WO2020221275A1 - 二氨基嘧啶类化合物或其水合物的固体形式及其制备方法和用途 - Google Patents

二氨基嘧啶类化合物或其水合物的固体形式及其制备方法和用途 Download PDF

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WO2020221275A1
WO2020221275A1 PCT/CN2020/087687 CN2020087687W WO2020221275A1 WO 2020221275 A1 WO2020221275 A1 WO 2020221275A1 CN 2020087687 W CN2020087687 W CN 2020087687W WO 2020221275 A1 WO2020221275 A1 WO 2020221275A1
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Prior art keywords
crystal form
compound
characteristic peaks
diffraction angles
xrpd pattern
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PCT/CN2020/087687
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English (en)
French (fr)
Inventor
郑翔玲
赵焰平
王红军
冯泽旺
黄淮
刘凯
刘雪莲
庞建梅
田娜娜
陈玺朝
付深圳
孟杰
周丽莹
刘亚男
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北京泰德制药股份有限公司
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Application filed by 北京泰德制药股份有限公司 filed Critical 北京泰德制药股份有限公司
Priority to KR1020217038591A priority Critical patent/KR20220008284A/ko
Priority to US17/607,449 priority patent/US20220204475A1/en
Priority to EP20798323.0A priority patent/EP3964505A4/en
Priority to JP2021564188A priority patent/JP2022530889A/ja
Priority to MX2021013300A priority patent/MX2021013300A/es
Priority to CA3138234A priority patent/CA3138234A1/en
Priority to BR112021021721A priority patent/BR112021021721A2/pt
Priority to CN202080032502.6A priority patent/CN113993858A/zh
Priority to SG11202111907UA priority patent/SG11202111907UA/en
Priority to AU2020265969A priority patent/AU2020265969A1/en
Publication of WO2020221275A1 publication Critical patent/WO2020221275A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • 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 a solid of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine (hereinafter referred to as "compound A”) or its hydrate Forms, methods for preparing the solid forms, pharmaceutical compositions comprising the solid forms, and use of the solid forms for preventing or treating diseases modulated by P2X3 and/or P2X2/3 receptor antagonists.
  • Purine compounds play a role through purinergic receptors on the cell surface, and they play a wide range of physiological and pathological effects.
  • ATP to a lesser extent adenosine
  • P2Y-purinergic receptors are G-protein coupled receptors
  • P2X-purinergic receptors are ATP-gated cation channel family. It is known that purinergic receptors (especially P2X receptors) can form homomultimers or heteromultimers.
  • P2X3 and/or P2X2/3 receptor antagonists can be used to treat pain and other diseases.
  • the applicant has discovered a class of diaminopyrimidine compounds, especially 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine, which can be used As an effective P2X3 and/or P2X2/3 receptor antagonist (see PCT/CN2018/112829, which is incorporated herein by reference in its entirety).
  • the present invention provides compound A (5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine) as shown below or its hydrate Crystal form:
  • the preferred crystal form of the present invention not only has excellent effects in preventing or treating diseases modulated by P2X3 and/or P2X2/3 receptor antagonists, but also has other advantages.
  • the preferred crystal form of the present invention has excellent physical properties (including solubility, dissolution rate, light resistance, low moisture absorption, high temperature resistance, high humidity resistance, fluidity, etc.), and has excellent properties such as bioavailability, physical and
  • the preferred crystal form of the present invention may have more excellent properties.
  • the preferred crystal form of the present invention has good powder properties, is more suitable and convenient for mass production and used in the formation of preparations, can reduce irritation and improve absorption, solve the problem of metabolic speed, and significantly reduce the accumulation of drugs. Toxicity improves safety and effectively guarantees the quality and efficacy of pharmaceutical products.
  • the invention provides a method of preparing the crystal form of the invention.
  • the present invention provides a pharmaceutical composition comprising any one or more crystal forms of the present invention and one or more pharmaceutically acceptable carriers.
  • the present invention provides the use of the crystal form of the present invention in the preparation of a medicament for the treatment of diseases modulated by P2X3 and/or P2X2/3 receptor antagonists.
  • Figure 1 is an X-ray powder diffraction pattern of the crystalline form I of Compound A anhydrate.
  • Figure 2 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of the crystalline form I of compound A anhydrate.
  • Figure 3 is a scanning electron micrograph of the crystalline form I of compound A anhydrate.
  • Figure 4 is an X-ray powder diffraction pattern of the crystal form II of compound A monohydrate.
  • Figure 5 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of the crystalline form II of compound A monohydrate.
  • Fig. 6 is an X-ray powder diffraction pattern of the crystal form III of compound A hemihydrate.
  • Figure 7 is a differential scanning calorimetry (DSC) spectrum of Form III of Compound A hemihydrate.
  • Figure 8 is an X-ray powder diffraction pattern of the crystalline form IV of Compound A sesquihydrate.
  • Figure 9 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of the crystalline form IV of Compound A sesquihydrate.
  • Figure 10 is an X-ray powder diffraction pattern of the crystalline form V of compound A monohydrate.
  • Figure 11 is a differential scanning calorimetry (DSC) spectrum of the crystalline form V of compound A monohydrate.
  • Figure 12 is an X-ray powder diffraction pattern of the crystalline form VI of compound A monohydrate.
  • Figure 13 is a differential scanning calorimetry (DSC) spectrum of Form VI of Compound A monohydrate.
  • Fig. 14 is an X-ray powder diffraction pattern of Form VII of Compound A sesquihydrate.
  • Figure 15 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of the crystalline form VII of compound A sesquihydrate.
  • Fig. 16 is an X-ray powder diffraction pattern of Form VIII of Compound A hemihydrate.
  • Figure 17 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of the crystalline form VIII of compound A hemihydrate.
  • Figure 18 is a comparison of XRPD patterns of the crystal form I of compound A anhydrate before and after the room temperature stability experiment.
  • Figure 19 is a comparison of XRPD patterns of the crystal form I of compound A anhydrate before and after the high temperature stability experiment.
  • Figure 20 is a comparison of XRPD patterns of the crystalline form I of Compound A anhydrate before and after the high humidity stability experiment.
  • Figure 21 is a comparison of XRPD patterns of the crystal form I of compound A anhydrate before and after the physical grinding stability experiment.
  • solid form used in the present invention includes all solid forms of Compound A or any hydrate thereof, such as crystalline form or amorphous form.
  • amorphous refers to any solid substance that has no order 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.
  • ssNMR solid state nuclear magnetic resonance
  • DSC solid state nuclear magnetic resonance
  • an amorphous solid produces a diffuse XRPD pattern, which usually includes one or two broad peaks (ie, a peak with a base width of about 5° 2 ⁇ or greater).
  • crystalline form or "crystalline” as used herein refers to any solid substance exhibiting a three-dimensional order, as opposed to an amorphous solid substance, which produces a characteristic XRPD pattern with well-defined peaks.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or a parameter derived from it.
  • the XRPD pattern is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).
  • 2 ⁇ refers to a peak position expressed in degrees based on an experimental setting of an X-ray diffraction experiment, and is usually a unit of abscissa in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle ⁇ with a certain lattice plane, the experimental setup needs to record the reflected beam at an angle of 2 ⁇ . It should be understood that the specific 2 ⁇ value of the specific crystal form mentioned herein is intended to mean the 2 ⁇ 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 radiation source.
  • I% means the percentage of peak intensity
  • DSC differential scanning calorimetry
  • thermogravimetric analysis (TGA) profile refers to a curve recorded by a thermogravimetric analyzer.
  • the term "substantially the same" for X-ray diffraction peak positions means that representative peak positions and intensity changes are taken into consideration. For example, those skilled in the art will understand that the peak position (2 ⁇ ) will show some variation, usually as much as 0.1-0.2 degrees, and the instrument used to measure diffraction will also show some variation. In addition, those skilled in the art will understand that the relative peak intensity will show changes between instruments and changes due to the degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art. Similarly, as used herein, “substantially the same” for the DSC profile is also intended to cover the changes known to those skilled in the art related to these analysis techniques. For example, for peaks with well-defined boundaries, the differential scanning calorimetry spectrum usually has a variation of up to ⁇ 0.2°C, and for broad peaks it is even larger (for example, up to ⁇ 1°C).
  • liquid NMR spectra in this application are preferably collected on a Bruker 400M NMR instrument, unless otherwise specified, using DMSO-d6 as the solvent.
  • the polarized light microscopy data in this application is preferably collected by Polarizing Microscope ECLIPSE LV100POL (Nikon, JPN).
  • the prepared salt or its crystal form can be recovered by a method including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for solid 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 content of residual solvent is reduced to the limit given in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines Within range.
  • 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 can be in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a spin flash dryer, a rapid dryer, etc. get on.
  • the drying may be at a temperature of less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperature, under atmospheric pressure or reduced pressure ( It is preferably carried out under vacuum) for any desired time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours, or overnight) that can achieve the desired result, as long as the quality of the salt does not deteriorate.
  • the drying can be performed any desired number of times until the desired product quality is achieved.
  • the dried product may optionally undergo a comminution operation to produce the desired particle size.
  • the product can be ground or micronized before or after drying. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller milling and hammer milling, and jet milling.
  • anhydrate as used herein preferably means a crystal form in which water molecules are not contained as a structural element.
  • the present invention provides the crystalline form I of Compound A anhydrate:
  • the XRPD pattern of the crystal form I includes characteristic peaks at diffraction angles (2 ⁇ ) of about 11.9 ⁇ 0.2°, 12.3 ⁇ 0.2°, 13.9 ⁇ 0.2°, 19.8 ⁇ 0.2°, and 20.3 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form I includes about 10.1 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.3 ⁇ 0.2°, 13.9 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.8 ⁇
  • the XRPD pattern of the crystalline form I includes about 6.2 ⁇ 0.2°, 10.1 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.3 ⁇ 0.2°, 13.9 ⁇ 0.2°, 16.9 ⁇ 0.2°, 17.8 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.8 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.0 ⁇ 0.2°, 23.6 ⁇ 0.2°, 24.1 ⁇ 0.2°, 26.2 ⁇ 0.2°, 26.5 ⁇ 0.2°, 27.8
  • the XRPD pattern of the crystalline form I includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form I includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 1.
  • the XRPD peak position of the crystalline form I is substantially the same as that shown in FIG. 1.
  • the DSC spectrum of the crystalline form I includes an endothermic/exothermic peak at about 245/255°C.
  • the crystal form I has a weight loss of about 0.1% when heated to about 100-150°C.
  • the DSC-TGA pattern of the crystal form I includes substantially the same characteristic peaks as shown in FIG. 2. In the most preferred embodiment, the DSC-TGA pattern of the crystalline form I is substantially the same as that shown in FIG. 2.
  • the scanning electron micrograph of the crystal form I is substantially the same as that shown in FIG. 3.
  • the present invention provides a method for preparing crystal form I, which includes the following steps:
  • step 2) Add alkali (such as sodium hydroxide, potassium hydroxide or ammonia) to the solution or filtrate obtained in step 1), and collect the precipitated solid by filtration; and
  • alkali such as sodium hydroxide, potassium hydroxide or ammonia
  • the present invention provides a method for preparing crystal form I, which includes dissolving compound A in a good solvent (which can be carried out at room temperature or under heating conditions (for example, heating to 30-60°C, preferably 50°C)), A solution is formed (if necessary, the mixture can be filtered to obtain a solution), and then an anti-solvent is added to the solution, while stirring (the addition of the anti-solvent and stirring can be at room temperature or under cooling conditions (for example, cooling to 0-10°C, Preferably, it is carried out at 5°C) to precipitate a solid, which is filtered to obtain crystals.
  • a good solvent which can be carried out at room temperature or under heating conditions (for example, heating to 30-60°C, preferably 50°C)
  • a solution is formed (if necessary, the mixture can be filtered to obtain a solution)
  • an anti-solvent is added to the solution, while stirring (the addition of the anti-solvent and stirring can be at room temperature or under cooling conditions (for example, cooling to 0-10
  • the good solvent is an ether with 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyl Tetrahydrofuran or dioxane;
  • the anti-solvent is a hydrocarbon with 5-10 carbon atoms (which includes alkanes, halogenated alkanes, alkenes, alkynes and aromatic hydrocarbons, including but not limited to methylene chloride, Trichloromethane (chloroform), n-hexane, n-heptane and toluene) or ethers having 2-6 carbon atoms (preferably chain ethers such as diethyl ether, diisopropyl ether or methyl tert-butyl ether).
  • the weight-to-volume ratio (g/mL) of Compound A and the good solvent is about 1:(30-120), preferably about 1:40 or 1:100.
  • the volume ratio of the good solvent and the anti-solvent is about 1:1 to 1:5.
  • the present invention provides crystal form II of compound A monohydrate:
  • the XRPD pattern of the crystal form II includes characteristic peaks at diffraction angles (2 ⁇ ) of about 13.0 ⁇ 0.2°, 19.5 ⁇ 0.2°, and 19.9 ⁇ 0.2°.
  • the XRPD pattern of the crystal form II includes diffraction angles (2 ⁇ ) at about 9.6 ⁇ 0.2°, 13.0 ⁇ 0.2°, 19.5 ⁇ 0.2°, 19.9 ⁇ 0.2°, and 22.7 ⁇ 0.2° Characteristic peaks.
  • the XRPD pattern of the crystalline form II includes about 9.6 ⁇ 0.2°, 10.9 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.9 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.8 ⁇ 0.2°, 19.5 ⁇ 0.2°, 19.9 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.7 ⁇ 0.2°, 25.2 ⁇ 0.2°, 26.0 ⁇ 0.2°, 28.5 ⁇ 0.2°, 29.0 ⁇ 0.2°, 30.0 ⁇ 0.2° and 32.5 ⁇ 0.2° diffraction The characteristic peak at angle (2 ⁇ ).
  • the XRPD pattern of the crystal form II includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form II includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 4.
  • the XRPD peak position of the crystalline form II is substantially the same as that shown in FIG. 4.
  • the DSC spectrum of the crystal form II includes an endothermic peak at about 73.9°C and an endothermic/exothermic peak at about 245/255°C.
  • the crystal form II has a weight loss of about 6.2% when heated to about 100°C.
  • the DSC-TGA pattern of the crystal form II includes the characteristic peaks substantially the same as those shown in FIG. 5. In the most preferred embodiment, the DSC-TGA pattern of the crystal form II is substantially the same as that shown in FIG. 5.
  • the present invention provides a method for preparing crystalline form II, which includes putting compound A in an aqueous alcohol solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Suspended in propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol) and stirred (for example at room temperature) (for example 1-5 days, such as Days), filtered to obtain crystals.
  • an aqueous alcohol solvent preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1- Suspended in propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol
  • stirred for example at room temperature
  • 1-5 days such as Days
  • the weight-to-volume ratio (g/mL) of compound A and the aqueous alcohol solvent is about 1:(30-100), preferably about 1:50.
  • the present invention provides crystalline form III of Compound A hemihydrate:
  • the XRPD pattern of the crystal form III includes characteristic peaks at diffraction angles (2 ⁇ ) of about 10.8 ⁇ 0.2° and 20.5 ⁇ 0.2°.
  • the XRPD pattern of the crystal form III includes diffraction angles (2 ⁇ ) at about 10.8 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.7 ⁇ 0.2° and 26.9 ⁇ 0.2° Characteristic peaks.
  • the XRPD pattern of the crystalline form III includes about 10.8 ⁇ 0.2°, 13.0 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.3 ⁇ 0.2°, 19.3 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.7 ⁇ 0.2°, 23.3 ⁇ 0.2°, 25.1 ⁇ 0.2°, 26.5 ⁇ 0.2°, 26.9 ⁇ 0.2°, 28.7 ⁇ 0.2° and 32.2 ⁇ 0.2° diffraction The characteristic peak at angle (2 ⁇ ).
  • the XRPD pattern of the crystal form III includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form III includes a peak at a diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 6.
  • the XRPD peak position of the crystal form III is substantially the same as that shown in FIG. 6.
  • the DSC spectrum of the crystal form III includes an endothermic peak at about 62.2°C and an endothermic/exothermic peak at about 245/255°C.
  • the crystal form III has a weight loss of about 3.6% when heated to about 80°C.
  • the DSC spectrum of the crystal form III includes characteristic peaks substantially the same as those shown in FIG. 7. In the most preferred embodiment, the DSC spectrum of the crystal form III is substantially the same as that shown in FIG. 7.
  • the present invention provides a method for preparing crystalline form III, which includes dissolving compound A in a good solvent (for example, at room temperature) to form a solution (if necessary, the mixture can be filtered to obtain a solution), and then An anti-solvent is added to the solution, and a solid is precipitated under stirring (the addition of the anti-solvent and stirring is performed at room temperature, for example), and the solid is filtered to obtain crystals.
  • a good solvent for example, at room temperature
  • An anti-solvent is added to the solution, and a solid is precipitated under stirring (the addition of the anti-solvent and stirring is performed at room temperature, for example), and the solid is filtered to obtain crystals.
  • the good solvent is a sulfone or sulfoxide with 2-10 carbon atoms, which includes but is not limited to dimethyl sulfoxide; the anti-solvent is preferably water.
  • the weight-to-volume ratio (g/mL) of Compound A and the good solvent is about 1:(1-20), preferably about 1:12.5.
  • the volume ratio of the good solvent and the anti-solvent is about 1:1 to 1:3.
  • the present invention provides the crystalline form IV of Compound A sesquihydrate:
  • the XRPD pattern of the crystal form IV includes characteristic peaks at diffraction angles (2 ⁇ ) of about 12.3 ⁇ 0.2°, 21.3 ⁇ 0.2°, and 24.1 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form IV includes about 12.3 ⁇ 0.2°, 12.6 ⁇ 0.2°, 17.2 ⁇ 0.2°, 20.0 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.3 ⁇ 0.2°, 23.8 ⁇
  • the XRPD pattern of the crystalline form IV includes about 12.3 ⁇ 0.2°, 12.6 ⁇ 0.2°, 14.3 ⁇ 0.2°, 17.2 ⁇ 0.2°, 20.0 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.3 ⁇ 0.2°, 23.2 ⁇ 0.2°, 23.8 ⁇ 0.2°, 24.1 ⁇ 0.2°, 25.0 ⁇ 0.2°, 25.7 ⁇ 0.2°, 27.9 ⁇ 0.2°, 31.2 ⁇ 0.2° and 31.7 ⁇ 0.2° diffraction angle (2 ⁇ ) The characteristic peak.
  • the XRPD pattern of the crystalline form IV includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form IV includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 8.
  • the XRPD peak position of the crystal form IV is substantially the same as that shown in FIG. 8.
  • the DSC spectrum of the crystal form IV includes an endothermic peak at about 42.6°C, an endothermic peak at about 66.9°C, and an endothermic/exothermic peak at about 245/255°C. .
  • the crystal form IV has a weight loss of about 9.4% when heated to about 100°C.
  • the DSC-TGA pattern of the crystal form IV includes the characteristic peaks substantially the same as those shown in FIG. 9. In the most preferred embodiment, the DSC-TGA pattern of the crystal form IV is substantially the same as that shown in FIG. 9.
  • the present invention provides a method for preparing crystalline form IV, which comprises stirring compound A in water (for example, at room temperature, for example, for 1-5 days, preferably 2-4 days), and filtering to obtain crystals.
  • the weight-to-volume ratio (g/mL) of Compound A and water is about 1:(30-100), preferably about 1:50.
  • the present invention provides a method for preparing crystalline form IV, which includes dissolving compound A in a good solvent (for example, at room temperature) to form a solution (if necessary, the mixture can be filtered to obtain a solution), and then An anti-solvent is added to the solution, and a solid is precipitated under stirring (the addition of the anti-solvent and stirring is performed at room temperature, for example), and the solid is filtered to obtain crystals.
  • a good solvent for example, at room temperature
  • An anti-solvent is added to the solution, and a solid is precipitated under stirring (the addition of the anti-solvent and stirring is performed at room temperature, for example), and the solid is filtered to obtain crystals.
  • the good solvent is an ether with 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyl Tetrahydrofuran or dioxane; the anti-solvent is preferably water.
  • the weight-to-volume ratio (g/mL) of Compound A and the good solvent is about 1:(50-120), preferably about 1:100.
  • the volume ratio of the good solvent and the anti-solvent is about 1:1 to 1:5.
  • the present invention provides crystalline form V of compound A monohydrate:
  • the XRPD pattern of the crystal form V includes characteristic peaks at diffraction angles (2 ⁇ ) of about 14.1 ⁇ 0.2°, 21.0 ⁇ 0.2°, and 29.6 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form V includes about 8.7 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.9 ⁇ 0.2°, 14.1 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.8 ⁇ 0.2°, 18.9 ⁇
  • the XRPD pattern of the crystalline form V includes about 8.7 ⁇ 0.2°, 9.4 ⁇ 0.2°, 11.6 ⁇ 0.2°, 11.9 ⁇ 0.2°, 12.4 ⁇ 0.2°, 14.1 ⁇ 0.2°, 14.5 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.2 ⁇ 0.2°, 16.8 ⁇ 0.2°, 17.6 ⁇ 0.2°, 18.2 ⁇ 0.2°, 18.9 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.6 ⁇ 0.2°, 21.0 ⁇ 0.2°, 22.5
  • the XRPD pattern of the crystal form V includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form V includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 10.
  • the XRPD peak position of the crystal form V is substantially the same as that shown in FIG. 10.
  • the DSC chart of the crystal form V includes an endothermic peak at about 52.6°C and an endothermic/exothermic peak at about 245/255°C.
  • the crystal form V has a weight loss of about 6.8% when heated to about 80°C.
  • the DSC spectrum of the crystal form V includes characteristic peaks substantially the same as those shown in FIG. 11. In the most preferred embodiment, the DSC spectrum of the crystal form V is substantially the same as that shown in FIG. 11.
  • the present invention provides a method for preparing crystal form V, which includes dissolving compound A in a good solvent (for example, at room temperature) to form a solution (if necessary, the mixture can be filtered to obtain a solution), and then An anti-solvent is added to the solution, and a solid is precipitated under stirring (the addition of the anti-solvent and stirring is performed at room temperature, for example), and the solid is filtered to obtain crystals.
  • a good solvent for example, at room temperature
  • An anti-solvent is added to the solution, and a solid is precipitated under stirring (the addition of the anti-solvent and stirring is performed at room temperature, for example), and the solid is filtered to obtain crystals.
  • the good solvent is a sulfone or sulfoxide with 2-10 carbon atoms, including but not limited to dimethyl sulfoxide;
  • the anti-solvent is preferably a water-containing alcohol solvent (preferably with 1 Alcohols of -6 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol) .
  • the weight-to-volume ratio (g/mL) of Compound A and the good solvent is about 1:(1-20), preferably about 1:12.5.
  • the volume ratio of the good solvent and the anti-solvent is about 1:1 to 1:3.
  • the present invention provides the crystalline form VI of Compound A monohydrate:
  • the XRPD pattern of the crystal form VI includes characteristic peaks at diffraction angles (2 ⁇ ) of about 10.4 ⁇ 0.2°, 12.1 ⁇ 0.2°, 16.6 ⁇ 0.2°, 20.7 ⁇ 0.2°, 22.8 ⁇ 0.2°, and 27.3 ⁇ 0.2° .
  • the XRPD pattern of the crystal form VI includes about 8.7 ⁇ 0.2°, 10.4 ⁇ 0.2°, 12.1 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.6 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.7 ⁇
  • the XRPD pattern of the crystalline form VI includes about 8.7 ⁇ 0.2°, 10.4 ⁇ 0.2°, 12.1 ⁇ 0.2°, 13.4 ⁇ 0.2°, 14.7 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.6 ⁇ 0.2°, 17.4 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.7 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.1 ⁇ 0.2°, 22.8 ⁇ 0.2°, 23.6 ⁇ 0.2°, 26.0 ⁇ 0.2°, 27.3 ⁇ 0.2°, 28.0
  • the XRPD pattern of the crystalline form VI includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form VI includes a peak at a diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 12.
  • the XRPD peak position of the crystal form VI is substantially the same as that shown in FIG. 12.
  • the DSC spectrum of the crystal form VI includes an endothermic peak at about 51.6°C, an endothermic peak at about 77.5°C, and an endothermic/exothermic peak at about 245/255°C .
  • the DSC spectrum of the crystal form VI includes characteristic peaks substantially the same as those shown in FIG. 13. In the most preferred embodiment, the DSC spectrum of the crystal form VI is substantially the same as that shown in FIG. 13.
  • the present invention provides a method for preparing crystal form VI, which includes putting compound A in a ketone solvent (for example, a ketone having 3-6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone).
  • a ketone solvent for example, a ketone having 3-6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone.
  • a mixed solvent of methyl ketone, methyl isobutyl ketone and diethyl ketone and water for example, at room temperature
  • stir for example, 1-5 days
  • the volume ratio of the ketone solvent to water is about 10:1 to 1:1, preferably about 5:1 to 2:1.
  • the weight-to-volume ratio (g/mL) of Compound A and the mixed solvent is about 1:(1-30), preferably about 1:20.
  • the present invention provides crystalline form VII of Compound A sesquihydrate:
  • the XRPD pattern of the crystal form VII includes characteristic peaks at diffraction angles (2 ⁇ ) of about 13.1 ⁇ 0.2°, 19.9 ⁇ 0.2°, and 20.2 ⁇ 0.2°.
  • the XRPD pattern of the crystalline form VII includes diffraction angles of about 13.1 ⁇ 0.2°, 16.9 ⁇ 0.2°, 19.9 ⁇ 0.2°, 20.2 ⁇ 0.2°, 24.9 ⁇ 0.2°, and 28.8 ⁇ 0.2° The characteristic peak at (2 ⁇ ).
  • the XRPD pattern of the crystalline form VII includes about 9.4 ⁇ 0.2°, 10.8 ⁇ 0.2°, 13.1 ⁇ 0.2°, 15.4 ⁇ 0.2°, 16.9 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.9
  • the XRPD pattern of the crystalline form VII includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form VII includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 14.
  • the XRPD peak position of the crystalline form VII is substantially the same as that shown in FIG. 14.
  • the DSC spectrum of the crystalline form VII includes an endothermic peak at about 54.8°C and an endothermic/exothermic peak at about 245/255°C.
  • the crystal form VII has a weight loss of about 9.5% when heated to about 75°C.
  • the DSC-TGA pattern of the crystal form VII includes the characteristic peaks substantially the same as those shown in FIG. 15. In the most preferred embodiment, the DSC-TGA pattern of the crystal form VII is substantially the same as that shown in FIG. 15.
  • the present invention provides a method for preparing Form VII, which includes putting compound A in an alcohol solvent (for example, an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propanol , 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol) and water mixed solvent under heating conditions (for example, heating to 30-60 °C, preferably 50 °C) to obtain The solution (if necessary, the mixture can be filtered to obtain a solution), the solution is cooled (for example, cooled to 0-10°C, preferably 5°C) to precipitate a solid, which is filtered to obtain crystals.
  • an alcohol solvent for example, an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propanol , 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol
  • water mixed solvent for example,
  • the volume ratio of the alcohol solvent to water is about 5:1 to 0.5:1, preferably about 3:1 to 1:1.
  • the weight-to-volume ratio (g/mL) of Compound A and the mixed solvent is about 1:(20-80), preferably about 1:50.
  • the present invention provides Form VIII of Compound A hemihydrate:
  • the XRPD pattern of the crystal form VIII includes characteristic peaks at diffraction angles (2 ⁇ ) of about 13.0 ⁇ 0.2°, 16.8 ⁇ 0.2°, 19.4 ⁇ 0.2°, 21.7 ⁇ 0.2°, 22.9 ⁇ 0.2°, and 27.4 ⁇ 0.2° .
  • the XRPD pattern of the crystalline form VIII includes about 10.3 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.8 ⁇ 0.2°, 19.1 ⁇ 0.2°, 19.4 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.7 ⁇
  • the XRPD pattern of the crystalline form VIII includes about 8.7 ⁇ 0.2°, 10.3 ⁇ 0.2°, 10.8 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.1 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.8 ⁇ 0.2° ⁇ 17.5 ⁇ 0.2° ⁇ 19.1 ⁇ 0.2° ⁇ 19.4 ⁇ 0.2° ⁇ 21.1 ⁇ 0.2° ⁇ 21.7 ⁇ 0.2° ⁇ 22.3 ⁇ 0.2° ⁇ 22.9 ⁇ 0.2° ⁇ 25.8 ⁇ 0.2° ⁇ 27.4 ⁇ 0.2° ⁇ 27.8 The characteristic peaks at diffraction angles (2 ⁇ ) of ⁇ 0.2°, 30.4 ⁇ 0.2°, and 31.6 ⁇ 0.2°.
  • the XRPD pattern of Form VIII includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form VIII includes the peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 16.
  • the XRPD peak position of the crystalline form VIII is substantially the same as that shown in FIG. 16.
  • the DSC chart of the crystalline form VIII includes an endothermic peak at about 50.9°C, an endothermic peak at about 79.1°C, an exothermic peak at about 124.9°C, and an endothermic peak at about 124.9°C, and an endothermic peak at about 124.9°C. Endothermic/exothermic peak at 255°C.
  • the crystal form VIII has a weight loss of about 3.6% when heated to about 105°C.
  • the DSC-TGA pattern of the crystal form VIII includes the characteristic peaks substantially the same as those shown in FIG. 17.
  • the DSC-TGA profile of the crystal form VIII is substantially the same as that shown in FIG. 17.
  • the present invention provides a method for preparing Form VIII, which includes putting Compound A in a ketone solvent (for example, a ketone having 3-6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone).
  • a ketone solvent for example, a ketone having 3-6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl ethyl ketone.
  • a mixed solvent of methyl ketone, methyl isobutyl ketone and diethyl ketone) and water stir under heating conditions (for example, heating to 30-60°C, preferably 50°C) to obtain a solution (the mixture can be filtered if necessary
  • the solution is cooled (for example, to 0-10°C, preferably 5°C) to precipitate a solid, which is filtered to obtain crystals.
  • the volume ratio of the alcohol solvent to water is about 5:1 to 0.5:1, preferably about 3:1 to 1:1.
  • the weight-to-volume ratio (g/mL) of Compound A and the mixed solvent is about 1:(20-80), preferably about 1:50.
  • the present invention provides a pharmaceutical composition comprising any one or more of crystal forms I, II, III, IV, V, VI, VII or VIII of the present invention, and one or more A pharmaceutically acceptable carrier.
  • the present invention provides that the crystal form I, II, III, IV, V, VI, VII or VIII of the present invention is prepared for the prevention or treatment of diseases modulated by P2X3 and/or P2X2/3 receptor antagonists. Use in medicine.
  • the present invention provides crystal forms I, II, III, IV, V, VI, VII, or VIII of the present invention, which are used to prevent or treat diseases modulated by P2X3 and/or P2X2/3 receptor antagonists .
  • the present invention provides a method for preventing or treating diseases modulated by P2X3 and/or P2X2/3 receptor antagonists, which comprises administering to an individual (preferably a mammal) in need thereof a preventive or therapeutically effective amount of the present Any one or more of the inventive crystal forms I, II, III, IV, V, VI, VII or VIII.
  • the diseases regulated by the P2X3 and/or P2X2/3 receptor antagonists are selected from urinary tract diseases, and the urinary tract diseases are selected from the group consisting of bladder volume reduction, frequent urination, urge incontinence, and stress incontinence.
  • the pain disease is selected from inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, burn pain, migraine and cluster headache; nerve injury, neuritis, neuralgia, poisoning, and ischemia Injury, interstitial cystitis, cancer pain, virus, parasite or bacterial infection, post-traumatic injury, and pain associated with irritable bowel syndrome; cardiovascular system disease, preferably hypertension; respiratory tract Disease, the respiratory disease is selected from chronic obstructive pulmonary disease, asthma and bronchospasm; gastrointestinal disease, the gastrointestinal disease is selected from irritable bowel syndrome (preferably diarrheal irritable bowel syndrome), inflammatory Intestinal disease, biliary colic, renal colic, and pain related to gastrointestinal
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle administered with a therapeutic agent, and which is suitable for contact within the scope of reasonable medical judgment Human and/or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • the pharmaceutically acceptable carriers that can be used in the pharmaceutical composition 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, and minerals. Oil, sesame oil, etc.
  • water is an exemplary carrier. It is also possible to use physiological saline and aqueous glucose and glycerol solutions as liquid carriers, especially for injections.
  • 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 etc.
  • the composition may also contain small amounts of wetting agents, emulsifiers or pH buffering agents as needed.
  • Oral preparations 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 described in Remington's Pharmaceutical Sciences (1990).
  • composition of the present invention can act systemically and/or locally.
  • they can be administered by suitable routes, such as by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, transnasal, transmucosal, topical, It is administered in the form of ophthalmic preparations or by inhalation.
  • composition of the present invention can be administered in a suitable dosage form.
  • the dosage form can be a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation, specifically including but not limited to tablets, capsules, powders, granules, lozenges, hard candy, powders, sprays, creams, ointments Preparations, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, syrups.
  • the pharmaceutical composition 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, freeze-drying and other treatments.
  • terapéuticaally effective amount refers to the amount of a compound that will relieve one or more symptoms of the condition being treated to a certain extent after being administered.
  • the dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgent need for the treatment situation. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of the compound of the present invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 50 mg per kg body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, for example, about 0.7 mg/day to about 700 mg/day.
  • a dose level not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose can still be used 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 content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2mg, 4mg, 10mg and 25mg etc.
  • treating means reversing, alleviating, or inhibiting the disease or condition to which such term is applied or the progression of one or more symptoms of such a condition or condition, or Preventing such a disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as the diseases described herein.
  • “non-human animals” include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • the preferred crystal form of the present invention has good stability, and its color and properties remain unchanged after being stored for a long time at room temperature (for example, 180 days).
  • the preferred crystal form of the present invention also has good stability under high temperature or high humidity conditions. For example, if the crystal form I is stored under high temperature conditions (such as 60° C.) for 30 days, the crystal form does not change.
  • the preferred crystal form of the present invention has good fluidity, is easy to pulverize, and is convenient for preparing pharmaceutical compositions.
  • the preparation method of the preferred crystal form of the present invention is simple and easy to implement, and the reaction conditions are mild. In addition, it does not require multiple purifications, the operation is safe and environmentally friendly, and is beneficial to the industrial production of crystal forms.
  • Test conditions The anode target material is copper, the light tube is set to (40KV 40mA), the 2 ⁇ scanning angle of the sample is from 3° to 40°, and the scanning step is 0.02°.
  • Test conditions The heating rate is 10°C/min, and dry nitrogen is used as the purge gas.
  • Test conditions automatic weighing in the heating furnace, the heating rate is 10°C/min, and dry nitrogen is used as the purge gas.
  • the XRPD pattern is shown in Figure 1 by X-ray powder diffraction; the DSC and TGA patterns are shown in Figure 2 by DSC and TGA analysis; the sample is observed under a scanning electron microscope, and the crystal morphology is shown in Figure 3. .
  • Thermogravimetric analysis showed that the crystal form sample lost 0.1% in mass between 25-150°C, indicating that the crystal form did not contain crystal water.
  • a V20 Karl Fischer moisture analyzer was used to determine the water content of 6.3%, and the theoretical water content of a sample containing 1 crystal water was 6.27%, indicating that the crystal form contains 1 molecule of crystal water.
  • Crystal Form I prepared in Example 2 The crystal form II prepared in Example 5, the crystal form III prepared in Example 6, the crystal form IV prepared in Example 7, the crystal form V prepared in Example 9 , Crystal Form VI prepared in Example 10, Crystal Form VII prepared in Example 11, and Crystal Form VIII prepared in Example 12 were placed in a medicinal low-density polyethylene bag, sealed, and placed at room temperature for 180 days.
  • the XRPD was measured with a Bruker D8 advance X-ray powder diffractometer. The results showed that the crystal forms of the samples of crystal forms I, II, III, IV, V, VI, VII and VIII had no change after 180 days, and the stability was good.
  • Figure 18 shows the comparison of X-ray powder diffraction patterns of crystal form I before and after being placed at room temperature for 180 days.
  • the stability of the crystal form I prepared in Example 2 was investigated at 60°C, and the XRPD pattern was measured with a Bruker D8 advanced X-ray powder diffractometer (see Figure 19). The results showed that the crystal form I samples were in 5, 10 and 30 There is no change in the crystal form after days, and the stability is excellent.
  • the stability of the crystal form I prepared in Example 2 was investigated under the conditions of 92.5%RH/25°C, and the XRPD pattern was measured with a Bruker D8advance X-ray powder diffractometer (see Figure 20). The result showed that the sample of crystal form I was in 5 , 10 and 30 days later, the crystal form has no change, and the stability is excellent.
  • Example 2 After the crystal form I prepared in Example 2 was physically ground for 2 minutes, the XRPD pattern was measured with a Bruker D8 advanced X-ray powder diffractometer (see FIG. 21). The result showed that the crystal form of the crystal form I sample had no change and had excellent stability.

Abstract

本发明涉及5-((2-乙炔基-5-异丙基吡啶-4-基)氧基)嘧啶-2，4-二胺或其水合物的固体形式，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预防或治疗P2X3和/或P2X2/3受体拮抗剂调节的疾病的用途。

Description

二氨基嘧啶类化合物或其水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5-((2-乙炔基-5-异丙基吡啶-4-基)氧基)嘧啶-2，4-二胺(在下文中称作“化合物A”)或其水合物的固体形式，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预防或治疗P2X3和/或P2X2/3受体拮抗剂调节的疾病的用途。
发明背景
嘌呤类化合物通过细胞表面嘌呤能受体发挥作用，其发挥着广泛的生理学和病理学作用。ATP(在更小的程度上腺苷)可以刺激感觉神经末梢产生强烈的疼痛以及显著增加的感觉神经放电。根据分子结构、转导机制和药理学特征，ATP受体被分为两个主要家族，P2Y-和P2X-嘌呤能受体。P2Y-嘌呤能受体为G-蛋白偶联受体，而P2X-嘌呤能受体为ATP-门控阳离子通道家族。已知嘌呤能受体(特别是P2X受体)能够形成同源多聚体或异源多聚体。迄今为止，多种P2X受体亚型的cDNA已经被克隆，包括：六种同源性受体：P2X1、P2X2、P2X3、P2X4、P2X5和P2X7；三种异源性受体：P2X2/3、P2X4/6、P2X1/5。小鼠基因组P2X3受体亚基的结构和基因图谱也有报道。
研究表明P2X3和/或P2X2/3受体拮抗剂可用于治疗疼痛等疾病。本申请人已发现了一类二氨基嘧啶化合物，特别是5-((2-乙炔基-5-异丙基吡啶-4-基)氧基)嘧啶-2，4-二胺，其可用作有效的P2X3和/或P2X2/3受体拮抗剂(参见PCT/CN2018/112829，将其整体通过援引加入本文)。
发明概述
在一个方面中，本发明提供如下所示的化合物A(5-((2-乙炔基-5-异丙基吡啶-4-基)氧基)嘧啶-2，4-二胺)或其水合物的晶型：
Figure PCTCN2020087687-appb-000001
本发明的优选晶型不仅在预防或治疗P2X3和/或P2X2/3受体拮抗剂调节的疾病中具有优异的效果，还具有其它优点。例如，本发明的优选晶型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，本发明的优选晶型可具有更优异的性质。本发明的优选晶型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。
在另一方面中，本发明提供制备本发明的晶型的方法。
在另一方面中，本发明提供药物组合物，其包含本发明中的任意一种或多种晶型，以及一种或多种药学上可接受的载体。
在另一方面中，本发明提供本发明的晶型在制备用于治疗P2X3和/或P2X2/3受体拮抗剂调节的疾病的药物中的用途。
附图简要说明
图1为化合物A无水合物的晶型I的X射线粉末衍射图谱。
图2为化合物A无水合物的晶型I的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图3为化合物A无水合物的晶型I的扫描电子显微镜照片。
图4为化合物A一水合物的晶型II的X射线粉末衍射图谱。
图5为化合物A一水合物的晶型II的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图6为化合物A半水合物的晶型III的X射线粉末衍射图谱。
图7为化合物A半水合物的晶型III的差示扫描量热(DSC)图谱。
图8为化合物A倍半水合物的晶型IV的X射线粉末衍射图谱。
图9为化合物A倍半水合物的晶型IV的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图10为化合物A一水合物的晶型V的X射线粉末衍射图谱。
图11为化合物A一水合物的晶型V的差示扫描量热(DSC)图谱。
图12为化合物A一水合物的晶型VI的X射线粉末衍射图谱。
图13为化合物A一水合物的晶型VI的差示扫描量热(DSC)图谱。
图14为化合物A倍半水合物的晶型VII的X射线粉末衍射图谱。
图15为化合物A倍半水合物的晶型VII的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图16为化合物A半水合物的晶型VIII的X射线粉末衍射图谱。
图17为化合物A半水合物的晶型VIII的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图18为室温稳定性实验前后化合物A无水合物的晶型I的XRPD图谱对比。
图19为高温稳定性实验前后化合物A无水合物的晶型I的XRPD图谱对比。
图20为高湿稳定性实验前后化合物A无水合物的晶型I的XRPD图谱对比。
图21为物理研磨稳定性实验前后化合物A无水合物的晶型I的XRPD图谱对比。
发明详细描述
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”包括化合物A或其任意水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。
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 PCTCN2020087687-appb-000002
：1.540598和Kα2
Figure PCTCN2020087687-appb-000003
：1.544426)作为辐射源。
如本文中所使用，“I％”表示峰强度百分比。
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。除非另外说明，在描述DSC图谱中特征峰时所提及的温度是指峰的起始温度。
如本文中所使用的术语“热重分析(TGA)图谱”是指由热重分析仪记录到的曲线。
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。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Polarizing Microscope ECLIPSE LV100POL(Nikon，JPN)进行采集。
如本文中所使用的数值范围(如“1-10个”、“1-6个”、“2-10个”、“2-6个”、“3-10个”、“5-10个”、“3-6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“无水合物”优选意指其中不含有水分子作为结构要素的晶型。
晶型及其制备方法
在一个实施方案中，本发明提供化合物A无水合物的晶型I：
Figure PCTCN2020087687-appb-000004
所述晶型I的XRPD图谱包括在约11.9±0.2°、12.3±0.2°、13.9±0.2°、19.8±0.2°和20.3±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述晶型I的XRPD图谱包括在约10.1±0.2°、11.9±0.2°、12.3±0.2°、13.9±0.2°、17.8±0.2°、18.6±0.2°、19.8±0.2°和20.3±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型I的XRPD图谱包括在约6.2±0.2°、10.1±0.2°、11.9±0.2°、12.3±0.2°、13.9±0.2°、16.9±0.2°、17.8±0.2°、18.6±0.2°、19.8±0.2°、20.3±0.2°、21.8±0.2°、23.0±0.2°、23.6±0.2°、24.1±0.2°、26.2±0.2°、26.5±0.2°、27.8±0.2°、28.5±0.2°、29.3±0.2°和30.6±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型I的XRPD图谱包括在以下衍射角(2θ)处的峰：
峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％
1 6.2° 19.7 15 19.8° 65.9 29 28.5° 13.8
2 9.4° 6.8 16 20.3° 100 30 29.3° 14.8
3 10.1° 40.9 17 20.7° 10.2 31 29.9° 7.0
4 11.9° 54.8 18 21.1° 10.5 32 30.6° 16.0
5 12.3° 54.7 19 21.8° 17.7 33 31.5° 9.0
6 13.9° 51.6 20 22.4° 7.9 34 32.0° 7.4
7 14.9° 8.1 21 23.0° 15.4 35 32.2° 6.0
8 15.2° 9.5 22 23.6° 22.5 36 33.3° 5.6
9 16.0° 5.6 23 24.1° 14.4 37 33.9° 6.0
10 16.9° 14.7 24 24.6° 7.0 38 35.2° 3.4
11 17.2° 10.8 25 26.2° 10.6 39 38.9° 5.7
12 17.8° 41.5 26 26.5° 13.4 40 39.6° 3.2
13 18.6° 27.9 27 27.3° 8.5      
14 18.9° 11.1 28 27.8° 15.6      
在更优选的实施方案中，所述晶型I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，所述晶型I的XRPD峰位与图1所示基本上相同。
在更优选的实施方案中，所述晶型I的DSC图谱包括在约245/255℃处的吸热/放热峰。
在更优选的实施方案中，在热重分析中，所述晶型I在加热至约100-150℃时有约0.1％的失重。
在更优选的实施方案中，所述晶型I的DSC-TGA图谱包括与图2所示基本上相同的特征峰。在最优选的实施方案中，所述晶型I的DSC-TGA图谱与图2所示基本上相同。
在更优选的实施方案中，所述晶型I的扫描电子显微镜照片与图3所示基本上相同。
在一些实施方案中，本发明提供制备晶型I的方法，其包括以下步骤：
1)将化合物A加入水中，然后加入酸(例如有机酸(如乙酸或三氟乙酸)或无机酸(如盐酸或硫酸)，优选盐酸)，搅拌使化合物A溶解得到溶液，任选地将其过滤以得到滤液；
2)向步骤1)中所得溶液或滤液中加入碱(如氢氧化钠、氢氧化钾或氨水)，通过过滤收集析出的固体；以及
3)将所得固体加入水中搅拌(例如0.5-5小时，优选1-3小时)，通过过滤收集固体，任选地将其干燥，得到晶型I。
在一些实施方案中，本发明提供制备晶型I的方法，其包括将化合物A在良溶剂中溶解(可在室温或者加热条件(例如加热至30-60℃，优选50℃)下进行)，形成溶液(视需要可将混合物进行过滤以得到溶液)，然后向所述溶液中添加反溶剂，在搅拌(所述添加反溶剂和搅拌可在室温或者冷却条件(例如冷却至0-10℃，优选5℃)下进行)下析出固体，将其过滤得到晶体。
在一些实施方案中，所述良溶剂为具有3-10个碳原子的醚，优选为环状醚，例如呋喃类(包括四氢呋喃类)和二氧六环类，优选为四氢呋喃、2-甲基四氢呋喃或二氧六环；所述反溶剂为具有5-10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)或者具有2-6个碳原子的醚(优选为链状醚，例如***、二异丙基醚或甲基叔丁基醚)。
在一些实施方案中，化合物A和良溶剂的重量体积比(g/mL)为约1∶(30-120)，优选约1∶40或1∶100。
在一些实施方案中，所述良溶剂和反溶剂的体积比为约1∶1至1∶5。
在另一实施方案中，本发明提供化合物A一水合物的晶型II：
Figure PCTCN2020087687-appb-000005
所述晶型II的XRPD图谱包括在约13.0±0.2°、19.5±0.2°和19.9±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述晶型II的XRPD图谱包括在约9.6±0.2°、13.0±0.2°、19.5±0.2°、19.9±0.2°和22.7±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型II的XRPD图谱包括在约9.6±0.2°、10.9±0.2°、13.0±0.2°、14.9±0.2°、15.8±0.2°、16.8±0.2°、19.5±0.2°、19.9±0.2°、22.7±0.2°、23.7±0.2°、25.2±0.2°、26.0±0.2°、28.5±0.2°、29.0±0.2°、30.0±0.2°和32.5±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型II的XRPD图谱包括在以下衍射角(2θ)处的峰：
峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％
1 9.6° 27.3 11 21.2° 8.5 21 29.0° 23.7
2 10.9° 22.0 12 22.1° 7.8 22 30.0° 13.1
3 13.0° 100 13 22.7° 42.1 23 31.0° 4.2
4 13.3° 23.3 14 23.7° 16.1 24 32.5° 7.2
5 14.9° 14.8 15 24.5° 8.2 25 33.0° 5.3
6 15.8° 25.0 16 25.2° 15.4 26 33.6° 4.1
7 16.8° 18.1 17 25.6° 10.6 27 34.7° 3.6
8 17.7° 6.5 18 26.0° 13.0 28 35.6° 4.3
9 19.5° 70.8 19 26.8° 6.6 29 36.3° 3.7
10 19.9° 82.2 20 28.5° 17.1 30 37.1° 4.2
在更优选的实施方案中，所述晶型II的XRPD图谱包括与图4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，所述晶型II的XRPD峰位与图4所示基本上相同。
在更优选的实施方案中，所述晶型II的DSC图谱包括在约73.9℃处的吸热峰以及约245/255℃处的吸热/放热峰。
在更优选的实施方案中，在热重分析中，所述晶型II在加热至约100℃时有约6.2％的失重。
在更优选的实施方案中，所述晶型II的DSC-TGA图谱包括与图5所示基本上相同的特征峰。在最优选的实施方案中，所述晶型II的DSC-TGA图谱与图5所示基本上相同。
在一些实施方案中，本发明提供制备晶型II的方法，其包括将化合物A在含水的醇类溶剂(优选具有1-6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)中悬浮并(例如在室温下)搅拌(例如1-5天，如3天)，过滤得到晶体。
在一些实施方案中，化合物A和所述含水的醇类溶剂的重量体积比(g/mL)为约1∶(30-100)，优选约1∶50。
在另一实施方案中，本发明提供化合物A半水合物的晶型III：
Figure PCTCN2020087687-appb-000006
所述晶型III的XRPD图谱包括在约10.8±0.2°和20.5±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述晶型III的XRPD图谱包括在约10.8±0.2°、19.3±0.2°、20.5±0.2°、21.7±0.2°和26.9±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型III的XRPD图谱包括在约10.8±0.2°、13.0±0.2°、15.0±0.2°、15.4±0.2°、16.5±0.2°、17.3±0.2°、19.3±0.2°、19.9±0.2°、20.5±0.2°、21.7±0.2°、23.3±0.2°、25.1±0.2°、26.5±0.2°、26.9±0.2°、28.7±0.2°和32.2±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型III的XRPD图谱包括在以下衍射角(2θ)处的峰：
峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％
1 8.4° 6.5 11 20.5° 86.6 21 26.9° 30.9
2 10.8° 100 12 21.7° 40.6 22 28.7° 11.8
3 13.0° 10.9 13 23.0° 9.7 23 29.6° 7.2
4 15.0° 19.3 14 23.3° 11.7 24 30.8° 4.9
5 15.4° 9.7 15 23.7° 6.7 25 31.5° 4.1
6 16.5° 19.7 16 24.4° 6.2 26 32.2° 10.4
7 16.8° 7.0 17 25.1° 10.9 27 32.6° 6.4
8 17.3° 10.3 18 25.7° 6.6 28 34.1° 5.6
9 19.3° 27.9 19 26.2° 9.3 29 35.0° 5.8
10 19.9° 16.8 20 26.5° 18.4      
在更优选的实施方案中，所述晶型III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，所述晶型III的XRPD峰位与图6所示基本上相同。
在更优选的实施方案中，所述晶型III的DSC图谱包括在约62.2℃处的吸热峰和约245/255℃处的吸热/放热峰。
在更优选的实施方案中，在热重分析中，所述晶型III在加热至约80℃时有约3.6％的失重。
在更优选的实施方案中，所述晶型III的DSC图谱包括与图7所示基本上相同的特征峰。在最优选的实施方案中，所述晶型III的DSC图谱与图7所示基本上相同。
在一些实施方案中，本发明提供制备晶型III的方法，其包括将化合物A在良溶剂中溶解(例如在室温下进行)，形成溶液(视需要可将混合物进行过滤以得到溶液)，然后向所述溶液中添加反溶剂，在搅拌(所述添加反溶剂和搅拌例如在室温下进行)下析出固体，将其过滤得到晶体。
在一些实施方案中，所述良溶剂为具有2-10个碳原子的砜或亚砜，其包括但不限于二甲基亚砜； 所述反溶剂优选为水。
在一些实施方案中，化合物A和良溶剂的重量体积比(g/mL)为约1∶(1-20)，优选约1∶12.5。
在一些实施方案中，所述良溶剂和反溶剂的体积比为约1∶1至1∶3。
在另一实施方案中，本发明提供化合物A倍半水合物的晶型IV：
Figure PCTCN2020087687-appb-000007
所述晶型IV的XRPD图谱包括在约12.3±0.2°、21.3±0.2°和24.1±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述晶型IV的XRPD图谱包括在约12.3±0.2°、12.6±0.2°、17.2±0.2°、20.0±0.2°、20.6±0.2°、21.3±0.2°、23.8±0.2°、24.1±0.2°、25.0±0.2°和27.9±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型IV的XRPD图谱包括在约12.3±0.2°、12.6±0.2°、14.3±0.2°、17.2±0.2°、20.0±0.2°、20.6±0.2°、21.3±0.2°、23.2±0.2°、23.8±0.2°、24.1±0.2°、25.0±0.2°、25.7±0.2°、27.9±0.2°、31.2±0.2°和31.7±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型IV的XRPD图谱包括在以下衍射角(2θ)处的峰：
峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％
1 7.4° 9.4 15 20.0° 32.1 29 28.5° 7.1
2 10.0° 9.1 16 20.2° 16.5 30 28.8° 8.5
3 11.9° 8.0 17 20.6° 33.4 31 30.0° 8.6
4 12.3° 100 18 21.3° 50.6 32 31.2° 18.0
5 12.6° 42.7 19 22.0° 8.5 33 31.7° 17.7
6 13.9° 8.5 20 23.2° 18.7 34 32.9° 7.4
7 14.3° 16.3 21 23.8° 36.1 35 33.2° 10.7
8 14.9° 6.3 22 24.1° 57.5 36 33.6° 9.4
9 16.6° 6.9 23 25.0° 30.2 37 34.2° 5.3
10 17.2° 37.1 24 25.7° 18.9 38 35.6° 5.4
11 17.8° 11.0 25 26.1° 13.9 39 36.6° 5.9
12 18.0° 8.4 26 26.4° 9.6 40 37.1° 6.2
13 18.5° 8.5 27 27.4° 11.6 41 38.1° 5.2
14 18.8° 5.3 28 27.9° 40.3      
在更优选的实施方案中，所述晶型IV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，所述晶型IV的XRPD峰位与图8所示基本上相同。
在更优选的实施方案中，所述晶型IV的DSC图谱包括在约42.6℃处的吸热峰、在约66.9℃处的吸热峰以及约245/255℃处的吸热/放热峰。
在更优选的实施方案中，在热重分析中，所述晶型IV在加热至约100℃时有约9.4％的失重。
在更优选的实施方案中，所述晶型IV的DSC-TGA图谱包括与图9所示基本上相同的特征峰。在最优选的实施方案中，所述晶型IV的DSC-TGA图谱与图9所示基本上相同。
在一些实施方案中，本发明提供制备晶型IV的方法，其包括将化合物A在水中搅拌(例如在室温下进行，例如持续1-5天，优选2-4天)，过滤得到晶体。
在一些实施方案中，化合物A和水的重量体积比(g/mL)为约1∶(30-100)，优选约1∶50。
在一些实施方案中，本发明提供制备晶型IV的方法，其包括将化合物A在良溶剂中溶解(例如在室温下进行)，形成溶液(视需要可将混合物进行过滤以得到溶液)，然后向所述溶液中添加反溶剂，在搅拌(所述添加反溶剂和搅拌例如在室温下进行)下析出固体，将其过滤得到晶体。
在一些实施方案中，所述良溶剂为具有3-10个碳原子的醚，优选为环状醚，例如呋喃类(包括四氢呋喃类)和二氧六环类，优选为四氢呋喃、2-甲基四氢呋喃或二氧六环；所述反溶剂优选为水。
在一些实施方案中，化合物A和良溶剂的重量体积比(g/mL)为约1∶(50-120)，优选约1∶100。
在一些实施方案中，所述良溶剂和反溶剂的体积比为约1∶1至1∶5。
在另一实施方案中，本发明提供化合物A一水合物的晶型V：
Figure PCTCN2020087687-appb-000008
所述晶型V的XRPD图谱包括在约14.1±0.2°、21.0±0.2°和29.6±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述晶型V的XRPD图谱包括在约8.7±0.2°、9.4±0.2°、11.9±0.2°、14.1±0.2°、15.8±0.2°、16.8±0.2°、18.9±0.2°、19.9±0.2°、20.6±0.2°、21.0±0.2°、22.5±0.2°和29.6±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型V的XRPD图谱包括在约8.7±0.2°、9.4±0.2°、11.6±0.2°、11.9±0.2°、12.4±0.2°、14.1±0.2°、14.5±0.2°、15.8±0.2°、16.2±0.2°、16.8±0.2°、17.6±0.2°、18.2±0.2°、18.9±0.2°、19.9±0.2°、20.6±0.2°、21.0±0.2°、22.5±0.2°、23.0±0.2°、23.6±0.2°、24.4±0.2°、25.2±0.2°、27.0±0.2°和29.6±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型V的XRPD图谱包括在以下衍射角(2θ)处的峰：
峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％
1 5.9° 6.4 19 19.4° 9.5 37 27.4° 6.5
2 8.7° 27.0 20 19.9° 24.1 38 27.8° 9.2
3 9.4° 23.4 21 20.6° 29.1 39 28.1° 7.7
4 9.9° 6.6 22 21.0° 100 40 28.5° 7.7
5 10.3° 6.8 23 21.4° 12.8 41 28.8° 6.5
6 11.6° 20.7 24 22.1° 9.6 42 29.6° 46.4
7 11.9° 32.7 25 22.5° 22.5 43 30.1° 8.0
8 12.4° 11.4 26 23.0° 14.4 44 31.1° 4.1
9 12.8° 7.1 27 23.4° 11.3 45 31.7° 6.0
10 13.4° 4.6 28 23.6° 19.9 46 32.6° 6.2
11 14.1° 60.9 29 23.9° 11.9 47 32.9° 7.0
12 14.5° 10.4 30 24.4° 18.5 48 33.1° 6.3
13 15.8° 25.3 31 24.7° 14.3 49 34.0° 4.3
14 16.2° 16.5 32 25.2° 16.2 50 34.7° 4.5
15 16.8° 22.5 33 25.6° 6.5 51 37.0° 3.5
16 17.6° 16.8 34 26.4° 8.7 52 38.5° 5.1
17 18.2° 13.7 35 26.6° 8.0 53 39.7° 3.9
18 18.9° 29.5 36 27.0° 16.7      
在更优选的实施方案中，所述晶型V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，所述晶型V的XRPD峰位与图10所示基本上相同。
在更优选的实施方案中，所述晶型V的DSC图谱包括在约52.6℃处的吸热峰和约245/255℃处的吸热/放热峰。
在更优选的实施方案中，在热重分析中，所述晶型V在加热至约80℃时有约6.8％的失重。
在更优选的实施方案中，所述晶型V的DSC图谱包括与图11所示基本上相同的特征峰。在最优选的实施方案中，所述晶型V的DSC图谱与图11所示基本上相同。
在一些实施方案中，本发明提供制备晶型V的方法，其包括将化合物A在良溶剂中溶解(例如在室温下进行)，形成溶液(视需要可将混合物进行过滤以得到溶液)，然后向所述溶液中添加反溶剂，在搅拌(所述添加反溶剂和搅拌例如在室温下进行)下析出固体，将其过滤得到晶体。
在一些实施方案中，所述良溶剂为具有2-10个碳原子的砜或亚砜，其包括但不限于二甲基亚砜；所述反溶剂优选为含水的醇类溶剂(优选具有1-6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)。
在一些实施方案中，化合物A和良溶剂的重量体积比(g/mL)为约1∶(1-20)，优选约1∶12.5。
在一些实施方案中，所述良溶剂和反溶剂的体积比为约1∶1至1∶3。
在另一实施方案中，本发明提供化合物A一水合物的晶型VI：
Figure PCTCN2020087687-appb-000009
所述晶型VI的XRPD图谱包括在约10.4±0.2°、12.1±0.2°、16.6±0.2°、20.7±0.2°、22.8±0.2°和27.3±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述晶型VI的XRPD图谱包括在约8.7±0.2°、10.4±0.2°、12.1±0.2°、15.4±0.2°、16.6±0.2°、19.5±0.2°、20.7±0.2°、21.2±0.2°、22.8±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，所述晶型VI的XRPD图谱包括在约8.7±0.2°、10.4±0.2°、12.1±0.2°、13.4±0.2°、14.7±0.2°、15.4±0.2°、16.6±0.2°、17.4±0.2°、19.5±0.2°、20.7±0.2°、21.2±0.2°、22.1±0.2°、22.8±0.2°、23.6±0.2°、26.0±0.2°、27.3±0.2°、28.0±0.2°和30.4±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型VI的XRPD图谱包括在以下衍射角(2θ)处的峰：
峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％
1 8.7° 31.8 10 20.7° 100 19 30.4° 18.1
2 10.4° 51.1 11 21.2° 44.8 20 31.6° 9.9
3 12.1° 63.0 12 22.1° 16.2 21 32.1° 10.0
4 13.4° 14.9 13 22.8° 53.3 22 33.9° 7.2
5 14.7° 15.4 14 23.6° 24.7 23 34.7° 8.4
6 15.4° 29.8 15 26.0° 23.4 24 35.9° 7.7
7 16.6° 61.9 16 27.3° 53.2 25 36.8° 6.8
8 17.4° 14.5 17 28.0° 20.9 26 38.8° 6.1
9 19.5° 49.5 18 28.6° 8.4      
在更优选的实施方案中，所述晶型VI的XRPD图谱包括与图12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，所述晶型VI的XRPD峰位与图12所示基本上相同。
在更优选的实施方案中，所述晶型VI的DSC图谱包括在约51.6℃处的吸热峰、在约77.5℃处的吸热峰以及约245/255℃处的吸热/放热峰。
在更优选的实施方案中，所述晶型VI的DSC图谱包括与图13所示基本上相同的特征峰。在最优选的实施方案中，所述晶型VI的DSC图谱与图13所示基本上相同。
在一些实施方案中，本发明提供制备晶型VI的方法，其包括将化合物A在酮类溶剂(例如具有3-6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)和水的混合溶剂中(例如在室温下)搅拌(例如1-5天)，过滤后得到晶体。
在一些实施方案中，所述酮类溶剂和水的体积比为约10∶1至1∶1，优选为约5∶1至2∶1。
在一些实施方案中，化合物A和混合溶剂的重量体积比(g/mL)为约1∶(1-30)，优选约1∶20。
在另一实施方案中，本发明提供化合物A倍半水合物的晶型VII：
Figure PCTCN2020087687-appb-000010
所述晶型VII的XRPD图谱包括在约13.1±0.2°、19.9±0.2°和20.2±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述晶型VII的XRPD图谱包括在约13.1±0.2°、16.9±0.2°、19.9±0.2°、20.2±0.2°、24.9±0.2°和28.8±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型VII的XRPD图谱包括在约9.4±0.2°、10.8±0.2°、13.1±0.2°、15.4±0.2°、16.9±0.2°、18.8±0.2°、19.9±0.2°、20.2±0.2°、22.2±0.2°、23.2±0.2°、24.9±0.2°、26.4±0.2°和28.8±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型VII的XRPD图谱包括在以下衍射角(2θ)处的峰：
峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％
1 9.4° 14.9 14 19.9° 31.0 27 29.5° 4.3
2 9.9° 3.7 15 20.2° 100 28 31.5° 2.1
3 10.8° 7.9 16 20.7° 2.9 29 32.5° 4.4
4 12.8° 6.7 17 21.8° 6.3 30 33.0° 6.1
5 13.1° 61.2 18 22.2° 15.9 31 33.6° 1.2
6 14.3° 5.4 19 23.2° 15.1 32 34.4° 1.5
7 15.0° 2.9 20 23.8° 2.0 33 34.7° 1.8
8 15.4° 10.6 21 24.1° 5.7 34 35.2° 1.6
9 15.8° 3.8 22 24.9° 20.4 35 35.5° 1.3
10 16.9° 17.3 23 25.8° 2.2 36 36.5° 2.2
11 17.4° 4.7 24 26.4° 9.5 37 37.8° 1.2
12 18.8° 10.8 25 28.1° 2.3 38 38.2° 1.6
13 19.5° 3.4 26 28.8° 22.3 39 38.5° 1.4
在更优选的实施方案中，所述晶型VII的XRPD图谱包括与图14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，所述晶型VII的XRPD峰位与图14所示基本上相同。
在更优选的实施方案中，所述晶型VII的DSC图谱包括在约54.8℃处的吸热峰以及约245/255℃处的吸热/放热峰。
在更优选的实施方案中，在热重分析中，所述晶型VII在加热至约75℃时有约9.5％的失重。
在更优选的实施方案中，所述晶型VII的DSC-TGA图谱包括与图15所示基本上相同的特征峰。在最优选的实施方案中，所述晶型VII的DSC-TGA图谱与图15所示基本上相同。
在一些实施方案中，本发明提供制备晶型VII的方法，其包括将化合物A在醇类溶剂(例如具有1-6个碳原子的醇，其包括但不限于甲醇、乙醇、1-丙醇、2-丙醇(异丙醇)、1-丁醇、2-丁醇和叔丁醇)和水的混合溶剂中在加热条件下(例如加热至30-60℃，优选50℃)搅拌以得到溶液(视需要可将混合物进行过滤以得到溶液)，将溶液冷却(例如冷却至0-10℃，优选5℃)以析出固体，将其过滤以得到晶体。
在一些实施方案中，所述醇类溶剂和水的体积比为约5∶1至0.5∶1，优选为约3∶1至1∶1。
在一些实施方案中，化合物A和混合溶剂的重量体积比(g/mL)为约1∶(20-80)，优选约1∶50。
在另一实施方案中，本发明提供化合物A半水合物的晶型VIII：
Figure PCTCN2020087687-appb-000011
所述晶型VIII的XRPD图谱包括在约13.0±0.2°、16.8±0.2°、19.4±0.2°、21.7±0.2°、22.9±0.2°和27.4±0.2°的衍射角(2θ)处的特征峰。
在优选的实施方案中，所述晶型VIII的XRPD图谱包括在约10.3±0.2°、13.0±0.2°、16.8±0.2°、19.1±0.2°、19.4±0.2°、21.1±0.2°、21.7±0.2°、22.9±0.2°、25.8±0.2°和27.4±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型VIII的XRPD图谱包括在约8.7±0.2°、10.3±0.2°、10.8±0.2°、13.0±0.2°、14.1±0.2°、14.8±0.2°、16.8±0.2°、17.5±0.2°、19.1±0.2°、19.4±0.2°、21.1±0.2°、21.7±0.2°、22.3±0.2°、22.9±0.2°、25.8±0.2°、27.4±0.2°、27.8±0.2°、30.4±0.2°和31.6±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型VIII的XRPD图谱包括在以下衍射角(2θ)处的峰：
峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％ 峰编号 2θ(°)±0.2° I％
1 8.7° 21.7 15 21.1° 24.4 29 31.6° 14.2
2 10.3° 47.6 16 21.7° 100 30 32.0° 10.8
3 10.8° 16.5 17 22.3° 19.5 31 32.8° 7.7
4 12.2° 12.2 18 22.9° 56.4 32 33.5° 8.7
5 13.0° 50.1 19 23.8° 11.9 33 33.9° 7.5
6 14.1° 13.9 20 24.1° 14.3 34 34.3° 6.8
7 14.8° 19.7 21 24.5° 13.5 35 35.3° 9.9
8 15.5° 7.7 22 25.0° 11.4 36 35.9° 10.0
9 16.4° 20.3 23 25.3° 11.1 37 36.5° 6.3
10 16.8° 72.4 24 25.8° 25.3 38 37.4° 6.4
11 17.5° 17.7 25 26.3° 12.0 39 37.9° 5.9
12 19.1° 30.0 26 27.4° 94.8      
13 19.4° 88.1 27 27.8° 22.3      
14 20.7° 16.3 28 30.4° 13.7      
在更优选的实施方案中，所述晶型VIII的XRPD图谱包括与图16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，所述晶型VIII的XRPD峰位与图16所示基本上相同。
在更优选的实施方案中，所述晶型VIII的DSC图谱包括在约50.9℃处的吸热峰、在约79.1℃处的吸热峰、在约124.9℃处的放热峰以及约245/255℃处的吸热/放热峰。
在更优选的实施方案中，在热重分析中，所述晶型VIII在加热至约105℃时有约3.6％的失重。
在更优选的实施方案中，所述晶型VIII的DSC-TGA图谱包括与图17所示基本上相同的特征峰。在最优选的实施方案中，所述晶型VIII的DSC-TGA图谱与图17所示基本上相同。
在一些实施方案中，本发明提供制备晶型VIII的方法，其包括将化合物A在酮类溶剂(例如具有3-6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)和水的混合溶剂中在加热条件下(例如加热至30-60℃，优选50℃)搅拌以得到溶液(视需要可将混合物进行过滤以得到溶液)，将溶液冷却(例如冷却至0-10℃，优选5℃)以析出固体，将其过滤以得到晶体。
在一些实施方案中，所述醇类溶剂和水的体积比为约5∶1至0.5∶1，优选为约3∶1至1∶1。
在一些实施方案中，化合物A和混合溶剂的重量体积比(g/mL)为约1∶(20-80)，优选约1∶50。
药物组合物、治疗方法和用途
在一些实施方案中，本发明提供药物组合物，其包含本发明的晶型I、II、III、IV、V、VI、VII或VIII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。
在一些实施方案中，本发明提供本发明的晶型I、II、III、IV、V、VI、VII或VIII在制备用于预防或治疗P2X3和/或P2X2/3受体拮抗剂调节的疾病的药物中的用途。
在一些实施方案中，本发明提供本发明的晶型I、II、III、IV、V、VI、VII或VIII，其用于预防或治疗P2X3和/或P2X2/3受体拮抗剂调节的疾病。
在一些实施方案中，本发明提供预防或治疗P2X3和/或P2X2/3受体拮抗剂调节的疾病的方法，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晶型I、II、III、IV、V、VI、VII或VIII中的任意一种或多种。
在优选实施方案中，所述P2X3和/或P2X2/3受体拮抗剂调节的疾病选自泌尿道疾病，所述泌尿道疾病选自膀胱容量减少、尿频、急迫性尿失禁、压力性尿失禁、膀胱活动过度、良性***肥大、***炎、逼尿肌反射亢进、夜尿、尿急、骨盆过度敏感、尿道炎、骨盆疼痛综合征、***痛、膀胱炎和特发性膀胱过敏；疼痛疾病，所述疼痛疾病选自炎性痛、手术痛、内脏痛、牙痛、经前痛、中枢痛、烧伤痛、偏头痛和丛集性头痛；神经损伤、神经炎、神经痛、中毒、局部缺血损伤、间质性膀胱炎、癌症痛、病毒，寄生虫或细菌感染、创伤后损伤以及与肠易激综合征有关的疼痛；心血管***疾病，所述心血管***疾病优选为高血压；呼吸道疾病，所述呼吸道疾病选自慢性阻塞性肺病、哮喘和支气管痉挛；胃肠道疾病，所述胃肠道疾病选自肠易激综合征(优选为腹泻型肠易激综合征)、炎症性肠病、胆绞痛、肾绞痛，以及与胃肠道扩张有关的疼痛。
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***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)。
本发明晶型的有益效果：
1)本发明的优选晶型具有良好的稳定性，在常温下长时间贮存(例如贮存180天)后，其颜色、性状未发生变化。此外，本发明的优选晶型在高温或高湿条件下也具有良好的稳定性，例如将晶型I在高温条件(如60℃)下保存30天，其晶型无变化。
2)本发明的优选晶型流动性好，易于粉碎，便于制备药物组合物。
3)本发明的优选晶型的制备方法简洁、易于实施，反应条件温和。此外，其不需要多次纯化，操作安全环保，有利于晶型的工业化生产。
实施例
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。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
以下实施例中使用的检测仪器及条件如下：
(1)X-射线粉末衍射(XRPD)
仪器型号：Bruker D8 advance，配备LynxEye检测器
测试条件：阳极靶材料为铜，光管设定为(40KV 40mA)，样品的2θ扫描角度从3°到40°，扫描步长为0.02°。
(2)差示扫描量热分析(DSC)
仪器型号：TA Discovery DSC 250(TA Instruments，US)
测试条件：升温速率为10℃/min，干燥氮气用作吹扫气体。
(3)热重分析(TGA)
仪器型号：Discovery TGA 55(TA Instruments，US)
测试条件：加热炉内自动称量，升温速率为10℃/min，干燥氮气用作吹扫气体。
(4)偏光显微镜分析(PLM)
仪器型号：Polarizing Microscope ECLIPSE LV100POL(Nikon，JPN)
实施例1：5-((2-乙炔基-5-异丙基吡啶-4-基)氧基)嘧啶-2，4-二胺(化合物A)的制备(参照PCT/CN2018/112829，将其整体通过援引加入本文)
Figure PCTCN2020087687-appb-000012
第一步：
将化合物A-1(100g，0.54mol)溶于1，4-二氧六环(700mL)中，将原料SM1(136g，0.81mol)、K 2CO 3(149g，1.08mol)和Pd(PPh 3) 4(6.2g，5.4mmol)依次加入，然后加入纯水(35mL)，氮气置换3次。氮气的保护下，反应液在100℃反应18小时。LC-MS检测原料基本反应完全。将反应液冷却至室温，过滤，将滤饼用1，4-二氧六环(200mL)洗涤，将滤液减压浓缩移除1，4-二氧六环，然后加入纯水(200mL)，用乙酸乙酯(400mL×3)萃取，合并有机相，加入无水硫酸钠(100g)干燥30min，过滤，减压浓缩得粗品，将粗品用硅胶柱色谱法分离纯化(石油醚∶乙酸乙酯＝20∶1～10∶1)，得到化合物A-2(79g，黄色油状物，产率：99.75％)。
1H NMR(400MHz，DMSO-d 6)δ8.37(d，J＝5.6Hz，1H)，8.22(s，1H)，7.04(d，J＝5.6Hz，1H)，5.18(s，1H)，5.09(s，1H)，3.85(s，3H)，2.05(s，3H)；MS m/z(ESI)：150.0[M+H] +.
第二步：
将化合物A-2(79g，0.53mol)溶于无水甲醇(700mL)中，加入10％的钯/碳(16g)，反应液在氢气(0.4MPa)下室温反应18小时，LC-MS检测，仍有少量原料剩余，补加钯/碳(4g)，继续在氢气(0.4MPa)下室温反应18小时，LC-MS检测，原料反应完全。将反应液过滤，将滤饼用甲醇(100mL)洗涤，滤液减压浓缩得到粗品化合物A-3(80g，橘黄色油状液体，产率：99.96％)。
1H NMR(400MHz，DMSO-d 6)δ8.31(d，J＝5.6Hz，1H)，8.28(s，1H)，6.98(d，J＝5.6Hz，1H)，3.86(s，3H)，3.21-3.09(m，1H)，1.21(d，J＝7.2Hz，6H)；MS m/z(ESI)：152.1[M+H] +.
第三步：
将化合物N，N-二甲基乙醇胺(46.3g，0.52mol)溶于正己烷(400mL)中，在氮气保护下，降温至-15℃～-20℃，缓慢滴入2.4M/L的正丁基锂(434mL，1.04mol)，滴加完毕，保温30分钟，然后在-15℃～-20℃缓慢滴入化合物A-3(40g，0.26mol)的甲苯溶液(200mL)，滴加完毕后，保温30分钟， 将反应液降温至-70℃，缓慢滴加四溴化碳(172.4g，0.52mol)的甲苯(500mL)溶液，控制温度在-70℃～-75℃，滴加完毕，保温1小时，LC-MS检测原料反应完毕，加入水(500mL)淬灭，并用乙酸乙酯(500mL×3)萃取，合并有机相，用饱和食盐水(500mL)洗涤一次，之后用无水硫酸钠(400g)干燥半小时，过滤，浓缩，粗品用硅胶柱色谱法(石油醚∶乙酸乙酯＝200∶1～50∶1)分离得到化合物A-4(25g，浅黄色油状液体，产率：41.81％)。
1H NMR(400MHz，DMSO-d 6)δ8.06(s，1H)，7.20(s，1H)，3.89(s，3H)，3.13-3.05(m，1H)，1.18(d，J＝6.8Hz，6H)；MS m/z(ESI)：229.9[M+H] +.
第四步：
将化合物A-4(25g，0.11mol)溶于二氯甲烷(300mL)中，在氮气保护的条件下，降温至0℃～5℃，缓慢加入三溴化硼溶液(140.3g，0.55mol)，加毕，将反应液升温至回流，反应18小时，LC-MS检测，原料反应完毕。将反应液降至室温，缓慢滴入到500g冰中，滴加完毕，滴加饱和碳酸氢钠溶液调节至pH＝7～8，过滤，将滤饼用乙酸乙酯(400mL)泡洗三次，滤液进行分液，水相再次用乙酸乙酯(400mL x 3)萃取，合并所有有机相，加入无水硫酸钠(500g)干燥半小时，过滤，将滤液减压浓缩得到化合物A-5(20g，浅黄色固体，产率：84.17％)。
1H NMR(400MHz，DMSO-d 6)δ11.11(s，1H)，7.99(s，1H)，6.90(s，1H)，3.10-3.02(m，1H)，1.18(d，J＝6.8Hz，6H)；MS m/z(ESI)：215.9[M+H] +.
第五步：
将化合物A-5(10g，0.047mol)溶于DMF(50mL)中，在氮气保护的条件下依次加入碳酸钾(12.8g，0.093mol)和溴乙腈(8.4g，0.07mol)，室温条件下搅拌2小时，LC-MS检测原料反应完毕。加水(50mL)淬灭，用乙酸乙酯(50mL×4)萃取，将合并的有机相用饱和食盐水(50mL×3)洗涤，向有机相加入无水硫酸钠，干燥半小时，过滤，滤液减压浓缩，粗品用硅胶柱色谱法分离(石油醚∶乙酸乙酯＝20∶1～5∶1)得到化合物A-6(4g，浅黄色固体，产率：33.38％)。
1H NMR(400MHz，DMSO-d 6)δ8.18(s，1H)，7.40(s，1H)，5.37(s，2H)，3.14-3.06(m，1H)，1.21(d，J＝6.8Hz，6H)；MS m/z(ESI)：254.8[M+H] +.
第六步：
将化合物A-6(4g，0.016mol)溶于DMF(50mL)中，在氮气保护的条件下，加入叔丁氧基二(二甲基氨基)甲烷(8.2g，0.048mol)，加热至100℃，搅拌2小时，LC-MS检测原料反应完毕。反应液冷却到室温，加入水(50mL)淬灭，然后用乙酸乙酯(50mL×3)萃取，有机相再用饱和食盐水(50mL x 3)洗涤，向有机相加入无水硫酸钠干燥半小时，过滤，滤液减压浓缩，粗品用硅胶柱色谱法分离(石油醚∶乙酸乙酯＝10∶1～5∶1)得到化合物A-7(3.8g，浅黄色固体，产率：66.90％)。MS m/z(ESI)：309.7[M-45+H] +.
第七步：
将化合物A-7(3.54g，0.01mol)溶于DMF(25mL)中，在氮气保护的条件下加入苯胺氢溴酸盐(2.08g，0.012mol)，加热至100℃，搅拌2小时，LC-MS检测原料反应完毕。反应液冷却到室温，加入水(25mL)淬灭，用乙酸乙酯(20mL×3)萃取，有机相再用饱和食盐水(20mL x3)洗涤，加入无水硫酸钠干燥半小时，过滤，滤液减压浓缩，粗品用硅胶柱色谱法分离(石油醚∶乙酸乙酯＝20∶1～5∶1)得到化合物A-8(3.1g，浅黄色固体，产率：86.59％)。
1H NMR(400MHz，DMSO-d 6)δ9.36(d，J＝12.8Hz，1H)，8.28(s，1H)，7.95(d，J＝12.8Hz，1H)，7.32-7.24(m，4H)，7.20(s，1H)，6.99(t，J＝7.2Hz，1H)，3.31-3.26(m，1H)，1.28(d，J＝6.8Hz，6H)；MS m/z(ESI)：357.7[M+H] +.
第八步：
将盐酸胍(2.4g，25.2mmol)加入到无水乙醇(50mL)中，在氮气保护的条件下加入甲醇钠(2.4g，25.2mmol)，室温条件下搅拌半小时，然后加入化合物A-8(3g，8.4mmol)，加毕，将反应液加热至回流，反应18小时，LC-MS检测原料反应完毕。将反应液降温至室温，过滤，滤液减压浓缩，粗品用硅胶柱色谱法分离(DCM∶MeOH＝50∶1～20∶1)得到化合物A-9(900mg，浅黄色固体，产率：33.17％，化合物2)。
1H NMR(400MHz，DMSO-d 6)δ8.19(s，1H)，7.62(s，1H)，6.56(s，1H)，6.47(s，2H)，6.06(s，2H)，3.32-3.27(m，1H)，1.28(d，J＝6.8Hz，6H)；MS m/z(ESI)：323.7[M+H] +.
第九步：
将化合物A-9(3g，9.29mmol)溶于1，4-二氧六环(40mL)中，将三甲基硅烷基乙炔(9g，92.9mmol)、DIEA(12g，92.9mmol)、CuI(0.6g)和Pd(PPh 3) 2Cl 2(0.6g)依次加入，氮气置换3次，氮气的保护下，反应液在50℃反应2小时。LC-MS检测原料基本反应完全。将反应液冷却至室温，过滤，滤饼用1，4-二氧六环(10mL)洗涤，滤液减压浓缩蒸去二氧六环，然后加入纯水(100mL)，用乙 酸乙酯(100mL×3)萃取，合并有机相，加入无水硫酸钠(20g)干燥30min，过滤，减压浓缩得粗品，粗品用硅胶柱色谱法分离(石油醚∶乙酸乙酯＝20∶1～5∶1)纯化得到化合物A-10(2g，产率63.1％)。MS m/z(ESI)：341.9[M+H] +.
第十步：
将化合物A-10(2g，5.87mmol)溶于THF(20mL)中，加入TBAF(1.53g，5.87mmol)。室温反应10分钟，LC-MS检测原料反应完全。将反应液旋干得油状残留物。该残留物用硅胶柱色谱法分离(石油醚∶乙酸乙酯＝1∶3)纯化得到化合物A(0.7g，黄色固体，产率44.6％)。
1H NMR(300MHz，DMSO-d 6)δ8.33(s，1H)，7.56(s，1H)，6.50(s，1H)，6.41(s，2H)，6.01(s，2H)，4.20(s，1H)，3.37-3.31(m，1H)，1.28(d，J＝6.8Hz，6H).MS m/z(ESI)：269.8[M+H] +.
实施例2：化合物A无水合物的晶型I的制备(方法一)
将10.0g化合物A加入到100mL水中，在0℃下滴加6M盐酸直至固体完全溶解，室温下搅拌1h。将溶液过滤后收集滤液，在0℃下向滤液中滴加1M NaOH水溶液至pH为12，有白色固体析出。过滤后收集固体。将所得固体用100mL水搅拌2h，过滤收集固体。将固体在50℃下真空干燥6h，得到的固体即为目标晶型。经X-射线粉末衍射检测，其XRPD图谱如图1所示；经DSC和TGA分析，其DSC和TGA图谱如图2所示；样品在扫描电子显微镜下观察，晶体形貌如图3所示。
热重分析(TGA)显示该晶型样品在25-150℃之间质量减重0.1％，表明该晶型不含结晶水。
实施例3：化合物A无水合物的晶型I的制备(方法二)
将1.3g化合物A加入到100mL四氢呋喃中，室温下搅拌至完全溶解，将所得溶液过滤并收集滤液。向滤液中缓慢滴加300ml正庚烷，室温下搅拌过夜，析出固体，过滤悬浮液，得到晶型。经X-射线粉末衍射检测，其XRPD图谱与图1相同。
实施例4：化合物A无水合物的晶型I的制备(方法三)
将2.0g化合物A加入到80mL四氢呋喃中，在50℃下搅拌至完全溶解，趁热过滤。将滤液冷却至5℃，向其中缓慢滴加100ml甲基叔丁基醚，在5℃下搅拌30min，析出固体，过滤悬浮液，得到晶型。经X-射线粉末衍射检测，其XRPD图谱与图1相同。
实施例5：化合物A一水合物的晶型II的制备
将2.0g化合物A悬浮于100mL甲醇(含1wt.％水)中，在室温下搅拌3天，过滤收集固体。经X-射线粉末衍射检测，其XRPD图谱如图4所示；经DSC和TGA分析，其DSC和TGA图谱如图5所示。热重分析(TGA)显示该晶型样品在25-100℃之间质量减重6.2％，而含有1个结晶水的样品理论含水量为6.27％，表明该晶型含有1分子的结晶水。
实施例6：化合物A半水合物的晶型III的制备
将4.0g化合物A加入到50mL二甲基亚砜中，在室温下搅拌至完全溶解。将所得溶液过滤并收集滤液。向滤液中缓慢滴加100ml水，将所得混合物在室温下搅拌过夜，析出固体。过滤悬浮液，得到晶型。经X-射线粉末衍射检测，其XRPD图谱如图6所示；经DSC和TGA分析，其DSC和TGA图谱如图7所示。热重分析(TGA)显示该晶型样品在25-80℃之间质量减重3.6％，而含有0.5个结晶水的样品理论含水量为3.24％，表明该晶型含有0.5分子的结晶水。
实施例7：化合物A倍半水合物的晶型IV的制备(方法一)
将2.0g化合物A悬浮于100mL水中，在室温下搅拌3天，过滤收集固体。经X-射线粉末衍射检测，其XRPD图谱如图8所示，经DSC和TGA分析，其DSC和TGA图谱如图9所示。热重分析(TGA)显示该晶型样品在25-100℃之间质量减重9.4％，而含有1.5个结晶水的样品理论含水量为9.12％，表明该晶型含有1.5分子的结晶水。
实施例8：化合物A倍半水合物的晶型IV的制备(方法二)
将1.3g化合物A加入到100mL四氢呋喃中，在室温下搅拌至完全溶解。将所得溶液过滤并收集滤液。向滤液中缓慢滴加300ml水，室温下搅拌过夜，析出固体。过滤悬浮液，得到晶型。经X-射线粉末衍射检测，其XRPD图谱与图8所示相同。
实施例9：化合物A一水合物的晶型V的制备
将4.0g化合物A加入到50mL二甲基亚砜中，室温下搅拌至完全溶解，过滤后收集滤液。向滤液中缓慢滴加100ml甲醇(含1wt.％水)，室温下搅拌过夜，析出固体，过滤悬浮液，得到晶型。经X-射线粉末衍射检测，其XRPD图谱如图10所示；经DSC和TGA分析，其DSC和TGA图谱如图11所示。热重分析(TGA)显示该晶型样品在25-80℃之间质量减重6.8％，而含有1个结晶水的样品理论含水量为6.27％，表明该晶型含有1分子的结晶水。
实施例10：化合物A一水合物的晶型VI的制备
将5.0g化合物A加入到100mL丙酮和水的混合溶剂(4/1)中形成悬浮液，将其在室温下搅拌3天，过滤收集固体。经X-射线粉末衍射检测，其XRPD图谱如图12所示；经DSC和TGA分析，其DSC和TGA图谱如图13所示。
采用V20卡尔费休水分测定仪测定含水量6.3％，而含有1个结晶水的样品理论含水量为6.27％，表明该晶型含有1分子的结晶水。
实施例11：化合物A倍半水合物的晶型VII的制备
将2.0g化合物A加入到100mL乙醇和水的混合溶剂(1/1)中，在50℃下搅拌至完全溶解，趁热过滤。将滤液缓慢冷却至5℃，过滤收集固体。经X-射线粉末衍射检测，其XRPD图谱如图14所示；经DSC和TGA分析，其DSC和TGA图谱如图15所示。热重分析(TGA)显示该晶型样品在25-75℃之间质量减重9.5％，而含有1.5个结晶水的样品理论含水量为9.12％，表明该晶型含有1.5分子的结晶水。
实施例12：化合物A半水合物的晶型VIII的制备
将2.0g化合物A加入到100mL丙酮和水的混合溶剂(1/1)中，在50℃下搅拌至完全溶解，趁热过滤。将滤液缓慢冷却至5℃，过滤收集固体。经X-射线粉末衍射检测，其XRPD图谱如图16所示；经DSC和TGA分析，其DSC和TGA图谱如图17所示。热重分析(TGA)显示该晶型样品在25-105℃之间质量减重3.6％，而含有0.5个结晶水的样品理论含水量为3.24％，表明该晶型含有0.5分子的结晶水。
实验例
实验例1：室温稳定性实验
将实施例2制备得到的晶型I、实施例5制备得到的晶型II、实施例6制备得到的晶型III、实施例7制备得到的晶型IV、实施例9制备得到的晶型V、实施例10制备得到的晶型VI、实施例11制备得到的晶型VII以及实施例12制备得到的晶型VIII分别放置在药用低密度聚乙烯袋中，密封，在室温下放置180天后，用Bruker D8 advance X射线粉末衍射仪分别测定XRPD，结果显示晶型I、II、III、IV、V、VI、VII和VIII的样品在180天后的晶型均无变化，稳定性良好。晶型I在室温放置180天前后的X射线粉末衍射图谱对比见图18。
实验例2：高温稳定性实验
将实施例2制备得到的晶型I在60℃下进行稳定性考察，用Bruker D8 advance X射线粉末衍射仪测定XRPD图谱(见图19)，结果显示晶型I的样品在5、10和30天后的晶型均无变化，稳定性优异。
实验例3：高湿稳定性实验
将实施例2制备得到的晶型I在92.5％RH/25℃条件下进行稳定性考察，用Bruker D8advance X射线粉末衍射仪测定XRPD图谱(见图20)，结果显示晶型I的样品在5、10和30天后的晶型均无变化，稳定性优异。
实验例4：物理研磨稳定性实验
将实施例2制备得到的晶型I经物理研磨2min后，用Bruker D8 advance X射线粉末衍射仪测定XRPD图谱(见图21)，结果显示晶型I的样品晶型无变化，稳定性优异。
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易 见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (11)

  1. 化合物A无水合物的晶型I：
    Figure PCTCN2020087687-appb-100001
    所述晶型I的XRPD图谱包括在约11.9±0.2°、12.3±0.2°、13.9±0.2°、19.8±0.2°和20.3±0.2°的衍射角(2θ)处的特征峰，优选包括在约10.1±0.2°、11.9±0.2°、12.3±0.2°、13.9±0.2°、17.8±0.2°、18.6±0.2°、19.8±0.2°和20.3±0.2°的衍射角(2θ)处的特征峰，最优选包括在约6.2±0.2°、10.1±0.2°、11.9±0.2°、12.3±0.2°、13.9±0.2°、16.9±0.2°、17.8±0.2°、18.6±0.2°、19.8±0.2°、20.3±0.2°、21.8±0.2°、23.0±0.2°、23.6±0.2°、24.1±0.2°、26.2±0.2°、26.5±0.2°、27.8±0.2°、28.5±0.2°、29.3±0.2°和30.6±0.2°的衍射角(2θ)处的特征峰。
  2. 制备权利要求1的化合物A无水合物的晶型I的方法，所述方法包括以下步骤：
    1)将化合物A加入水中，然后加入酸，搅拌使化合物A溶解得到溶液，任选地将其过滤以得到滤液；
    2)向步骤1)中所得溶液或滤液中加入碱，通过过滤收集析出的固体；以及
    3)将所得固体加入水中搅拌，通过过滤收集固体，任选地将其干燥，得到晶型I；
    或者，所述方法包括将化合物A在良溶剂中溶解，形成溶液，然后向所述溶液中添加反溶剂，在搅拌下析出固体，将其过滤得到晶体。
  3. 化合物A一水合物的晶型II：
    Figure PCTCN2020087687-appb-100002
    所述晶型II的XRPD图谱包括在约13.0±0.2°、19.5±0.2°和19.9±0.2°的衍射角(2θ)处的特征峰，优选包括在约9.6±0.2°、13.0±0.2°、19.5±0.2°、19.9±0.2°和22.7±0.2°的衍射角(2θ)处的特征峰，最优选包括在约9.6±0.2°、10.9±0.2°、13.0±0.2°、14.9±0.2°、15.8±0.2°、16.8±0.2°、19.5±0.2°、19.9±0.2°、22.7±0.2°、23.7±0.2°、25.2±0.2°、26.0±0.2°、28.5±0.2°、29.0±0.2°、30.0±0.2°和32.5±0.2°的衍射角(2θ)处的特征峰。
  4. 化合物A半水合物的晶型III：
    Figure PCTCN2020087687-appb-100003
    所述晶型III的XRPD图谱包括在约10.8±0.2°和20.5±0.2°的衍射角(2θ)处的特征峰，优选包括在约10.8±0.2°、19.3±0.2°、20.5±0.2°、21.7±0.2°和26.9±0.2°的衍射角(2θ)处的特征峰，最优选包括在约10.8±0.2°、13.0±0.2°、15.0±0.2°、15.4±0.2°、16.5±0.2°、17.3±0.2°、19.3±0.2°、19.9±0.2°、20.5±0.2°、21.7±0.2°、23.3±0.2°、25.1±0.2°、26.5±0.2°、26.9±0.2°、28.7±0.2°和32.2±0.2°的衍射角(2θ)处的特征 峰。
  5. 化合物A倍半水合物的晶型IV：
    Figure PCTCN2020087687-appb-100004
    所述晶型IV的XRPD图谱包括在约12.3±0.2°、21.3±0.2°和24.1±0.2°的衍射角(2θ)处的特征峰，优选包括在约12.3±0.2°、12.6±0.2°、17.2±0.2°、20.0±0.2°、20.6±0.2°、21.3±0.2°、23.8±0.2°、24.1±0.2°、25.0±0.2°和27.9±0.2°的衍射角(2θ)处的特征峰，最优选包括在约12.3±0.2°、12.6±0.2°、14.3±0.2°、17.2±0.2°、20.0±0.2°、20.6±0.2°、21.3±0.2°、23.2±0.2°、23.8±0.2°、24.1±0.2°、25.0±0.2°、25.7±0.2°、27.9±0.2°、31.2±0.2°和31.7±0.2°的衍射角(2θ)处的特征峰。
  6. 化合物A一水合物的晶型V：
    Figure PCTCN2020087687-appb-100005
    所述晶型V的XRPD图谱包括在约14.1±0.2°、21.0±0.2°和29.6±0.2°的衍射角(2θ)处的特征峰，优选包括在约8.7±0.2°、9.4±0.2°、11.9±0.2°、14.1±0.2°、15.8±0.2°、16.8±0.2°、18.9±0.2°、19.9±0.2°、20.6±0.2°、21.0±0.2°、22.5±0.2°和29.6±0.2°的衍射角(2θ)处的特征峰，最优选包括在约8.7±0.2°、9.4±0.2°、11.6±0.2°、11.9±0.2°、12.4±0.2°、14.1±0.2°、14.5±0.2°、15.8±0.2°、16.2±0.2°、16.8±0.2°、17.6±0.2°、18.2±0.2°、18.9±0.2°、19.9±0.2°、20.6±0.2°、21.0±0.2°、22.5±0.2°、23.0±0.2°、23.6±0.2°、24.4±0.2°、25.2±0.2°、27.0±0.2°和29.6±0.2°的衍射角(2θ)处的特征峰。
  7. 化合物A一水合物的晶型VI：
    Figure PCTCN2020087687-appb-100006
    所述晶型VI的XRPD图谱包括在约10.4±0.2°、12.1±0.2°、16.6±0.2°、20.7±0.2°、22.8±0.2°和27.3±0.2°的衍射角(2θ)处的特征峰，优选包括在约8.7±0.2°、10.4±0.2°、12.1±0.2°、15.4±0.2°、16.6±0.2°、19.5±0.2°、20.7±0.2°、21.2±0.2°、22.8±0.2°和27.3±0.2°的衍射角(2θ)处的特征峰，最优选包括在约8.7±0.2°、10.4±0.2°、12.1±0.2°、13.4±0.2°、14.7±0.2°、15.4±0.2°、16.6±0.2°、17.4±0.2°、19.5±0.2°、20.7±0.2°、21.2±0.2°、22.1±0.2°、22.8±0.2°、23.6±0.2°、26.0±0.2°、27.3±0.2°、28.0±0.2°和30.4±0.2°的衍射角(2θ)处的特征峰。
  8. 化合物A倍半水合物的晶型VII：
    Figure PCTCN2020087687-appb-100007
    所述晶型VII的XRPD图谱包括在约13.1±0.2°、19.9±0.2°和20.2±0.2°的衍射角(2θ)处的特征峰，优选包括在约13.1±0.2°、16.9±0.2°、19.9±0.2°、20.2±0.2°、24.9±0.2°和28.8±0.2°的衍射角(2θ)处的特征峰，最优选包括在约9.4±0.2°、10.8±0.2°、13.1±0.2°、15.4±0.2°、16.9±0.2°、18.8±0.2°、19.9±0.2°、20.2±0.2°、22.2±0.2°、23.2±0.2°、24.9±0.2°、26.4±0.2°和28.8±0.2°的衍射角(2θ)处的特征峰。
  9. 化合物A半水合物的晶型VIII：
    Figure PCTCN2020087687-appb-100008
    所述晶型VIII的XRPD图谱包括在约13.0±0.2°、16.8±0.2°、19.4±0.2°、21.7±0.2°、22.9±0.2°和27.4±0.2°的衍射角(2θ)处的特征峰，优选包括在约10.3±0.2°、13.0±0.2°、16.8±0.2°、19.1±0.2°、19.4±0.2°、21.1±0.2°、21.7±0.2°、22.9±0.2°、25.8±0.2°和27.4±0.2°的衍射角(2θ)处的特征峰，最优选包括在约8.7±0.2°、10.3±0.2°、10.8±0.2°、13.0±0.2°、14.1±0.2°、14.8±0.2°、16.8±0.2°、17.5±0.2°、19.1±0.2°、19.4±0.2°、21.1±0.2°、21.7±0.2°、22.3±0.2°、22.9±0.2°、25.8±0.2°、27.4±0.2°、27.8±0.2°、30.4±0.2°和31.6±0.2°的衍射角(2θ)处的特征峰。
  10. 药物组合物，其包含权利要求1的晶型I、权利要求3的晶型II、权利要求4的晶型III、权利要求5的晶型IV、权利要求6的晶型V、权利要求7的晶型VI、权利要求8的晶型VII或者权利要求9的晶型VIII，以及一种或多种药学上可接受的载体。
  11. 权利要求1的晶型I、权利要求3的晶型II、权利要求4的晶型III、权利要求5的晶型IV、权利要求6的晶型V、权利要求7的晶型VI、权利要求8的晶型VII或者权利要求9的晶型VIII在制备用于预防或治疗P2X3和/或P2X2/3受体拮抗剂调节的疾病的药物中的用途；优选地，所述疾病选自泌尿道疾病，所述泌尿道疾病选自膀胱容量减少、尿频、急迫性尿失禁、压力性尿失禁、膀胱活动过度、良性***肥大、***炎、逼尿肌反射亢进、夜尿、尿急、骨盆过度敏感、尿道炎、骨盆疼痛综合征、***痛、膀胱炎和特发性膀胱过敏；疼痛疾病，所述疼痛疾病选自炎性痛、手术痛、内脏痛、牙痛、经前痛、中枢痛、烧伤痛、偏头痛和丛集性头痛；神经损伤、神经炎、神经痛、中毒、局部缺血损伤、间质性膀胱炎、癌症痛、病毒，寄生虫或细菌感染、创伤后损伤以及与肠易激综合征有关的疼痛；心血管***疾病，所述心血管***疾病优选为高血压；呼吸道疾病，所述呼吸道疾病选自慢性阻塞性肺病、哮喘和支气管痉挛；胃肠道疾病，所述胃肠道疾病选自肠易激综合征(优选为腹泻型肠易激综合征)、炎症性肠病、胆绞痛、肾绞痛，以及与胃肠道扩张有关的疼痛。
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