a cream, an ointment.
  • compositions of the present invention can be prepared by any method well known in the art, for example by mixing, dissolving, granulating, sugar coating, milling, emulsifying, lyophilizing, and the like.
  • terapéuticaally effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, and 25 mg, and the like.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • Figure 1 is an XRPD pattern of crystal A of the compound of formula (I).
  • Figure 2 is a DSC chart of crystal A of the compound of formula (I).
  • Figure 3 is an XRPD pattern of crystal B of the compound of formula (I).
  • Figure 4 is a DSC chart of crystal B of the compound of formula (I).
  • Figure 5 is an XRPD pattern of crystal C of the compound of formula (I).
  • Figure 6 is an XRPD pattern of crystal D of the compound of formula (I).
  • Figure 7 is a DSC chart of crystal D of the compound of formula (I).
  • Figure 8 is an XRPD pattern of crystal E of the compound of formula (I).
  • Figure 9 is a DSC chart of crystal E of the compound of formula (I).
  • Figure 10 is an XRPD pattern of crystal F of the compound of formula (I).
  • Figure 11 is a DSC chart of crystal F of the compound of formula (I).
  • the compound A used in this example was prepared according to a literature method (J. Org. Chem. 1999, 64, 7912-7920).
  • the obtained crystal A was subjected to XRPD analysis, and the obtained XRPD pattern is shown in Fig. 1, and the relevant data is shown in the following table.
  • the obtained crystal A was subjected to DSC analysis, and the obtained spectrum is shown in Fig. 2. From this analysis, the sample had a sharp endothermic peak at 155.67 ° C (starting temperature).
  • the compound of the formula (I) in the amounts shown in the table below was weighed, dissolved in the solvent shown in the table below, and the supernatant was filtered, transferred to a 3 ml vial, and a 20 ml vial was taken. About 4.0 ml of the anti-solvent was added thereto, and the 3 ml vial containing the supernatant was placed in a 20 ml vial, and the 20 ml vial was sealed and allowed to stand at room temperature. When solid precipitation was observed, separation was carried out to obtain crystal B.
  • the obtained crystal B was subjected to XRPD analysis, and the obtained XRPD pattern is shown in Fig. 3, and the relevant data is shown in the following table.
  • the obtained crystal B was subjected to DSC analysis, and the obtained spectrum is shown in Fig. 4. From this analysis, the sample had a sharp endothermic peak at 125.3 ° C (starting temperature).
  • the compound of the formula (I) in the amounts shown in the table below was weighed, added to a 3 ml vial, dissolved in a corresponding amount of a good solvent shown in the table below and filtered to a 20 ml vial, and the following table was added to the clear solution.
  • the corresponding anti-solvent shown in the figure was stirred while stirring until a solid precipitated. If there is no solid after adding about 10.0 ml of the anti-solvent, the clear solution is stirred at 5 ° C overnight; if no solids are still precipitated, the clear solution is allowed to stand at room temperature to slowly evaporate. The precipitated solid was separated by centrifugation.
  • the XRPD pattern and the DSC pattern of the obtained solid were substantially the same as those of the XRPD pattern and the DSC pattern in Example 6, indicating that the crystal B was obtained.
  • the obtained crystal C was subjected to XRPD analysis, and the obtained XRPD pattern is shown in Fig. 5, and the relevant data is shown in the following table.
  • the obtained crystal D was subjected to XRPD analysis, and the obtained XRPD pattern is shown in Fig. 6, and the relevant data is shown in the following table.
  • the obtained crystal D was subjected to DSC analysis, and the obtained spectrum is as shown in FIG. From this analysis, the sample had a sharp endothermic peak at 144.2 ° C (starting temperature).
  • Example 17 Room temperature suspension stirring method
  • the obtained crystal E was subjected to XRPD analysis, and the obtained XRPD pattern is shown in Fig. 8, and the relevant data is shown in the following table.
  • the obtained crystal E was subjected to DSC analysis, and the obtained spectrum is shown in Fig. 9. From this analysis, the sample had a sharp endothermic peak at 96.6 ° C (starting temperature).
  • the obtained crystal F was subjected to XRPD analysis, and the obtained XRPD pattern is shown in Fig. 10, and the relevant data is shown in the following table.
  • the obtained crystal F was subjected to DSC analysis, and the obtained spectrum is shown in FIG. From this analysis, the sample had a sharp endothermic peak at 121.9 ° C (starting temperature).
  • the compound of formula (I) was weighed about 2.0 to 5.0 mg each of crystal A, crystal B and crystal D, added to a 3 ml vial, and 1.0 ml of deionized water was added, and the resulting suspension was placed in a rotary incubator. On the upper (rotation speed of 25 rpm), and after equilibrating in a biochemical incubator at 25 ° C for 24 hours, 0.8 ml of the suspension was weighed, and the solid was centrifuged (6000 rpm, 15 minutes), and the supernatant was taken. Solubility was measured by HPLC and the solid detection XRPD pattern was taken.
  • the crystal A of the compound of the formula (I) was allowed to stand under the conditions of 4500 lx of light intensity, 25 ° C, and RH 25% for 30 days, and samples were taken at 0 days, 5 days, 11 days, and 30 days, respectively, and the sample properties were observed.
  • the specific rotation was measured with a polarimeter, the loss on drying was measured, and the total impurity content was measured by HPLC.
  • the test results showed that after standing for 30 days under the condition of 4500 lx light intensity, 25 ° C and RH 25%, the crystal A was still white powder, and the appearance did not change; the specific rotation did not change more than 3 during the period from 0 days to 30 days. °; The loss on drying was measured at different time points, and the % loss on drying was not more than 1.0%; the total impurity content detected by HPLC at different time points remained basically unchanged.
  • the crystal A of the compound of the formula (I) has good photostability, can ensure the reliability of the crystal A during storage and transportation, thereby ensuring the safety of the medicine, and the crystal A does not need to be protected from light. And take special packaging to reduce costs. Crystal A does not degrade due to the influence of light, which improves the safety of the drug and the effectiveness after long-term storage. Patients taking Crystal A do not develop a photosensitivity response due to exposure to sunlight.
  • the crystal A of the compound of the formula (I) was allowed to stand at a high temperature of 60 ° C for 30 days, and samples were taken at 0 days, 5 days, 10 days, and 30 days, respectively, and the changes in the properties of the samples were observed, and the specific rotation was measured by a polarimeter. Loss on drying was carried out and the total impurity content was measured by HPLC.
  • the test results show that after standing for 30 days at 60 °C, the crystal A is still a white powder, and the appearance does not change; the specific rotation does not change more than 2° during the period from 0 days to 30 days; the weight loss of the drying is detected at different time points.
  • the % loss on drying was not more than 1.07%; the total impurity content was not changed by HPLC at different time points.
  • the crystal A of the compound of the formula (I) has good high temperature resistance (thermal stability).
  • Crystal A of the compound of formula (I) was placed under high humidity conditions of 25 ° C and RH 75% for 30 days, and samples were taken at 0, 5, 10 and 30 days, respectively, to observe changes in the properties of the sample, using optical rotation.
  • the instrument measures the specific rotation, detects the loss on drying, and measures the total impurity content by HPLC.
  • the test results showed that after standing for 30 days at 25 ° C and RH 75% under high humidity conditions, the crystal A was still a white powder, and the appearance did not change; the specific rotation did not change more than 1 ° during the period from 0 days to 30 days; The loss on drying was measured at different time points, and the % loss on drying was not more than 1.0%; the total impurity content was not changed by HPLC at different time points.
  • the crystal A of the compound of the formula (I) has good high moisture resistance (i.e., has high stability under high humidity conditions) and low hygroscopicity.
  • the crystal B-F of the present invention also has good properties of high temperature resistance, high humidity resistance and/or light resistance.
  • Crystal A of the compound of formula (I) was formulated into a suspension of 0.5% sodium carboxymethylcellulose (CMC-Na), and ICR mice were administered by single gavage to investigate its pharmacokinetic characteristics. .
  • the single intragastric doses were 2 mg/kg, 4 mg/kg and 8 mg/kg, respectively. After crystal A enters the body, it is rapidly metabolized to a pharmacologically active metabolite I:
  • the maximum plasma concentration (C max ) of the metabolite I after a single intragastric administration of the mice was 211 ng/mL at a dose of 2 mg/kg, and the exposure (AUC 0- ⁇ ) was 239 ng. h/mL; at a dose of 4 mg/kg, Cmax was 284 ng/mL, AUC0 - ⁇ was 332 ng ⁇ h/mL; at a dose of 8 mg/kg, Cmax was 633 ng/mL, AUC 0- ⁇ was 796 ng ⁇ h/ml. It can be seen that the active metabolite of crystal A of the compound of formula (I) of the present invention has excellent blood concentration and exposure.
  • Crystal A of the compound of formula (I) was formulated into a suspension in 0.5% CMC-Na and administered in a single gavage in comparison to dogs.
  • the single intragastric doses were 0.1 mg/kg, 0.2 mg/kg and 0.4 mg/kg, respectively.
  • crystal A is rapidly metabolized to a pharmacologically active metabolite I, and each pharmacokinetic parameter is calculated based on the concentration-time curve of metabolite I in plasma.
  • Table 2 The results are shown in Table 2:
  • the maximum plasma concentration (C max ) of the metabolite I after a single intragastric administration of Beagle was 45.3 ng/mL, and the exposure (AUC 0- ⁇ ) 296 ng ⁇ h/mL; at a dose of 0.2 mg/kg, C max was 81.6 ng/mL, AUC 0- ⁇ was 567 ng ⁇ h/mL; at a dose of 0.4 mg/kg, C max was 164 ng/mL , AUC 0- ⁇ is 1120 ng ⁇ h/mL.
  • the active metabolite of crystal A of the compound of formula (I) in the present invention is shown to have excellent blood concentration and exposure.
  • Crystalline A [ 14 C] crystal A) having a radioisotope is formulated into a suspension of 0.5% sodium carboxymethylcellulose (CMC-Na), and a single intragastric administration of ICR mice is administered.
  • dose 117 ⁇ Ci / 4.08mg / kg [14 C ] crystal a, by measuring the radioactivity in urine and faeces investigated crystals a recovery absorption and excretion characteristics.
  • the radioactivity recovery in urine was determined to be 78.7% within 0 to 120 hours after intragastric administration of [ 14 C] crystal A in mice. It indicates that the proportion of the drug component absorbed into the blood by oral administration is at least 78.7%, that is, the absolute bioavailability of the intragastric administration of the crystal A is above 78.7%. It can be seen that crystal A has good oral absorption characteristics and is suitable for preparation into an oral preparation.
  • a conventional auxiliary material such as an appropriate amount of cellulose powder is added to the crystal A to prepare a mixed powder.
  • the angle of repose of the mixed powder was measured by a fixed funnel method.
  • the funnel is fixed at a certain height H, and the mixed powder is placed in the funnel so that it naturally flows down into a pile until the tip of the cone just contacts the funnel outlet, and the radius r of the conical bottom surface is measured to calculate the angle of repose.
  • Angle of repose arc tg (H / r).

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Abstract

本发明涉及式(I)的化合物的固体形式，制备所述固体形式的方法、包含所述固体形式的药物组合物，以及所述固体形式用于治疗细胞增殖异常性疾病或病毒感染性疾病的用途。

Description

4’-硫代-2’-氟代核苷磷酰胺化合物的固体形式及其制备方法和用途 发明领域
本发明涉及(S)-异丙基2-(((S)-(((2R,3S,4S,5R)-5-(4-氨基-2-氧代嘧啶-1(2H)-基)-4-氟-3-羟基-四氢噻吩-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯(在下文中称作“式(I)的化合物”)的固体形式，制备所述固体形式的方法、包含所述固体形式的药物组合物，以及所述固体形式用于治疗细胞增殖异常性疾病或病毒感染性疾病的用途。
发明背景
人工合成的核苷类似物是一类重要的肿瘤化疗药物，通常将其称为抗代谢药物，如已上市的吉西他滨、氮杂胞苷、地西他滨、阿糖胞苷、氟达拉滨、克拉屈滨、6-氮尿苷、噻唑呋林及安妥明等。其作用机制主要通过影响肿瘤细胞的酶系，由此抑制DNA和RNA的合成。
4’-硫代核苷是指呋喃糖环内氧原子被硫原子取代的核苷类似物。其合成路线长，合成难度大，极大地制约了此类化合物的研究。US6147058公开了一种4’-硫代核苷化合物，其可以抑制裸鼠模型上的结肠癌。该化合物在肿瘤生长抑制方面优于吉西他滨，并且毒性较小(Cancer Let.1999，144，177-182)。该化合物对裸鼠模型上的胰腺癌和卵巢癌也有抑制作用，其抑制活性和安全性均优于吉西他滨(Int.J.Cancer，2005，114,1002–1009)。US5128458和US5128458公开了2',3'-二脱氧-4’硫代核糖核苷在抗病毒疾病(如HIV、乙型肝炎或丙型肝炎)或异常细胞增殖性疾病的治疗中均有很好的效果。
迄今为止，4’-硫代核苷类药物在研发中遇到诸如口服生物利用度低、代谢快、不良反应多以及易产生耐药性等难题，导致此类化合物无法被开放上市。人们已研究前药来克服所述核苷类药物的不足。现在很多制药公司仍在积极地研究其它使用前药来治疗癌症的方法(G.Xu，H.L.McLeod，Clin.Cancer Res.，2001，7，3314-3324；M.Rooseboom，J.N.M.Commandeur，N.P.E.Vermeulen，Pharmacol.Rev.，2004，56，53-102；W.D.Wu，J.Sigmond，G.J.Peters，R.F.Borch，J.Med.Chem.2007，50，3743-3746)。
因此，找到一种理化性质优良、生物利用度高和/或不易产生耐药性的新型4’-硫代-2’-氟代核苷磷酰胺化合物，并研发获得其适用于制备药物制剂的晶体，在医药领域有迫切需求。
发明概述
本发明的一个方面提供如下所示的式(I)的化合物((S)-异丙基2-(((S)-(((2R,3S,4S,5R)-5-(4-氨基-2-氧代嘧啶-1(2H)-基)-4-氟-3-羟基-四氢噻吩-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯)的晶体：
Figure PCTCN2017116396-appb-000001
本发明的优选晶体不仅在预防或治疗细胞增殖异常性疾病或病毒感染性疾病中具有优异的效果，还具有其它优点。例如，本发明的式(I)的化合物的优选晶体具有优良的物理性质(包括溶解度、溶出率、耐光照性、低吸湿性、耐高温性、耐高湿性、流动性等)，并且在诸如生物利用度、物理和/或化学稳定性及易于制备性等性质上，本发明的优选晶体形式可具有更优异的性质。本发明的优选晶体形式具有良好的粉体学性质，更适合和便于大量制造和用于形成制剂，可减少刺激性并提高吸收，解决了代谢速度方面的问题，显著降低了药物蓄积带来的毒性，提高了安全性，有效保证了药物产品的质量和效能。
优选的本发明的式(I)的化合物的晶体表现出良好的化学稳定性和热稳定性，因而其更利于给药和配制时的充分溶解，并能保持足够的生物活性。此外，优选的本发明的式(I)的化合物的晶体表现 出高生物利用度，可在体内提供式(I)的化合物的有效治疗剂量。
由于优选的本发明的式(I)的化合物的晶体在环境温度下储存或运输时极少或较少降解，且优选的本发明的优选式(I)的化合物的晶体的差示扫描量热(DSC)分析中显示在大于50℃时熔化或去溶剂化。这一性质表明本发明的优选晶体更适用于标准的制剂生产过程。
通过对优选的本发明的式(I)的化合物的晶体进行碾磨，然后通过500和250μm筛，使其产生精细粉末，通过对上述精细粉末进行X射线粉末衍射(XRPD)检测，实验结果表明并未发生晶体改变。这表明本发明的优选晶体具有良好的稳定性，易于制备并且更适合用于制剂的制备。
根据反溶剂添加法，优选的本发明的式(I)的化合物的晶体在水系药物制剂中更稳定，因此，本发明的优选晶体更利于开发成为控释制剂或缓释制剂。
优选的本发明的式(I)的化合物的晶体具有良好的光稳定性，可保证所述晶体(例如晶体A)在储存和运输时的可靠性，从而保证药品的安全性，并且所述晶体(例如晶体A)不需要为防止受光照影响而采取的特殊包装处理，从而降低成本。所述晶体(例如晶体A)不会因光照影响产生降解，提高了药品的安全性和长期贮藏后的有效性。服用所述晶体(例如晶体A)的患者不会因暴露于日光而产生光敏反应。
优选的本发明的式(I)的化合物的晶体具有的良好的流动性和微粒形状，以及明显改善的粘黏性，在制剂过程中可明显降低过滤时间，缩短生产周期，节约成本。
本发明的另一方面提供制备本发明的晶体的方法，所述方法选自气液渗透法、室温缓慢挥发法、高聚物诱导结晶法、气固渗透法、缓慢降温法、反溶剂添加法、室温悬浮搅拌法和高温悬浮搅拌法。
本发明的另一方面提供药物组合物，其包含本发明中的任意一种或多种晶体，以及一种或多种药学上可接受的载体。
本发明的另一方面提供本发明的晶体在制备用于预防或治疗细胞增殖异常性疾病或病毒感染性疾病的药物中的用途。
发明详细描述
晶体及其制备方法
在一个实施方案中，本发明提供式(I)的化合物的晶体A，所述晶体A的XRPD图谱包括在约10.5±0.2°、13.5±0.2°和17.9±0.2°的衍射角(2θ)处的特征峰。
在优选实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括在约10.5±0.2°、13.5±0.2°、15.8±0.2°、17.9±0.2°、18.3±0.2°和21.3±0.2°的衍射角(2θ)处的特征峰。
在更优选实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括在约10.5±0.2°、13.5±0.2°、15.8±0.2°、17.9±0.2°、18.3±0.2°、21.3±0.2°、22.3±0.2°、24.2±0.2°和26.8±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2°
5.3
7.8
8.7
10.5
13.5
15.2
15.8
16.4
17.4
17.9
18.3
19.2
19.9
20.3
20.6
21.3
22.3
23.3
23.6
24.2
25.0
25.8
26.4
26.8
27.9
28.6
28.9
30.2
在更优选的实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％
5.3 29.7
7.8 5.9
8.7 8.3
10.5 100.0
13.5 21.8
15.2 1.9
15.8 12.2
16.4 4.6
17.4 2.4
17.9 27.8
18.3 6.2
19.2 2.7
19.9 1.1
20.3 0.8
20.6 3.1
21.3 18.6
22.3 5.1
23.3 2.9
23.6 3.9
24.2 11.1
25.0 1.4
25.8 2.0
26.4 5.0
26.8 6.1
27.9 4.1
28.6 2.3
28.9 4.9
30.2 1.0
在更优选的实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 晶面间距(d间隔) 强度％
5.3 16.8 29.7
7.8 11.3 5.9
8.7 10.2 8.3
10.5 8.4 100.0
13.5 6.6 21.8
15.2 5.8 1.9
15.8 5.6 12.2
16.4 5.4 4.6
17.4 5.1 2.4
17.9 5.0 27.8
18.3 4.9 6.2
19.2 4.6 2.7
19.9 4.5 1.1
20.3 4.4 0.8
20.6 4.3 3.1
21.3 4.2 18.6
22.3 4.0 5.1
23.3 3.8 2.9
23.6 3.8 3.9
24.2 3.7 11.1
25.0 3.6 1.4
25.8 3.5 2.0
26.4 3.4 5.0
26.8 3.3 6.1
27.9 3.2 4.1
28.6 3.1 2.3
28.9 3.1 4.9
30.2 3.0 1.0
在更优选的实施方案中，所述式(I)的化合物的晶体A的XRPD图谱包括与图1所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(I)的化合物的晶体A的XRPD峰位与图1所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的晶体A的DSC图谱包括在约155.7±0.2℃(起点温度)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体A的DSC图谱包括与图2所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶体A的DSC图谱的特征峰位与图2所示基本上相同。
在优选实施方案中，本发明的式(I)的化合物的晶体A为非溶剂合物。在更优选的实施方案中，本发明的式(I)的化合物的晶体A为无水晶型。
在另一实施方案中，本发明提供式(I)的化合物的晶体B，所述晶体B的XRPD图谱包括在约7.0±0.2°、14.0±0.2°和21.1±0.2°的衍射角(2θ)处的特征峰。
在优选实施方案中，所述式(I)的化合物的晶体B的XRPD图谱包括在约6.2±0.2°、7.0±0.2°、13.2±0.2°、14.0±0.2°、21.1±0.2°和26.2±0.2°的衍射角(2θ)处的特征峰。
在更优选实施方案中，所述式(I)的化合物的晶体B的XRPD图谱包括在约6.2±0.2°、7.0±0.2°、9.3±0.2°、13.2±0.2°、14.0±0.2°、15.5±0.2°、18.7±0.2°、21.1±0.2°和26.2±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体B的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2°
6.2
7.0
9.3
11.8
12.5
13.2
14.0
14.7
15.5
16.5
17.4
18.7
19.7
21.1
22.9
23.4
23.7
24.3
26.2
26.5
27.5
29.4
33.3
35.2
在更优选的实施方案中，所述式(I)的化合物的晶体B的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％
6.2 100.0
7.0 15.3
9.3 36.7
11.8 3.5
12.5 10.1
13.2 13.3
14.0 31.2
14.7 2.7
15.5 8.8
16.5 5.6
17.4 6.8
18.7 9.8
19.7 10.4
21.1 52.5
22.9 4.0
23.4 8.5
23.7 5.2
24.3 5.9
26.2 10.0
26.5 12.7
27.5 5.1
29.4 1.0
33.3 1.7
35.2 2.6
在更优选的实施方案中，所述式(I)的化合物的晶体B的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 晶面间距(d间隔) 强度％
6.2 14.1 100.0
7.0 12.6 15.3
9.3 9.5 36.7
11.8 7.5 3.5
12.5 7.1 10.1
13.2 6.7 13.3
14.0 6.3 31.2
14.7 6.0 2.7
15.5 5.7 8.8
16.5 5.4 5.6
17.4 5.1 6.8
18.7 4.7 9.8
19.7 4.5 10.4
21.1 4.2 52.5
22.9 3.9 4.0
23.4 3.8 8.5
23.7 3.8 5.2
24.3 3.7 5.9
26.2 3.4 10.0
26.5 3.4 12.7
27.5 3.2 5.1
29.4 3.0 1.0
33.3 2.7 1.7
35.2 2.6 2.6
在更优选的实施方案中，所述式(I)的化合物的晶体B的XRPD图谱包括与图3所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(I)的化合物的晶体B的XRPD峰位与图3所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的晶体B的DSC图谱包括在约125.3±0.2℃(起点温度)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体B的DSC图谱包括与图4所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶体B的DSC图谱的特征峰位与图4所示基本上相同。
在优选实施方案中，本发明的式(I)的化合物的晶体B为非溶剂合物。在更优选的实施方案中，本发明的式(I)的化合物的晶体B为无水晶型。
在另一实施方案中，本发明提供式(I)的化合物的晶体C，所述晶体C的XRPD图谱包括在约8.6±0.2°、17.2±0.2°和21.0±0.2°的衍射角(2θ)处的特征峰。
在优选实施方案中，所述式(I)的化合物的晶体C的XRPD图谱包括在约8.6±0.2°、10.1±0.2°、14.4±0.2°、17.2±0.2°、18.0±0.2°和21.0±0.2°的衍射角(2θ)处的特征峰。
在更优选实施方案中，所述式(I)的化合物的晶体C的XRPD图谱包括在约8.6±0.2°、10.1±0.2°、14.4±0.2°、17.2±0.2°、18.0±0.2°、18.6±0.2°、21.0±0.2°、24.9±0.2°和26.0±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体C的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2°
4.7
8.6
10.1
13.3
14.1
14.4
16.1
16.6
17.2
18.0
18.6
19.7
21.0
24.9
26.0
26.8
29.3
在更优选的实施方案中，所述式(I)的化合物的晶体C的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％
4.7 0.8
8.6 100.0
10.1 5.2
13.3 2.0
14.1 3.3
14.4 5.2
16.1 2.8
16.6 2.6
17.2 12.4
18.0 6.0
18.6 4.2
19.7 1.7
21.0 17.1
24.9 3.9
26.0 4.4
26.8 1.8
29.3 2.6
在更优选的实施方案中，所述式(I)的化合物的晶体C的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 晶面间距(d间隔) 强度％
4.7 18.7 0.8
8.6 10.3 100.0
10.1 8.8 5.2
13.3 6.7 2.0
14.1 6.3 3.3
14.4 6.2 5.2
16.1 5.5 2.8
16.6 5.3 2.6
17.2 5.2 12.4
18.0 4.9 6.0
18.6 4.8 4.2
19.7 4.5 1.7
21.0 4.2 17.1
24.9 3.6 3.9
26.0 3.4 4.4
26.8 3.3 1.8
29.3 3.0 2.6
在更优选的实施方案中，所述式(I)的化合物的晶体C的XRPD图谱包括与图5所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(I)的化合物的晶体C的XRPD峰位与图5所示基本上相同。
在另一实施方案中，本发明提供式(I)的化合物的晶体D，所述晶体D的XRPD图谱包括在约10.2±0.2°、18.8±0.2°和20.4±0.2°的衍射角(2θ)处的特征峰。
在优选实施方案中，所述式(I)的化合物的晶体D的XRPD图谱包括在约10.2±0.2°、15.4±0.2°、16.9±0.2°、18.2±0.2°、18.8±0.2°和20.4±0.2°的衍射角(2θ)处的特征峰。
在更优选实施方案中，所述式(I)的化合物的晶体D的XRPD图谱包括在约10.2±0.2°、14.3±0.2°、15.4±0.2°、16.9±0.2°、18.2±0.2°、18.8±0.2°、20.4±0.2°、25.0±0.2°和28.6±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体D的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2°
8.3
10.2
13.4
14.3
15.4
16.9
17.6
18.2
18.8
19.2
20.4
23.0
25.0
25.8
27.2
28.6
31.2
在更优选的实施方案中，所述式(I)的化合物的晶体D的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％
8.3 5.1
10.2 100.0
13.4 4.2
14.3 3.4
15.4 8.9
16.9 7.2
17.6 5.6
18.2 10.4
18.8 20.9
19.2 4.3
20.4 12.8
23.0 3.0
25.0 1.8
25.8 1.9
27.2 1.4
28.6 6.1
31.2 0.6
在更优选的实施方案中，所述式(I)的化合物的晶体D的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 晶面间距(d间隔) 强度％
8.3 10.7 5.1
10.2 8.7 100.0
13.4 6.6 4.2
14.3 6.2 3.4
15.4 5.8 8.9
16.9 5.3 7.2
17.6 5.0 5.6
18.2 4.9 10.4
18.8 4.7 20.9
19.2 4.6 4.3
20.4 4.5 12.8
23.0 3.9 3.0
25.0 3.6 1.8
25.8 3.4 1.9
27.2 3.3 1.4
28.6 3.1 6.1
31.2 2.9 0.6
在更优选的实施方案中，所述式(I)的化合物的晶体D的XRPD图谱包括与图6所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(I)的化合物的晶体D的XRPD峰位与图6所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的晶体D的DSC图谱包括在约144.2±0.2℃(起点温度)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体D的DSC图谱包括与图7所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶体D的DSC图谱的特征峰位与图7所示基本上相同。
在优选实施方案中，本发明的式(I)的化合物的晶体D为非溶剂合物。在更优选的实施方案中，本发明的式(I)的化合物的晶体D为无水晶型。
在另一实施方案中，本发明提供式(I)的化合物的晶体E，所述晶体E的XRPD图谱包括在约4.0±0.2°、6.8±0.2°和8.0±0.2°的衍射角(2θ)处的特征峰。
在优选实施方案中，所述式(I)的化合物的晶体E的XRPD图谱包括在约4.0±0.2°、6.8±0.2°、8.0±0.2°、11.6±0.2°、18.6±0.2°和19.8±0.2°的衍射角(2θ)处的特征峰。
在更优选实施方案中，所述式(I)的化合物的晶体E的XRPD图谱包括在约4.0±0.2°、6.8±0.2°、8.0±0.2°、11.6±0.2°、18.6±0.2°、19.8±0.2°、23.8±0.2°、29.6±0.2°和33.9±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体E的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2°
4.0
6.8
8.0
11.6
18.6
19.8
23.8
29.6
33.9
在更优选的实施方案中，所述式(I)的化合物的晶体E的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％
4.0 100.0
6.8 83.9
8.0 84.9
11.6 27.8
18.6 26.8
19.8 31.3
23.8 16.2
29.6 0.5
33.9 1.1
在更优选的实施方案中，所述式(I)的化合物的晶体E的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 晶面间距(d间隔) 强度％
4.0 21.9 100.0
6.8 13.0 83.9
8.0 11.0 84.9
11.6 7.7 27.8
18.6 4.8 26.8
19.8 4.5 31.3
23.8 3.7 16.2
29.6 3.0 0.5
33.9 2.7 1.1
在更优选的实施方案中，所述式(I)的化合物的晶体E的XRPD图谱包括与图8所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(I)的化合物的晶体E的XRPD峰位与图8所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的晶体E的DSC图谱包括在约96.6±0.2℃(起点温度)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体E的DSC图谱包括与图9所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶体E的DSC图谱的特征峰位与图9所示基本上相同。
在优选实施方案中，本申请的式(I)的化合物的晶体E为式(I)的化合物与四氢呋喃形成的溶剂合物。
在另一实施方案中，本发明提供式(I)的化合物的晶体F，所述晶体F的XRPD图谱包括在约6.7±0.2°、13.5±0.2°和20.4±0.2°的衍射角(2θ)处的特征峰。
在优选实施方案中，所述式(I)的化合物的晶体F的XRPD图谱包括在约5.8±0.2°、6.7±0.2°、13.5±0.2°、14.2±0.2°、17.8±0.2°和20.4±0.2°的衍射角(2θ)处的特征峰。
在更优选实施方案中，所述式(I)的化合物的晶体F的XRPD图谱包括在约5.8±0.2°、6.7±0.2°、9.4±0.2°、11.7±0.2°、13.5±0.2°、14.2±0.2°、17.8±0.2°、20.4±0.2°和27.3±0.2°的衍射角(2θ)处的特征峰。 在更优选的实施方案中，所述式(I)的化合物的晶体F的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2°
3.1
5.8
6.7
9.4
10.5
11.7
13.5
14.2
14.9
15.6
17.1
17.8
19.3
20.4
20.5
24.0
24.5
25.4
26.5
27.3
29.1
30.9
32.7
34.3
36.2
37.1
在更优选的实施方案中，所述式(I)的化合物的晶体F的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 强度％
3.1 23.9
5.8 23.0
6.7 61.8
9.4 7.9
10.5 8.0
11.7 6.6
13.5 94.9
14.2 10.1
14.9 1.8
15.6 2.3
17.1 9.1
17.8 9.3
19.3 4.9
20.4 100.0
20.5 92.4
24.0 10.3
24.5 5.5
25.4 6.6
26.5 3.9
27.3 4.4
29.1 1.2
30.9 0.6
32.7 0.7
34.3 1.7
36.2 1.0
37.1 2.4
在更优选的实施方案中，所述式(I)的化合物的晶体F的XRPD图谱包括在以下衍射角(2θ)处的峰：
2θ(°)±0.2° 晶面间距(d间隔) 强度％
3.1 28.3 23.9
5.8 15.2 23.0
6.7 13.2 61.8
9.4 9.4 7.9
10.5 8.5 8.0
11.7 7.6 6.6
13.5 6.6 94.9
14.2 6.2 10.1
14.9 6.0 1.8
15.6 5.7 2.3
17.1 5.2 9.1
17.8 5.0 9.3
19.3 4.6 4.9
20.4 4.4 100.0
20.5 4.3 92.4
24.0 3.7 10.3
24.5 3.6 5.5
25.4 3.5 6.6
26.5 3.4 3.9
27.3 3.3 4.4
29.1 3.1 1.2
30.9 2.9 0.6
32.7 2.7 0.7
34.3 2.6 1.7
36.2 2.5 1.0
37.1 2.4 2.4
在更优选的实施方案中，所述式(I)的化合物的晶体F的XRPD图谱包括与图10所示基本上相同的衍射角(2θ)处的峰。在最优选的实施方案中，所述式(I)的化合物的晶体F的XRPD峰位与图10所示基本上相同。
在优选的实施方案中，本发明的式(I)的化合物的晶体F的DSC图谱包括在约121.9±0.2℃(起点温 度)处的特征峰。
在更优选的实施方案中，所述式(I)的化合物的晶体F的DSC图谱包括与图11所示基本上相同的温度处的特征峰。在最优选的实施方案中，所述式(I)的化合物的晶体F的DSC图谱的特征峰位与图11所示基本上相同。
在优选实施方案中，本发明的式(I)的化合物的晶体F为式(I)的化合物与四氢呋喃形成的溶剂合物。
在一个实施方案中，本发明还提供制备上述晶体A-F的中的任意一种的方法，所述方法包括但不限于气液渗透法、室温缓慢挥发法、高聚物诱导结晶法、气固渗透法、缓慢降温法、反溶剂添加法、室温悬浮搅拌法和高温悬浮搅拌法等。
在本发明的一些实施方案中，采用气液渗透法制备晶体，所述方法包括将式(I)的化合物在第一容器的良溶剂中溶解以形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，向第二容器中装入反溶剂，将第一容器敞口放置于第二容器中，将第二容器密封并静置，将析出的固体过滤得到晶体。
在一些实施方案中，所述良溶剂包括但不限于有机溶剂，例如具有1-10个碳原子的醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))和有机酸等，具体例如丙酮、乙酸、甲醇、乙醇、四氢呋喃或三氯甲烷，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，所述反溶剂包括但不限于有机溶剂，例如具有1-10个碳原子的酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类和腈类等，例如二氯甲烷、三氯甲烷、甲基叔丁基醚、甲苯、正己烷、乙腈、2-甲基四氢呋喃、乙酸乙酯、丁酮等，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，所述式(I)的化合物与良溶剂的重量体积比(mg/mL)为约(10-50):1。在一些实施方案中，所述良溶剂与反溶剂的体积比为1:(2-10)。在一些实施方案中，所述将第二容器密封并静置可在室温下进行。在本发明的一些实施方案中，对本发明晶体制备方法及结果举例说明如下：
良溶剂 反溶剂 固体晶体
乙醇 2-甲基四氢呋喃 晶体B
三氯甲烷 丁酮 晶体B
在本发明的一些实施方案中，采用室温缓慢挥发法制备晶体，所述方法包括将式(I)的化合物在容器中的溶剂中溶解形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，将容器密封(例如使用封口膜)，在封口处留小孔或缝隙，将所述澄清溶液放置，使溶剂挥发，得到晶体。
在一些实施方案中，所述溶剂包括但不限于有机溶剂，例如具有1-10个碳原子的醇类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酮类、腈类或酯类，具体例如甲醇、乙醇、异丙醇、三氯甲烷(氯仿)、四氢呋喃、丙酮、甲基叔丁基醚、乙酸乙酯或乙腈，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(5-20):1。在一些实施方案中，所述放置可在室温下进行。在本发明的一些实施方案中，对本发明晶体制备方法及结果举例说明如下：
溶剂 固体晶体
乙醇 晶体B
三氯甲烷 晶体D
异丙醇:乙腈(1:5) 晶体A
在本发明的一些实施方案中，采用高聚物诱导结晶法制备晶体，所述方法包括将式(I)的化合物在容器的溶剂中形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，加入高聚物，将所述容器密封，在封口处留小孔或缝隙，将所述澄清溶液放置，使溶剂挥发，得到晶体。
在一些实施方案中，所述溶剂包括但不限于有机溶剂，例如具有1-10个碳原子的醇类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酮类、腈类或酯类，具体例如甲醇、乙醇、异丙醇、三氯甲烷(氯仿)、四氢呋喃、丙酮、甲基叔丁基醚、乙酸乙酯、乙腈，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，所述高聚物可以是多种高聚物的混合物(混合高聚物)，所述多种高聚物可以任意比例混合，条件是可以用于制备晶体。
在一些实施方案中，所述混合高聚物例如是混合高聚物A：聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯，聚醋酸乙烯酯、羟丙基甲基纤维素和甲基纤维素的混合物。在一些实施方案中，所述混合高聚物例如是混合高聚物B：聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠和羟乙基纤维素的混合物。
在一些实施方案中，所述放置在室温下进行。在一些实施方案中，所述混合高聚物为各组分等重量混合。在一些实施方案中，所述式(I)的化合物与混合高聚物的重量比为(5-10):1。在一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(5-20):1。在本发明的一些实施方案中，对本发明晶体制备方法及结果举例说明如下：
溶剂 高聚物 固体晶体
丙酮 混合高聚物A 晶体B
乙腈/四氢呋喃，1:5 混合高聚物B 晶体F
在本发明的一些实施方案中，采用气固渗透法制备晶体，所述方法包括将装有式(I)的化合物的第一容器放置于装有溶剂的第二容器中，其中所述固态形式的式(I)的化合物与所述溶剂不直接接触，将第二容器密封，放置后得到晶体。
在一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)和有机溶剂，例如具有1-10个碳原子的酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、腈类和酯类，例如二氯甲烷、乙腈、四氢呋喃、丙酮、乙酸乙酯、甲基叔丁基醚、甲苯或三氯甲烷。
在一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为约(1-10):1。在本发明的一些实施方案中，对本发明晶体制备方法及结果举例说明如下：
溶剂 固体晶体
乙腈 晶体A
四氢呋喃 晶体F
乙酸乙酯 晶体A
甲苯 晶体A
三氯甲烷 晶体F
在本发明的一些实施方案中，采用缓慢降温法制备晶体，所述方法包括将式(I)的化合物加入至溶剂中，加热搅拌使其溶解，将所得澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)放置，缓慢降温，得到晶体。
在一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂，例如具有1-10个碳原子的醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、腈类和酯类，具体例如异丙醇、丙酮、三氯甲烷、乙腈、四氢呋喃、甲醇、正己烷或乙酸乙酯，或者由上述溶剂中的两种或更多种形成的混合溶剂。
在一些实施方案中，所述缓慢降温是指例如降温速度为0.1-0.5℃/分钟，例如0.1-0.3℃/分钟，优选0.1℃/分钟。在一些实施方案中，所述加热温度为例如30-80℃，如50℃。在一些实施方案中所述降温结束时的温度为室温或0-10℃，如5℃。
在一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(10-50):1。在本发明的一些实施方案中，对本发明晶体制备方法及结果举例说明如下：
溶剂 固体晶体
异丙醇 晶体B
四氢呋喃 晶体F
在本发明的一些实施方案中，采用反溶剂添加法制备晶体，所述方法包括但不限于将式(I)的化合物在良溶剂中溶解，形成澄清溶液(视需要可将溶液进行过滤以得到澄清溶液)，然后向所述澄清溶液中添加反溶剂，在搅拌(所述搅拌可在室温或者加热条件(例如加热至30-60℃，优选50℃)下进行)下析出晶体，或者静置(例如于室温下放置)(优选同时缓慢地挥发溶剂)从而析出晶体。
在一些实施方案中，所述良溶剂包括但不限于有机溶剂，如具有1-10个碳原子的醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、砜类、酰胺类和有机酸类，例如甲醇、乙醇、丙酮、四氢呋喃、乙酸、三氯甲烷、二甲亚砜或二甲基乙酰胺。在一些实施方案中，所述反溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如具有1-10个碳原子的酮类、烃类(包括烷烃类、卤代烷烃类、烯烃 类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类和腈类)，例如正己烷、正庚烷、环戊基甲醚、乙腈、甲基异丁基甲酮、2-甲基四氢呋喃、二氧六环、乙酸异丙酯、二氯甲烷、甲苯、乙腈、丁酮、甲基叔丁基醚、异丙酸乙酯、碳酸二甲酯和乙酸乙酯。
在一些实施方案中，所述良溶剂与反溶剂的体积比为(0.2-1):(1-20)。在一些实施方案中，所述式(I)的化合物与良溶剂的重量体积比(mg/mL)为(10-80):1。在本发明的一些实施方案中，对本发明晶体制备方法及结果举例说明如下：
Figure PCTCN2017116396-appb-000002
在本发明的一些实施方案中，采用室温悬浮搅拌法制备晶体，所述方法包括但不限于将式(I)的化合物加入溶剂中得到悬浮液，搅拌，然后分离得到晶体。
在一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如具有1-10个碳原子的醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类、腈类和有机酸类，例如正丙醇、异丙醇、丙酮、甲基异丁基甲酮、乙酸异丙酯、乙腈、正己烷、正庚烷、二氯甲烷、甲基叔丁基醚、二氧六环、碳酸二甲酯、乙酸乙酯、四氢呋喃、2-甲基四氢呋喃、乙酸、甲苯、三氯甲烷、环戊基甲醚)，或者选自上述溶剂中的两种或更多种的混合溶剂。
在一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(20-250):1，优选(20-200):1，更优选(20-150):1，最优选(20-100):1。在本发明的一些实施方案中，对本发明晶体制备方法及结果举例说明如下：
溶剂 固体晶体
异丙醇 晶体B
丙酮 晶体A
甲基叔丁基醚 晶体A
异丙醇/正己烷，1:1 晶体B
四氢呋喃/乙腈，1:1 晶体A
在本发明的一些实施方案中，采用高温悬浮搅拌法制备晶体，所述方法包括但不限于将式(I)的化合物加入至溶剂中，得到悬浮液，将所述悬浮液加热(例如加热至30-100℃，优选50℃或80℃)搅拌，然后分离得到晶体。
在一些实施方案中，所述溶剂包括但不限于无机溶剂(例如水)以及有机溶剂(例如具有1-10个碳原子的醇类、酮类、烃类(包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类)、醚类(包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类))、酯类、腈类以及氮杂环类，例如丙酮、甲基异丁基甲酮、乙酸异丙酯、碳酸二甲酯、二氯甲烷、乙腈、四氢呋喃、2-甲基四氢呋喃、三氯甲烷、正己烷、二氧六环、N-甲基吡咯烷酮、环戊基甲醚、甲苯和苯甲醚)。
在一些实施方案中，所述式(I)的化合物与溶剂的重量体积比(mg/mL)为(15-100):1，优选(20-100):1。在一些实施方案中所述加热温度为50-80℃。在本发明的一些实施方案中，对本发明晶体制备方法及结果举例说明如下：
Figure PCTCN2017116396-appb-000003
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员 通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用的词语“约”是指本领域的普通技术人员认为在所述值的可接受的标准误差内，例如±0.05、±0.1、±0.2、±0.3、±1、±2或±3等。
本发明所使用的术语“固体形式”包括式(I)的化合物的所有固态形式，例如晶体形式或无定形形式。
如本文中所使用的术语“无定形”是指三维上无排序的任意固体物质。在一些情况中，无定形固体可通过已知技术表征，所述技术包括XRPD晶体学、固态核磁共振(ssNMR)波谱学、DSC或这些技术的一些组合。如以下所说明，无定形固体产生弥散的XRPD图谱，其通常包括一个或两个宽峰(即具有约5° 2θ或更大的基宽的峰)。
如本文中所使用的术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定形固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。
如本文中所使用的术语“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。本申请中的XRPD图谱优选在PANalytacal Empyrean和X’Pert3X射线粉末衍射分析仪上采集，透射模式优选在PANalytacal EmpyreanX射线粉末衍射分析仪上采集。
如本文中所使用的术语“2θ”是指基于X射线衍射实验的实验设置的以度数表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果当入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶体形式的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。例如，如本文所述，使用Cu-Kα(Kα1
Figure PCTCN2017116396-appb-000004
1.540598和Kα2
Figure PCTCN2017116396-appb-000005
1.544426)作为辐射源。
如本文中所使用的术语“差示扫描量热(DSC)图谱”是指由差示扫描量热仪记录到的曲线。本申请中的DSC图谱优选在TAQ200/2000差示扫描量热仪上采集。
如本文中所使用的，对于X射线衍射峰位的术语“基本上相同”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1-0.2度，并且用于测量衍射的仪器也会显示一些变化。另外，本领域技术人员会理解相对峰强度会显示仪器间的变化以及由于结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素的变化，并应将其看作仅为定性测量。相似地，如本文中所使用，对于DSC图谱的“基本上相同”也意图涵盖本领域技术人员已知的与这些分析技术有关的变化。例如，对于边界清楚的峰，在差示扫描量热图谱通常会具有多达±0.2℃的变化，对于宽峰甚至更大(例如多达±1℃)。
本申请中的液态核磁谱图优选在Bruker 400M核磁共振仪上采集，除非另外说明，以DMSO-d6作为溶剂。
本申请中的偏光显微数据优选通过Axio Lab.A1正置式显微镜在室温下进行采集。
如本文中所使用的术语“烃类”优选意指具有1-10个碳原子的烃，其包括烷烃类、卤代烷烃类、烯烃类、炔烃类和芳烃类，具体包括但不限于二氯甲烷、三氯甲烷(氯仿)、正己烷、正庚烷和甲苯。
如本文中所使用的术语“醇类”优选意指具有1-10个碳原子的醇，其包括但不限于甲醇、乙醇、1-丙醇(正丙醇)、2-丙醇(异丙醇)、1-丁醇、2-丁醇和叔丁醇。
如本文中所使用的术语“醚类”优选意指具有2-6个碳原子的醚，其包括包括链状醚类和环状醚类(例如呋喃类(包括四氢呋喃类)和二氧六环类)，具体包括但不限于乙醚、二异丙基醚、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、二氧六环、环戊基甲醚、苯甲醚和二甲氧基乙烷。
如本文中所使用的术语“腈类”优选意指具有2-6个碳原子的腈，其包括但不限于乙腈和丙腈。
如本文中所使用的术语“酮类溶剂”优选意指具有2-6个碳原子的酮，其包括但不限于丙酮、丁酮、甲基乙基酮、甲基异丁基酮和二乙基酮。
如本文中所使用的术语“酯类”优选意指具有3-10个碳原子的酯，其包括但不限于乙酸乙酯、乙酸丙酯、乙酸异丙酯、异丙酸乙酯、碳酸二甲酯和乙酸丁酯。
如本文中所使用的术语“有机酸类”优选意指具有1-10个碳原子的有机酸，其包括但不限于甲酸和乙酸。
如本文中所使用的术语“砜类”优选意指具有2-10个碳原子的砜或亚砜，其包括但不限于二甲基亚砜。
如本文中所使用的术语“酰胺类”优选意指具有1-10个碳原子的酰胺，其包括但不限于二甲基甲酰胺或二甲基乙酰胺。
如本文中所使用的术语“氮杂环类”优选意指具有3-10个碳原子和至少一个氮原子的含氮杂环，其包括但不限于N-甲基吡咯烷酮。
如本文中所使用的数值范围(如“1-10个”)及其子范围(如“2-10个”、“2-6个”、“3-10个”)等涵盖所述数值范围中的任意个(例如1个、2个、3个、4个、5个、6个、7个、8个、9个或10个)。
可将制备的盐或其晶体形式通过包括倾析、离心、蒸发、重力过滤、抽滤或者在加压下或在减压下的任何其它用于固体回收的技术在内的方法进行回收。可将回收的固体任选地进行干燥。本发明中的“干燥”是在减压(优选真空)下进行直到残留溶剂的含量降低至International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use(“ICH”)指南所给出的限度的范围内。残留溶剂含量取决于溶剂的类型，但不超过约5000ppm、或优选约4000ppm、或更优选约3000ppm。所述干燥可以在盘式干燥器、真空烘箱、空气烘箱、锥形真空干燥器(cone vacuum dryer)、旋转式真空干燥器、流化床干燥器、旋转闪蒸干燥器、快速干燥器等中进行。所述干燥可以在低于约100℃、低于约80℃、低于约60℃、低于约50℃、低于约30℃的温度或任何其它合适的温度下，在大气压或减压(优选真空)下在能够实现期望的结果的任何期望的时间内(如约1、2、3、5、10、15、20、24小时或者过夜)进行，只要盐的品质不劣化。所述干燥可以进行任何期望的次数，直到实现所需的产物品质。干燥的产物可以任选地经历粉碎操作，以产生期望的粒度。可在产物的干燥前或干燥完成后进行研磨或微粉化。可用于减小粒度的技术包括但不限于球磨、辊磨和锤磨，以及喷射研磨(jet milling)。
如本文中所使用的术语“无水晶型”优选意指其中不含有水分子作为结构要素的晶型。
药物组合物和用途
在另一实施方案中，本发明提供药物组合物，其包含本发明的式(I)的化合物的晶体A、B、C、D、E或F中的任意一种或多种，以及一种或多种药学上可接受的载体。
在另一实施方案中，本发明提供本发明的式(I)的化合物的晶体A、B、C、D、E或F在制备用于预防或治疗细胞增殖异常性疾病或病毒感染性疾病的药物中的用途。
在另一实施方案中，本发明提供本发明的式(I)的化合物的晶体A、B、C、D、E或F，其用于预防或治疗细胞增殖异常性疾病或病毒感染性疾病。
在另一实施方案中，本发明提供预防或治疗细胞增殖异常性疾病或病毒感染性疾病的方法，其包括向需要其的个体(优选哺乳动物)给药预防或治疗有效量的本发明的式(I)的化合物的晶体A、B、C、D、E或F中的任意一种或多种。
在一优选实施方案中，所述细胞增殖异常性疾病包括食道、胃、肠、直肠、口腔、咽、喉、肺、结肠、乳腺、子宫、子宫内膜、卵巢、前列腺、睾丸、膀胱、肾、肝、胰腺、骨、结缔组织、皮肤、眼、脑和中枢神经系统等部位发生的肿瘤和/或癌症以及相关病症，以及甲状腺癌、白血病、霍杰金式病、淋巴瘤和骨髓瘤等。
如本文中所使用的术语“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的组合物。
所述剂型可为固体制剂、半固体制剂、液体制剂或气态制剂，具体包括但不限于片剂、胶囊剂、散剂、颗粒剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、混悬剂、酏剂、糖浆剂。
本发明所述的药物组合物可以通过本领域熟知的任何方法来制备，例如通过混合、溶解、制粒、糖包衣、碾磨、乳化、冻干等处理来制备。
如本文中所使用的术语“治疗有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg，特别优选1-50mg，例如1.5mg、2mg、4mg、10mg和25mg等。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
附图说明
图1为式(I)的化合物的晶体A的XRPD图谱。
图2为式(I)的化合物的晶体A的DSC图谱。
图3为式(I)的化合物的晶体B的XRPD图谱。
图4为式(I)的化合物的晶体B的DSC图谱。
图5为式(I)的化合物的晶体C的XRPD图谱。
图6为式(I)的化合物的晶体D的XRPD图谱。
图7为式(I)的化合物的晶体D的DSC图谱。
图8为式(I)的化合物的晶体E的XRPD图谱。
图9为式(I)的化合物的晶体E的DSC图谱。
图10为式(I)的化合物的晶体F的XRPD图谱。
图11为式(I)的化合物的晶体F的DSC图谱。
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非用于限定本发明的范围，本领域技术人员可进行一些非本质的改进和调整，仍属于本发明的保护范围。
实施例1
式(I)的化合物((S)-异丙基2-(((S)-(((2R,3S,4S,5R)-5-(4-氨基-2-氧代嘧啶-1(2H)-基)-4-氟-3-羟基-四氢噻吩-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯)的制备
Figure PCTCN2017116396-appb-000006
(1)1-((2R,3S,4S,5R)-3-氟-4-羟基-5-(羟甲基)-四氢噻吩-2-基)胞嘧啶(化合物A)的制备
Figure PCTCN2017116396-appb-000007
(a)SO2Cl2,咪唑,DCM；(b)KF,2-甲氧基乙醇,回流；(c)2M HCl,THF；(d)BzCl,吡啶,DCM；(e)MsCl,吡啶；(f)NaOMe,MeOH；(g)硫脲,MeOH,回流；(h)AcOK,Ac2O,AcOH,回流；(i)90％TFA；(j)NaIO4,MeOH,H2O；(k)HCl,MeOH,回流；(l)BzCl,吡啶；(m)H2SO4,Ac2O,AcOH；(n)HBr,AcOH,DCM；(o)甲硅烷基化N-乙酰胞嘧啶,80C；(p)aq.NH3,MeOH,HPLC分离
本实施例所用的化合物A按照文献方法制备(J.Org.Chem.1999,64,7912-7920)。
(2)(S)-异丙基2-(((S)-(五氟苯氧基)(苯氧基)磷酰基)氨基)丙酸酯(化合物B)
标题化合物按照文献方法制备(J.Org.Chem.2011,76,8311-8319)，表征数据如文献中所记载。
(3)式(I)的化合物的制备
将化合物A(1mmol)溶于无水四氢呋喃(50ml)中，氩气置换三次。于-10℃滴加叔丁基氯化镁(1.0mol/L，1.2mmol)，搅拌2小时，升至室温反应0.5小时。滴加化合物B(1.2mmol)的无水THF(10ml)溶液，将此混合物在30℃反应15小时。滴加甲醇(10ml)淬灭反应，浓缩，柱层析纯化，得到式(I)的化合物。
ESI-MS:531.1(M+1)
1H NMR(DMSO-d6,400MHz)δ7.86(d,J＝3.4Hz,1H),7.38(t,J＝7.6Hz,2H),7.31-7.17(m,5H)，6.56(dd,J＝4Hz,14Hz,1H),6.09-6.03(m,2H),5.77(d,J＝7.6Hz,1H),5.03-4.87(m,2H)，4.36-4.32(m,2H),4.14-4.12(m,1H),3.80-3.78(m,1H),1.23(d,J＝6.4Hz,3H),1.17(d,J＝5.2Hz,6H)
31P-NMR(CD3OD,162MHz):δ3.29。
由所制备的式(I)的化合物培养单晶，并对所得晶体进行X射线单晶衍射，结果表明所制备的 化合物为(S)-异丙基2-(((S)-(((2R,3S,4S,5R)-5-(4-氨基-2-氧代嘧啶-1(2H)-基)-4-氟-3-羟基-四氢噻吩-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯。
另外测定了(S)-异丙基2-(((R)-(((2R,3S,4S,5R)-5-(4-氨基-2-氧代嘧啶-1(2H)-基)-4-氟-3-羟基-四氢噻吩-2-基)甲氧基)(苯氧基)磷酰基)氨基)丙酸酯，其表征数据如下：
31P-NMR(CD3OD,162MHz):δ3.57
实施例2：室温悬浮搅拌法
称取15.5mg式(I)的化合物，将其加入至1.5ml玻璃小瓶中，加入0.3ml乙腈，将得到的悬浮液于20℃下磁力搅拌(500转/分钟)约2天后，离心分离得到晶体A。
对所获得的晶体A进行XRPD分析，所得XRPD图谱如图1中所示，相关数据如下表中所示。
2θ(°) 晶面间距(d间隔) 强度％
5.3 16.8 29.7
7.8 11.3 5.9
8.7 10.2 8.3
10.5 8.4 100.0
13.5 6.6 21.8
15.2 5.8 1.9
15.8 5.6 12.2
16.4 5.4 4.6
17.4 5.1 2.4
17.9 5.0 27.8
18.3 4.9 6.2
19.2 4.6 2.7
19.9 4.5 1.1
20.3 4.4 0.8
20.6 4.3 3.1
21.3 4.2 18.6
22.3 4.0 5.1
23.3 3.8 2.9
23.6 3.8 3.9
24.2 3.7 11.1
25.0 3.6 1.4
25.8 3.5 2.0
26.4 3.4 5.0
26.8 3.3 6.1
27.9 3.2 4.1
28.6 3.1 2.3
28.9 3.1 4.9
30.2 3.0 1.0
对所获得的晶体A进行DSC分析，所获得的图谱如图2中所示。由该分析可知，样品在155.67℃(起点温度)处有较尖锐的吸热峰。
实施例3：气固渗透法
称取约15mg的式(I)的化合物，将其加入3ml小瓶中，另在20ml小瓶中加入约4ml乙酸乙酯，将3ml小瓶敞口置于20ml小瓶中后，将20ml小瓶密封。在室温下静置6天后收集固体。所得晶体的XRPD图谱和DSC图谱与实施例2中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体A。
实施例4：室温悬浮搅拌法
称取约15mg的式(I)的化合物，将其加入1.5ml玻璃小瓶中，加入0.2ml二氯甲烷，将得到的悬浮液置于室温下磁力搅拌(500转/分钟)约4天后，离心分离固体。所得固体的XRPD图谱和DSC图谱与实施例2中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体A。
实施例5：高温悬浮搅拌法
称取约15mg的式(I)的化合物，将其加入1.5ml玻璃小瓶中，加入0.3ml水，将得到的悬浮液置于50℃下磁力搅拌(500转/分钟)约4天后，离心收集固体。所得固体的XRPD图谱和DSC图谱与实施例2中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体A。
实施例6：气液渗透法
称取下表中所示量的式(I)的化合物，将其溶于下表中所示体积的溶剂中，过滤取上清液，将其转移至3ml小瓶，另取20ml的小瓶，向其中加入约4.0ml的反溶剂，将装有上清液的3ml小瓶敞口置于20ml小瓶后，将20ml的小瓶密封，并于室温下静置。当观察到有固体析出时，进行分离，得到晶体B。
气液渗透法制备晶体B
Figure PCTCN2017116396-appb-000008
对所获得的晶体B进行XRPD分析，所得XRPD图谱如图3中所示，相关数据如下表中所示。
2θ(°) 晶面间距(d间隔) 强度％
6.2 14.1 100.0
7.0 12.6 15.3
9.3 9.5 36.7
11.8 7.5 3.5
12.5 7.1 10.1
13.2 6.7 13.3
14.0 6.3 31.2
14.7 6.0 2.7
15.5 5.7 8.8
16.5 5.4 5.6
17.4 5.1 6.8
18.7 4.7 9.8
19.7 4.5 10.4
21.1 4.2 52.5
22.9 3.9 4.0
23.4 3.8 8.5
23.7 3.8 5.2
24.3 3.7 5.9
26.2 3.4 10.0
26.5 3.4 12.7
27.5 3.2 5.1
29.4 3.0 1.0
33.3 2.7 1.7
35.2 2.6 2.6
对所获得的晶体B进行DSC分析，所获得的图谱如图4中所示。由该分析可知，样品在125.3℃(起点温度)处有较尖锐的吸热峰。
实施例7：缓慢降温法
称取19.8mg的式(I)的化合物，将其加入3ml小瓶中，加0.5ml的异丙醇，在50℃下搅拌约1小时后过滤取上清液，将所得上清液放置在生物培养箱(所述培养箱以0.1℃/分钟从50℃降温至5℃，然后在5℃下恒温)中。此时无固体析出，使上清液中的溶剂在室温下缓慢挥发析出固体，分离所得 的固体。所得固体的XRPD图谱和DSC图谱与实施例6中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体B。
实施例8：室温缓慢挥发法
称取约15.0mg的式(I)的化合物，将其加入3ml小瓶中，加入1.5ml的丙酮形成澄清溶液(或过滤后得到澄清溶液)，用封口膜封住装有所述澄清溶液的小瓶，并在封口膜上面扎5～6个小孔，然后在室温下放置缓慢挥发。收集所得的固体。所得固体的XRPD图谱和DSC图谱与实施例6中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体B。
实施例9：室温悬浮搅拌法
称取15.5mg的式(I)的化合物，将其加入1.5～3.0ml玻璃小瓶中，加入0.2ml的异丙醇，将得到的悬浮液置于室温下磁力搅拌(500转/分钟)约3～4天后，离心分离固体。所得固体的XRPD图谱和DSC图谱与实施例6中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体B。
实施例10：室温悬浮搅拌法
称取235.8mg的式(I)的化合物，将其加入1.5～3.0ml玻璃小瓶中，加入1.0ml异丙醇/正庚烷(v/v,2:1)的混合溶剂，将得到的悬浮液置于室温下磁力搅拌(500转/分钟)约3～4天后，离心分离固体。所得固体的XRPD图谱和DSC图谱与实施例6中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体B。
实施例11：高温悬浮搅拌法
称取15.5mg的式(I)的化合物，将其加入1.5ml玻璃小瓶中，加入0.3ml碳酸二甲酯，将得到的悬浮液置于50℃下磁力搅拌(500转/分钟)约4天后，离心分离固体。所得固体的XRPD图谱和DSC图谱与实施例6中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体B。
实施例12：反溶剂添加法
称取下表所示量的式(I)的化合物，将其加入3ml的小瓶内，用下表中所示相应量的良溶剂溶解并过滤至20ml小瓶后，向该澄清溶液中加入下表中所示相应的反溶剂，边滴加边搅拌直至有固体析出。若加入约10.0ml反溶剂后无固体，则将澄清溶液体在5℃搅拌过夜；若仍无固体析出，则将澄清溶液放置在室温缓慢挥发析晶。离心分离所析出的固体。所得固体的XRPD图谱和DSC图谱与实施例6中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体B。
反溶剂添加法制备晶体B
Figure PCTCN2017116396-appb-000009
实施例13：高聚物诱导结晶法
称取15.0mg的式(I)的化合物，将其加入至含有1.5ml丙酮的小瓶中，得到澄清溶液。然后向小瓶中加入1.8mg的混合高聚物(等重量混合的聚乙烯吡咯烷酮、聚乙烯醇、聚氯乙烯、聚醋酸乙烯酯、羟丙基甲基纤维素和甲基纤维素)，使用封口膜封住小瓶，并在封口膜上扎5～6个小孔，将小瓶置于室温条件下挥发，分离得到固体。所得固体的XRPD图谱和DSC图谱与实施例6中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体B。
实施例14：高聚物诱导结晶法
称取15.0mg的式(I)的化合物，将其加入至含有1.5ml丙酮的小瓶中，得到澄清溶液。然后向小瓶中加入2.1mg的混合高聚物(等重量混合的聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠和羟乙基纤维素)，使用封口膜封住小瓶，并在封口膜上面扎5～6个小孔，将小瓶置于室温条件下挥发，分离得到固体。所得固体的XRPD图谱和DSC图谱与实施例6中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体B。
实施例15：反溶剂添加法
称取20mg的式(I)的化合物，将其加入至3ml小瓶内，用0.5ml甲醇溶解，并将澄清溶液过滤至20ml小瓶后，向所述澄清溶液中加入环戊基甲醚(反溶剂)，边滴加边搅拌。最终反溶剂添加体积为10.0ml，将澄清溶液在室温下搅拌2小时后，有固体析出，离心分离得到晶体C。
对所获得的晶体C进行XRPD分析，所得XRPD图谱如图5中所示，相关数据如下表中所示。
2θ(°) 晶面间距(d间隔) 强度％
4.7 18.7 0.8
8.6 10.3 100.0
10.1 8.8 5.2
13.3 6.7 2.0
14.1 6.3 3.3
14.4 6.2 5.2
16.1 5.5 2.8
16.6 5.3 2.6
17.2 5.2 12.4
18.0 4.9 6.0
18.6 4.8 4.2
19.7 4.5 1.7
21.0 4.2 17.1
24.9 3.6 3.9
26.0 3.4 4.4
26.8 3.3 1.8
29.3 3.0 2.6
实施例16：室温缓慢挥发法
称取14.8mg的式(I)的化合物，将其加入至3ml小瓶中，加入1.5ml的氯仿/乙酸乙酯(v/v,3:1)的混合溶剂，以配制得到澄清溶液(或过滤后得到澄清溶液)，用封口膜封住装有所述澄清溶液的小瓶，并在封口膜上面扎5～6个小孔后，将小瓶放置在室温下缓慢挥发。收集得到晶体D。
对所获得的晶体D进行XRPD分析，所得XRPD图谱如图6中所示，相关数据如下表中所示。
2θ(°) 晶面间距(d间隔) 强度％
8.3 10.7 5.1
10.2 8.7 100.0
13.4 6.6 4.2
14.3 6.2 3.4
15.4 5.8 8.9
16.9 5.3 7.2
17.6 5.0 5.6
18.2 4.9 10.4
18.8 4.7 20.9
19.2 4.6 4.3
20.4 4.5 12.8
23.0 3.9 3.0
25.0 3.6 1.8
25.8 3.4 1.9
27.2 3.3 1.4
28.6 3.1 6.1
31.2 2.9 0.6
对所获得的晶体D进行DSC分析，所获得的图谱如图7中所示。由该分析可知，样品在144.2℃(起点温度)处有较尖锐的吸热峰。
实施例17：室温悬浮搅拌法
称取235.8mg的式(I)的化合物，将其加入至3ml玻璃小瓶中，向其中加入1.0ml 2-甲基四氢呋喃，得到悬浮液，将所得悬浮液置于室温下磁力搅拌(500转/分钟)约3天后，离心分离固体。所得固体的XRPD图谱和DSC图谱与实施例16中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体D。
实施例18：反溶剂添加法
称取14.9mg的式(I)的化合物，将其溶于1.0ml的丙酮中得到澄清溶液，加入0.3ml的2-甲基四氢呋喃，得到悬浮液，将所得悬浮液置于50℃下磁力搅拌(500转/分钟)约4天后，离心分离固体。所得固体的XRPD图谱和DSC图谱与实施例16中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体D。
实施例19：反溶剂添加法
称取15.6mg的式(I)的化合物，将其溶于1.0ml的丙酮中得澄清溶液，加入0.3ml的苯甲醚，得到悬浮液，将所得悬浮液置于80℃下磁力搅拌(500转/分钟)约4天后，离心分离固体。所得固体的XRPD图谱和DSC图谱与实施例16中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体D。
实施例20：高温悬浮搅拌法
称取19.1mg的式(I)的化合物，将其加入至1.5ml玻璃小瓶中，然后加入1.0ml的四氢呋喃(预先用晶体A样品饱和)，得到悬浮液，将所得悬浮液置于50℃下磁力搅拌(500转/分钟)约1天后，离心分离得到晶体E。
对所获得的晶体E进行XRPD分析，所得XRPD图谱如图8中所示，相关数据如下表中所示。
2θ(°) 晶面间距(d间隔) 强度％
4.0 21.9 100.0
6.8 13.0 83.9
8.0 11.0 84.9
11.6 7.7 27.8
18.6 4.8 26.8
19.8 4.5 31.3
23.8 3.7 16.2
29.6 3.0 0.5
33.9 2.7 1.1
对所获得的晶体E进行DSC分析，所获得的图谱如图9中所示。由该分析可知，样品在96.6℃(起点温度)处有较尖锐的吸热峰。
实施例21：室温缓慢挥发法
称取65.3mg的式(I)的化合物，将其加入至3ml小瓶中，加入2.0ml的四氢呋喃配制成澄清溶液(或过滤后得到澄清溶液)，用封口膜封住装有所述澄清溶液的小瓶，并在封口膜上面扎5～6个小孔，然后将小瓶放置在室温下缓慢挥发。所得固体为晶体F。
对所获得的晶体F进行XRPD分析，所得XRPD图谱如图10中所示，相关数据如下表中所示。
2θ(°) 晶面间距(d间隔) 强度％
3.1 28.3 23.9
5.8 15.2 23.0
6.7 13.2 61.8
9.4 9.4 7.9
10.5 8.5 8.0
11.7 7.6 6.6
13.5 6.6 94.9
14.2 6.2 10.1
14.9 6.0 1.8
15.6 5.7 2.3
17.1 5.2 9.1
17.8 5.0 9.3
19.3 4.6 4.9
20.4 4.4 100.0
20.5 4.3 92.4
24.0 3.7 10.3
24.5 3.6 5.5
25.4 3.5 6.6
26.5 3.4 3.9
27.3 3.3 4.4
29.1 3.1 1.2
30.9 2.9 0.6
32.7 2.7 0.7
34.3 2.6 1.7
36.2 2.5 1.0
37.1 2.4 2.4
对所获得的晶体F进行DSC分析，所获得的图谱如图11中所示。由该分析可知，样品在121.9℃(起点温度)处有较尖锐的吸热峰。
实施例22：缓慢降温法
称取20.1mg的式(I)的化合物，将其加入至3ml小瓶中，加1.0ml的四氢呋喃，在50℃下搅拌约0.5小时后过滤取上清液，将所得上清液放置在生物培养箱(所述培养箱以0.1℃/分钟从50℃降温至5℃，然后在5℃下恒温)中，分离得到固体。所得固体的XRPD图谱和DSC图谱与实施例21中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体F。
实施例23：气固渗透法
称取14.8mg的式(I)的化合物，将其加入至3ml的小瓶内，另取20ml的小瓶向其中加入约4.0ml的四氢呋喃，将装有式(I)的化合物的3ml小瓶敞口置于20ml小瓶后，密封20ml的小瓶，并将其于室温下静置6天，分离得到固体。所得固体的XRPD图谱和DSC图谱与实施例21中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体F。
实施例24：高聚物诱导法
称取15.1mg的式(I)的化合物，将其加入至含有1.5ml的乙腈/四氢呋喃(v/v,1:5)的混合溶剂的小瓶中，得到澄清溶液，向其中加入约2mg的混合高聚物(等重量混合的聚己酸内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠和羟乙基纤维素)，使用封口膜封住小瓶，并在封口膜上面扎5～6个小孔，将小瓶置于室温条件下挥发，分离得到固体。所得固体的XRPD图谱和DSC图谱与实施例21中的XRPD图谱和DSC图谱基本上相同，表明得到了晶体F。
实验例
实验例1 平衡溶解度研究
称取式(I)的化合物的晶体A、晶体B和晶体D各约2.0～5.0mg，将其加入至3ml的小瓶中，并加入1.0ml去离子水，然后将所得悬浮液放置在旋转孵化器上(转速为25转/分钟)，并置于25℃的生化培养箱中平衡24小时后，量取0.8ml悬浮液，离心分离固体(6000转/分钟，15分钟)，取上清液用HPLC测量溶解度，取固体检测XRPD图谱。
试验结果表明：式(I)的化合物的晶体A和晶体B在水中25℃下24小时的溶解度分别为约1.0mg/ml和1.8mg/ml，溶解性良好。同时，晶体A和晶体B未发生晶体转变，而晶体D在水中分散24小时后发生晶体转变。
实验例2 固态稳定性
称取适量式(I)的化合物的晶体A作为待测样品，将其在40℃/75％ RH(RH表示相对湿度)条件下敞口放置8天。检测放置后的待测样品的XRPD图谱，并用HPLC测量纯度。
试验结果表明：在40℃/75％ RH条件下敞口放置8天后，晶体A未发生晶体变化，样品相对纯度为99.9％。由此可见，式(I)的化合物的晶体A在40℃/75％ RH条件下具有良好的固态稳定性。
实验例3 光照实验
将式(I)的化合物的晶体A于4500lx的光照强度、25℃、RH 25％的条件下放置30天，分别在0天、5天、11天和30天进行取样，观察样品性状变化，用旋光仪测量比旋度，检测干燥失重，通过HPLC测量总的杂质含量。
试验结果表明：在4500lx的光照强度、25℃、RH 25％的条件下放置30天后，晶体A仍为白色粉末，外观没有发生变化；比旋度在0天到30天期间的变化不超过3°；在不同时间点检测干燥失重，干燥失重％不大于1.0％；在不同时间点HPLC检测出总的杂质含量基本保持不变。
由此可见，式(I)的化合物的晶体A具有良好的光稳定性，可保证晶体A在储存和运输时的可靠性，从而保证药品的安全性，并且晶体A不需要为防止受光照影响而采取的特殊包装处理，从而降低成本。晶体A不会因光照影响产生降解，提高了药品的安全性和长期贮藏后的有效性。服用晶体A的患者不会因暴露于日光而产生光敏反应。
实验例4 高温实验
将式(I)的化合物的晶体A在60℃的高温下放置30天，分别在0天、5天、10天和30天进行取样，观察样品性状变化，用旋光仪测量比旋度，检测干燥失重，通过HPLC测量总的杂质含量。
试验结果表明：在60℃高温下放置30天后，晶体A仍为白色粉末，外观没有发生变化；比旋度在0天到30天期间的变化不超过2°；在不同时间点检测干燥失重，干燥失重％不大于1.07％；在不同时间点HPLC检测出总的杂质含量基本无变化。
由此可见，式(I)的化合物的晶体A具有良好的耐高温性(热稳定性)。
实验例5 高湿实验
将式(I)的化合物的晶体A在25℃、RH 75％的高湿条件下分别放置30天，分别在0天、5天、10天和30天进行取样，观察样品性状变化，用旋光仪测量比旋度，检测干燥失重，通过HPLC测量总的杂质含量。
试验结果显示：在25℃、RH 75％的高湿条件下放置30天后，晶体A仍为白色粉末，外观没有发生变化；比旋度在0天到30天期间的变化不超过1°；在不同时间点检测干燥失重，干燥失重％不大于1.0％；在不同时间点HPLC检测出总的杂质含量基本未变化。
由此可见，式(I)的化合物的晶体A具有良好的耐高湿性(即在高湿条件是具有较高的稳定性)和低吸湿性。
本发明的晶体B-F也具有较好的耐高温、耐高湿和/或耐光照的性质。
实验例6 稳定性关系
称取等重量的晶体A、B和D(各8mg)，将其分别加入至在室温下用晶体A样品预饱和后的H2O溶液(0.3毫升)中，将由此形成的悬浮液在室温下打浆约4天后，分离固体，并将湿样与干样分别进行XRPD图谱测定。结果表明，晶体B和D在室温下均转变为晶体A。这表明晶体A在室温下更稳定。
实验例7 小鼠中的药代动力学实验
将式(I)的化合物的晶体A配制成0.5％羧甲基纤维素钠(CMC-Na)中的悬浮液，并对ICR小鼠进行单次灌胃给药，考察其药代动力学特征。单次灌胃剂量分别为2mg/kg、4mg/kg和8mg/kg。晶体A进入体内后迅速代谢为具有药效活性的代谢产物I：
活性代谢产物I的结构：
Figure PCTCN2017116396-appb-000010
根据血浆中代谢产物I的浓度-时间曲线计算各药代动力学参数。结果如表1所示：
表1.小鼠单次灌胃给药后的代谢产物I的药代动力学参数
Figure PCTCN2017116396-appb-000011
由表1可见，小鼠单次灌胃给药后的代谢产物I在2mg/kg的剂量下，最大血药浓度(Cmax)为211ng/mL，暴露量(AUC0-∞)为239ng·h/mL；在4mg/kg的剂量下，Cmax为284ng/mL，AUC0-∞为332ng·h/mL；在8mg/kg的剂量下，Cmax为633ng/mL，AUC0-∞为796ng·h/ml。可见，本发明式(I)化合物的晶体A的活性代谢产物具有优良的血药浓度和暴露量。
实验例8 比格犬中的药代动力学实验
将式(I)的化合物的晶体A配制成0.5％CMC-Na中的悬浮液，并对比格犬进行单次灌胃给药。单次灌胃剂量分别为0.1mg/kg、0.2mg/kg和0.4mg/kg。晶体A进入体内后迅速代谢为具有药效活性的代谢产物I，根据血浆中代谢产物I的浓度-时间曲线计算各药代动力学参数。结果如表2所示：
表2.比格犬灌胃给药后的代谢产物I的药代动力学参数
Figure PCTCN2017116396-appb-000012
由表2可见，比格犬单次灌胃给药后的代谢产物I在0.1mg/kg的剂量下，最大血药浓度(Cmax)为45.3ng/mL，暴露量(AUC0-∞)为296ng·h/mL；在0.2mg/kg的剂量下，Cmax为81.6ng/mL，AUC0-∞为567ng·h/mL；在0.4mg/kg的剂量下，Cmax为164ng/mL，AUC0-∞为1120ng·h/mL。说明本发明中式(I)化合物的晶体A的活性代谢产物具有优良的血药浓度和暴露量。
实验例9 小鼠中的药物排泄实验
将具有放射性同位素的晶体A([14C]晶体A)配制成0.5％羧甲基纤维素钠(CMC-Na)中的悬浮液，并对ICR小鼠进行单次灌胃给药，给药剂量为117μCi/4.08mg/kg[14C]晶体A，通过测定尿液及粪便的放射性回收率考察晶体A的吸收及排泄特征。
经测定，小鼠灌胃给予[14C]晶体A后0至120小时内尿液中的放射性回收率为78.7％。说明经口服吸收进入血液的药物成分比例至少为78.7％，即晶体A灌胃给药的绝对生物利用度在78.7％以上。可见晶体A具有良好的口服吸收特点，适合制备成口服制剂。
小鼠灌胃给予[14C]晶体A后放射性物质的排泄主要集中在给药后48小时以内，在该段时间经尿和粪排泄的放射性物质占给药量的84.5％，说明晶体A排泄较完全，因药物蓄积而造成的安全性风险较低。
实验例10 药物组合物稳定性
向晶体A中加入适量纤维素粉末等常规辅料，制备成混合粉末。分别在光照(4500lx±500lx)、高温(60℃)、高湿(92.5％)的条件下储存30天，测试混合粉末的总杂质含量及30分钟内溶出度的变化 情况，结果如下表所示：
表3.药物组合物稳定性实验结果
Figure PCTCN2017116396-appb-000013
结果证明，通过晶体A与常规辅料制备而成的混合粉末分别在光照、高温(60℃)、高湿(92.5％)的条件下储存30天，总杂质含量均保持在0.9％以下，粉末溶出度均保持在30分钟内溶出度93％以上。证明晶体A适合制备成稳定性及溶出性质良好的药物组合物。本发明的其他晶体也具有较好组合物稳定性。
实验例11 药物组合物粉体学性质
将晶体A与微晶纤维素以1:3的重量比例混合后，利用固定漏斗法测定该混合粉末的休止角。即将漏斗固定在一定高度H，混合粉末置于漏斗中，使其自然流下成堆，至圆锥体的顶端刚接触到漏斗出口为止，测定圆锥底面的半径r，计算休止角。休止角＝arc tg(H/r)。
测定结果表明混合粉末休止角在36-40度范围内，证明晶体A与常规辅料混合而成的粉末具有良好的流动性，能够满足生产中对原辅料混合粉末流动性的要求，适合用于药物组合物的工业化生产。本发明的其他晶体也具有较好粉体学性质。
上述具体实施方式对本发明作进一步的详细描述。但不应将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明内容所实施的技术方案均落入于本发明的范围。

Claims (14)

  1. 式(I)的化合物的晶体A：
    Figure PCTCN2017116396-appb-100001
    所述晶体A的XRPD图谱包括在10.5±0.2°、13.5±0.2°和17.9±0.2°的衍射角(2θ)处的特征峰，优选包括在10.5±0.2°、13.5±0.2°、15.8±0.2°、17.9±0.2°、18.3±0.2°和21.3±0.2°的衍射角(2θ)处的特征峰，最优选包括在10.5±0.2°、13.5±0.2°、15.8±0.2°、17.9±0.2°、18.3±0.2°、21.3±0.2°、22.3±0.2°、24.2±0.2°和26.8±0.2°的衍射角(2θ)处的特征峰。
  2. 制备权利要求1的式(I)的化合物的晶体A的方法，所述方法选自气固渗透法、反溶剂添加法、室温缓慢挥发法、室温悬浮搅拌法和高温悬浮搅拌法。
  3. 式(I)的化合物的晶体B：
    Figure PCTCN2017116396-appb-100002
    所述晶体B的XRPD图谱包括在7.0±0.2°、14.0±0.2°和21.1±0.2°的衍射角(2θ)处的特征峰，优选包括在6.2±0.2°、7.0±0.2°、13.2±0.2°、14.0±0.2°、21.1±0.2°和26.2±0.2°的衍射角(2θ)处的特征峰，最优选包括在6.2±0.2°、7.0±0.2°、9.3±0.2°、13.2±0.2°、14.0±0.2°、15.5±0.2°、18.7±0.2°、21.1±0.2°和26.2±0.2°的衍射角(2θ)处的特征峰。
  4. 制备权利要求3的式(I)的化合物的晶体B的方法，所述方法选自气液渗透法、缓慢降温法、室温缓慢挥发法、室温悬浮搅拌法、高温悬浮搅拌法、反溶剂添加法和高聚物诱导结晶法。
  5. 式(I)的化合物的晶体C：
    Figure PCTCN2017116396-appb-100003
    所述晶体C的XRPD图谱包括在8.6±0.2°、17.2±0.2°和21.0±0.2°的衍射角(2θ)处的特征峰，优选包括在8.6±0.2°、10.1±0.2°、14.4±0.2°、17.2±0.2°、18.0±0.2°和21.0±0.2°的衍射角(2θ)处的特征峰，最优选包括在8.6±0.2°、10.1±0.2°、14.4±0.2°、17.2±0.2°、18.0±0.2°、18.6±0.2°、21.0±0.2°、24.9±0.2°和26.0±0.2°的衍射角(2θ)处的特征峰。
  6. 制备权利要求5的式(I)的化合物的晶体C的方法，所述方法为反溶剂添加法，其包括将式(I)的化合物在良溶剂中溶解，形成澄清溶液，然后向所述澄清溶液中添加反溶剂，在搅拌下析出晶体C，或者通过挥发溶剂从而析出晶体C。
  7. 式(I)的化合物的晶体D：
    Figure PCTCN2017116396-appb-100004
    所述晶体D的XRPD图谱包括在10.2±0.2°、18.8±0.2°和20.4±0.2°的衍射角(2θ)处的特征峰，优选包括在10.2±0.2°、15.4±0.2°、16.9±0.2°、18.2±0.2°、18.8±0.2°和20.4±0.2°的衍射角(2θ)处的特征峰，最优选包括在10.2±0.2°、14.3±0.2°、15.4±0.2°、16.9±0.2°、18.2±0.2°、18.8±0.2°、20.4±0.2°、25.0±0.2°和28.6±0.2°的衍射角(2θ)处的特征峰。
  8. 制备权利要求7的式(I)的化合物的晶体D的方法，所述方法选自反溶剂添加法、室温缓慢挥发法、室温悬浮搅拌法和高温悬浮搅拌法。
  9. 式(I)的化合物的晶体E：
    Figure PCTCN2017116396-appb-100005
    所述晶体E的XRPD图谱包括在4.0±0.2°、6.8±0.2°和8.0±0.2°的衍射角(2θ)处的特征峰，优选包括在4.0±0.2°、6.8±0.2°、8.0±0.2°、11.6±0.2°、18.6±0.2°和19.8±0.2°的衍射角(2θ)处的特征峰，最优选包括在4.0±0.2°、6.8±0.2°、8.0±0.2°、11.6±0.2°、18.6±0.2°、19.8±0.2°、23.8±0.2°、29.6±0.2°和33.9±0.2°的衍射角(2θ)处的特征峰。
  10. 制备权利要求9的式(I)的化合物的晶体E的方法，所述方法为高温悬浮搅拌法，其包括将式(I)的化合物加入至溶剂中，得到悬浮液，将所述悬浮液在加热下搅拌，然后分离得到晶体E。
  11. 式(I)的化合物的晶体F：
    Figure PCTCN2017116396-appb-100006
    所述晶体F的XRPD图谱包括在6.7±0.2°、13.5±0.2°和20.4±0.2°的衍射角(2θ)处的特征峰，优 选包括在5.8±0.2°、6.7±0.2°、13.5±0.2°、14.2±0.2°、17.8±0.2°和20.4±0.2°的衍射角(2θ)处的特征峰，最优选包括在5.8±0.2°、6.7±0.2°、9.4±0.2°、11.7±0.2°、13.5±0.2°、14.2±0.2°、17.8±0.2°、20.4±0.2°和27.3±0.2°的衍射角(2θ)处的特征峰。
  12. 制备权利要求11的式(I)的化合物的晶体F的方法，所述方法选自室温缓慢挥发法、缓慢降温法、气固渗透法和高聚物诱导结晶法。
  13. 药物组合物，其包含权利要求1、3、5、7、9和11中任一项的式(I)的化合物的晶体A、B、C、D、E或F，以及一种或多种药学上可接受的载体。
  14. 权利要求1、3、5、7、9和11中任一项的式(I)的化合物的晶体A、B、C、D、E或F在制备用于预防或治疗细胞增殖异常性疾病或病毒感染性疾病的药物中的用途。
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