WO2020221276A1 - 二氨基嘧啶类化合物的盐、其固体形式及其制备方法和用途 - Google Patents

二氨基嘧啶类化合物的盐、其固体形式及其制备方法和用途 Download PDF

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WO2020221276A1
WO2020221276A1 PCT/CN2020/087688 CN2020087688W WO2020221276A1 WO 2020221276 A1 WO2020221276 A1 WO 2020221276A1 CN 2020087688 W CN2020087688 W CN 2020087688W WO 2020221276 A1 WO2020221276 A1 WO 2020221276A1
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compound
acid
salt
crystal form
diffraction angles
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PCT/CN2020/087688
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English (en)
French (fr)
Inventor
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 CN202080032505.XA priority Critical patent/CN114008027B/zh
Priority to US17/607,464 priority patent/US20220177447A1/en
Priority to JP2021564187A priority patent/JP2022531571A/ja
Priority to KR1020217038609A priority patent/KR20220008285A/ko
Priority to AU2020266699A priority patent/AU2020266699A1/en
Priority to EP20799420.3A priority patent/EP3964500A4/en
Priority to CA3138235A priority patent/CA3138235A1/en
Publication of WO2020221276A1 publication Critical patent/WO2020221276A1/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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • 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 the salt of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine (hereinafter referred to as "compound A”) and its solid form , A method for preparing the solid form, a pharmaceutical composition comprising the solid form, and the use of the solid form 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 a salt of Compound A (5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine) as shown below
  • the present invention provides a crystalline form of the salt of Compound A.
  • 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 compound A hydrochloride (molar ratio 1:1) crystal form Ia.
  • FIG. 1 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of compound A hydrochloride (molar ratio 1:1) form Ia.
  • Figure 3 is a scanning electron micrograph of compound A hydrochloride (molar ratio 1:1) crystal form Ia.
  • Figure 4 is an X-ray powder diffraction pattern of compound A hydrochloride (molar ratio 1:1) crystalline form Ib.
  • Figure 5 is a differential scanning calorimetry (DSC) spectrum of compound A hydrochloride (molar ratio 1:1) crystalline form Ib.
  • Figure 6 is a thermogravimetric analysis (TGA) spectrum of compound A hydrochloride (molar ratio 1:1) crystalline form Ib.
  • Figure 7 is an X-ray powder diffraction pattern of compound A hydrochloride (molar ratio 1:2) crystal form II.
  • Fig. 8 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of the crystal form II of compound A hydrochloride (molar ratio 1:2).
  • Figure 9 is an X-ray powder diffraction pattern of compound A citrate (molar ratio 1:0.5) crystal form III.
  • Figure 10 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of the crystalline form III of compound A citrate (molar ratio 1:0.5).
  • Figure 11 is a scanning electron micrograph of Compound A citrate (molar ratio 1:0.5) crystal form III.
  • Figure 12 is an X-ray powder diffraction pattern of compound A sulfate (molar ratio 1:0.5) crystal form IV.
  • Figure 13 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of compound A sulfate (molar ratio 1:0.5) crystal form IV.
  • Figure 14 is an X-ray powder diffraction pattern of Compound A sulfate (molar ratio 1:1) crystal form V.
  • Figure 15 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of the crystalline form V of compound A sulfate (molar ratio 1:1).
  • Figure 16 is an X-ray powder diffraction pattern of compound A p-toluenesulfonate (molar ratio 1:1) crystal form VI.
  • Figure 17 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of Compound A p-toluenesulfonate (molar ratio 1:1) crystalline form VI.
  • Figure 18 is an X-ray powder diffraction pattern of Compound A mesylate (molar ratio 1:1) crystal form VII.
  • Figure 19 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of Compound A mesylate (molar ratio 1:1) crystalline form VII.
  • Figure 20 is a scanning electron micrograph of Compound A mesylate (molar ratio 1:1) crystal form VII.
  • Figure 21 is an X-ray powder diffraction pattern of Compound A mesylate (molar ratio 1:2) Form VIII.
  • Figure 22 is a differential scanning calorimetry (DSC) spectrum and a thermogravimetric analysis (TGA) spectrum of Compound A mesylate (molar ratio 1:2) crystalline form VIII.
  • Figure 23 is a scanning electron micrograph of Compound A mesylate (molar ratio 1:2) crystal form VIII.
  • Figure 24 is an X-ray powder diffraction pattern of compound A phosphate (molar ratio 1:1) crystal form IX.
  • Figure 25 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of compound A phosphate (molar ratio 1:1) crystalline form IX.
  • Figure 26 is a scanning electron micrograph of compound A phosphate (molar ratio 1:1) crystal form IX.
  • Figure 27 is an X-ray powder diffraction pattern of Compound A maleate (molar ratio 1:1) crystalline form X.
  • Figure 28 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of Compound A maleate (molar ratio 1:1) crystalline form X.
  • Figure 29 is a scanning electron micrograph of Compound A maleate (molar ratio 1:1) crystal form X.
  • Figure 30 is an X-ray powder diffraction pattern of Compound A L-tartrate (molar ratio 1:1) crystalline form XI.
  • Figure 31 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of Compound A L-tartrate (molar ratio 1:1) crystalline form XI.
  • Figure 32 is a scanning electron microscope photograph of Compound A L-tartrate (molar ratio 1:1) crystalline form XI.
  • Figure 33 is an X-ray powder diffraction pattern of compound A fumarate (molar ratio 1:1) crystalline form XII.
  • Figure 34 shows the differential scanning calorimetry (DSC) spectrum and the thermogravimetric analysis (TGA) spectrum of compound A fumarate (molar ratio 1:1) crystalline form XII.
  • Figure 35 is a comparison of X-ray powder diffraction patterns of compound A hydrochloride (molar ratio 1:1) crystal form Ia before and after the high temperature stability experiment.
  • Figure 36 is a comparison of X-ray powder diffraction patterns of compound A citrate (molar ratio 1:0.5) crystal form III before and after the high temperature stability experiment.
  • solid form includes all solid forms of the salt of Compound A, 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 spectra 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 the Bruker Advance 300 NMR instrument, unless otherwise specified, using DMSO-d 6 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.
  • the present invention provides a salt of Compound A,
  • the inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid and any combination thereof;
  • the organic acid is selected from formic acid, acetic acid, acetoacetic acid, trifluoroacetic acid, propionic acid, pyruvic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, stearic acid, palmitic acid, oxalic acid, propylene Diacid, succinic acid, glutaric acid, adipic acid, maleic acid, fumaric acid, lactic acid, L-malic acid, citric acid, L-tartaric acid, benzoic acid, salicylic acid, cinnamic acid, naphthoic acid, pu Acid, niacin, orotic acid, methyl sulfuric acid, dodecyl sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanedisulfonic acid, isethionic acid, p-toluenesulfonic acid, benzenesulfonic acid
  • the salt of compound A is selected from L-tartrate, phosphate, methanesulfonate, maleate, hydrochloride, fumarate, citrate, p-toluenesulfonic acid Salt and sulfate.
  • the present invention provides a salt of compound A, which is the hydrochloride salt of compound A;
  • the molar ratio of compound A to hydrochloric acid is 1:1;
  • the hydrochloride salt of compound A is crystal form Ia;
  • the XRPD pattern of the crystalline form Ia includes diffraction angles (2 ⁇ ) at about 7.8 ⁇ 0.2°, 10.4 ⁇ 0.2°, 15.7 ⁇ 0.2°, 20.0 ⁇ 0.2°, 20.7 ⁇ 0.2°, 22.3 ⁇ 0.2°, and 26.0 ⁇ 0.2° ) At the characteristic peak;
  • the XRPD pattern of the crystalline form Ia includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystalline form Ia includes the peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 1.
  • the XRPD peak position of the crystalline form Ia is substantially the same as that shown in FIG. 1.
  • the DSC spectrum of the crystalline form Ia includes an endothermic peak at about 108°C and an exothermic peak at about 190°C.
  • the crystal form Ia has a weight loss of about 5.6% when heated to about 130°C.
  • the DSC-TGA pattern of the crystal form Ia includes substantially the same characteristic peaks as shown in FIG. 2. In the most preferred embodiment, the DSC-TGA pattern of the crystal form Ia is substantially the same as that shown in FIG. 2.
  • the scanning electron micrograph of the crystal form Ia is substantially the same as that shown in FIG. 3.
  • the present invention provides a method for preparing crystalline form Ia, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1 to 6 carbon atoms, including but not limited to methanol, ethanol, 1-propane).
  • Alcohol n-propanol
  • 2-propanol isopropanol
  • ketone solvents such as ketones with 3-6 carbon atoms, including but not Limited to acetone, methyl ethyl ketone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone
  • heat for example, heating to 40-80°C, preferably 50°C or 60°C
  • Hydrochloric acid hydrochloric acid concentration is 2-15mol/L, preferably 4mol/L or 12mol/L
  • the present invention provides a salt of compound A, which is the hydrochloride salt of compound A;
  • the molar ratio of compound A to hydrochloric acid is 1:1;
  • the hydrochloride salt of compound A is crystal form Ib;
  • the XRPD pattern of the crystalline form Ib includes characteristic peaks at diffraction angles (2 ⁇ ) of about 5.4 ⁇ 0.2°, 11.2 ⁇ 0.2°, and 20.0 ⁇ 0.2°;
  • diffraction angles (2 ⁇ ) of about 5.4 ⁇ 0.2°, 9.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.6 ⁇ 0.2°, 20.0 ⁇ 0.2°, 20.8 ⁇ 0.2°, 24.9 ⁇ 0.2° and 25.5 ⁇ 0.2° Characteristic peak
  • the XRPD pattern of the crystalline form Ib includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystalline form Ib 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 Ib is substantially the same as that shown in FIG. 4.
  • the DSC spectrum of the crystalline form Ib includes an exothermic peak at about 207°C.
  • the DSC spectrum of the crystalline form Ib includes substantially the same characteristic peaks as shown in FIG. 5. In the most preferred embodiment, the DSC spectrum of the crystalline form Ib is substantially the same as that shown in FIG. 5.
  • the crystalline form Ib has a weight loss of about 2.6% when heated to about 167°C.
  • the TGA pattern of the crystalline form Ib is substantially the same as that shown in FIG. 6.
  • the present invention provides a method for preparing crystalline form Ib, which includes adding compound A to an ester solvent (preferably an ester having 3-10 carbon atoms, including but not limited to ethyl acetate, propyl acetate , I The concentration is 2-15 mol/L, preferably 4 mol/L or 12 mol/L), cooled to room temperature and stirred, filtered and optionally dried to obtain crystals, wherein the molar ratio of compound A and HCl is 1: (1-1.3).
  • an ester solvent preferably an ester having 3-10 carbon atoms, including but not limited to ethyl acetate, propyl acetate , I
  • the concentration is 2-15 mol/L, preferably 4 mol/L or 12 mol/L
  • the present invention provides a salt of compound A, which is the hydrochloride salt of compound A;
  • the molar ratio of compound A to hydrochloric acid is 1:2;
  • the hydrochloride salt of compound A is crystal form II;
  • the XRPD pattern of the crystal form II includes characteristic peaks at diffraction angles (2 ⁇ ) of about 13.3 ⁇ 0.2°, 14.2 ⁇ 0.2°, 21.9 ⁇ 0.2°, and 27.4 ⁇ 0.2°;
  • 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. 7.
  • the XRPD peak position of the crystalline form II is substantially the same as that shown in FIG. 7.
  • the DSC spectrum of the crystal form II includes an endothermic peak at about 40°C.
  • the crystal form II has a weight loss of about 0.9% when heated to about 180°C.
  • the DSC-TGA pattern of the crystal form II includes the characteristic peaks substantially the same as those shown in FIG. 8. In the most preferred embodiment, the DSC-TGA pattern of the crystal form II is substantially the same as that shown in FIG. 8.
  • the present invention provides a method for preparing crystalline form II, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane In alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heating (for example, heating to 40-80°C, preferably 50°C or 60°C) Compound A is dissolved, then hydrochloric acid is added (hydrochloric acid concentration is 2-15mol/L, preferably 4mol/L or 12mol/L), cooled to room temperature and stirred, filtered and optionally dried to obtain crystals, wherein the molar ratio of compound A and HCl It is 1: (2-2.5).
  • an alcohol solvent preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane In alcohol (n-propanol), 2-propanol (isoprop
  • the present invention provides a salt of compound A, which is the citrate salt of compound A;
  • the molar ratio of compound A to citric acid is 1:0.5;
  • the citrate of compound A is crystal form III;
  • the XRPD pattern of the crystal form III includes characteristic peaks at diffraction angles (2 ⁇ ) of about 6.9 ⁇ 0.2°, 10.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 20.3 ⁇ 0.2°, and 22.5 ⁇ 0.2°;
  • diffraction angles (2 ⁇ ) of about 6.9 ⁇ 0.2°, 10.8 ⁇ 0.2°, 14.6 ⁇ 0.2°, 16.3 ⁇ 0.2°, 20.3 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.4 ⁇ 0.2°, and 26.6 ⁇ 0.2° Characteristic peak
  • 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. 9.
  • the XRPD peak position of the crystal form III is substantially the same as that shown in FIG. 9.
  • the DSC spectrum of the crystal form III includes an endothermic peak at about 117°C.
  • the crystal form III has a weight loss of about 2.9% when heated to about 150°C.
  • the DSC-TGA pattern of the crystal form III includes substantially the same characteristic peaks as shown in FIG. 10. In the most preferred embodiment, the DSC-TGA pattern of the crystal form III is substantially the same as that shown in FIG. 10.
  • the scanning electron micrograph of the crystal form III is substantially the same as that shown in FIG. 11.
  • the present invention provides a method for preparing Form III, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1 to 6 carbon atoms, including but not limited to methanol, ethanol, 1-propane In alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heating (for example, heating to 40-80°C, preferably 50°C or 60°C) Compound A is dissolved, then citric acid (preferably a methanol or ethanol solution of citric acid) is added, cooled to room temperature and stirred, filtered and optionally dried to obtain crystals, wherein the molar ratio of compound A and citric acid is 1: (1-1.3 ).
  • an alcohol solvent preferably an alcohol having 1 to 6 carbon atoms, including but not limited to methanol, ethanol, 1-propane In alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-
  • the present invention provides a salt of compound A, which is a sulfate salt of compound A;
  • the molar ratio of compound A to sulfuric acid is 1:0.5;
  • the sulfate salt of compound A is crystal form IV;
  • the XRPD pattern of the crystal form IV includes characteristic peaks at diffraction angles (2 ⁇ ) of about 8.0 ⁇ 0.2°, 11.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, and 26.3 ⁇ 0.2°;
  • diffraction angles (2 ⁇ ) of about 8.0 ⁇ 0.2°, 10.5 ⁇ 0.2°, 11.2 ⁇ 0.2°, 20.9 ⁇ 0.2°, 21.8 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.8 ⁇ 0.2°, and 26.3 ⁇ 0.2° 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. 12.
  • the XRPD peak position of the crystal form IV is substantially the same as that shown in FIG. 12.
  • the DSC spectrum of the crystalline form IV includes an endothermic peak at about 41°C.
  • the crystal form IV has a weight loss of about 2.1% when heated to about 150°C.
  • the DSC-TGA pattern of the crystal form IV includes the characteristic peaks substantially the same as those shown in FIG. 13. In the most preferred embodiment, the DSC-TGA pattern of the crystal form IV is substantially the same as that shown in FIG. 13.
  • the present invention provides a method for preparing crystalline form IV, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heating (for example, heating to 40-80 °C, preferably 55 °C or 60 °C) to Compound A is dissolved, then sulfuric acid (such as sulfuric acid in methanol or ethanol) is added, cooled to room temperature and stirred, filtered and optionally dried to obtain crystals, wherein the molar ratio of compound A to sulfuric acid is 1: (0.4-0.6), preferably 1:0.5.
  • an alcohol solvent preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (isopropanol), 1-
  • the present invention provides a salt of compound A, which is a sulfate salt of compound A;
  • the molar ratio of compound A to sulfuric acid is 1:1;
  • the sulfate salt of compound A is crystal form V;
  • the XRPD pattern of the crystal form V includes characteristic peaks at diffraction angles (2 ⁇ ) of about 7.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.7 ⁇ 0.2°, and 26.3 ⁇ 0.2°;
  • diffraction angles (2 ⁇ ) of about 7.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 20.3 ⁇ 0.2°, 21.7 ⁇ 0.2°, 22.5 ⁇ 0.2°, 23.7 ⁇ 0.2°, 24.8 ⁇ 0.2°, and 26.3 ⁇ 0.2° Characteristic peak
  • 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. 14.
  • the XRPD peak position of the crystal form V is substantially the same as that shown in FIG. 14.
  • the DSC spectrum of the crystal form V includes an endothermic peak at about 35°C.
  • the crystal form V has a weight loss of about 0.8% when heated to about 150°C.
  • the DSC-TGA pattern of the crystal form V includes characteristic peaks substantially the same as those shown in FIG. 15. In the most preferred embodiment, the DSC-TGA pattern of the crystal form V is substantially the same as that shown in FIG. 15.
  • the present invention provides a method for preparing crystalline form V, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heating (for example, heating to 40-80 °C, preferably 55 °C or 60 °C) to Compound A is dissolved, then sulfuric acid (such as sulfuric acid in methanol or ethanol solution) is added, cooled to room temperature and stirred, filtered and optionally dried to obtain crystals, wherein the molar ratio of compound A to sulfuric acid is 1: (1-1.3), preferably About 1:1.
  • an alcohol solvent preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (isopropanol), 1-but
  • the present invention provides a salt of compound A, which is the p-toluenesulfonate salt of compound A;
  • the molar ratio of compound A to p-toluenesulfonic acid is 1:1;
  • the p-toluenesulfonate of compound A is in crystal form VI;
  • the XRPD pattern of the crystal form VI includes characteristic peaks at diffraction angles (2 ⁇ ) of about 9.2 ⁇ 0.2°, 10.8 ⁇ 0.2°, 18.0 ⁇ 0.2°, and 19.5 ⁇ 0.2°;
  • 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 the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 16.
  • the XRPD peak position of the crystalline form VI is substantially the same as that shown in FIG. 16.
  • the DSC spectrum of the crystal form VI includes an endothermic peak at about 36°C.
  • the crystal form VI has a weight loss of about 3% when heated to about 180°C.
  • the DSC-TGA pattern of the crystal form VI includes characteristic peaks substantially the same as those shown in FIG. 17. In the most preferred embodiment, the DSC-TGA pattern of the crystal form VI is substantially the same as that shown in FIG. 17.
  • the present invention provides a method for preparing crystalline form VI, which includes adding compound A to a ketone solvent (for example, a ketone having 3-6 carbon atoms, including but not limited to acetone, methyl ethyl ketone, methyl Ethyl ketone, methyl isobutyl ketone and diethyl ketone), heat (for example, heating to 40-80 °C, preferably 50 °C or 60 °C) to dissolve compound A, and then add p-toluenesulfonic acid (for example, p-toluene Sulfonic acid in methanol or ethanol) to obtain the reactant solution, optionally concentrate the reactant solution to dryness and add the above-mentioned ketone solvent again, cool the resulting solution to room temperature and stir, filter to obtain crystals, wherein compound A and p-toluene
  • a ketone solvent for example, a ketone having 3-6 carbon atoms, including but not
  • the present invention provides a salt of compound A, which is the mesylate salt of compound A;
  • the molar ratio of compound A to methanesulfonic acid is 1:1;
  • the methanesulfonate salt of compound A is crystal form VII;
  • the XRPD pattern of the crystal form VII includes characteristic peaks at diffraction angles (2 ⁇ ) of about 7.7 ⁇ 0.2°, 10.5 ⁇ 0.2°, 19.0 ⁇ 0.2°, 20.1 ⁇ 0.2°, and 20.5 ⁇ 0.2°;
  • 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. 18.
  • the XRPD peak position of the crystalline form VII is substantially the same as that shown in FIG. 18.
  • the DSC spectrum of the crystal form VII includes an endothermic peak at about 99°C.
  • the crystal form VII has a weight loss of about 0.9% when heated to about 150°C.
  • the DSC-TGA pattern of the crystal form VII includes the characteristic peaks substantially the same as those shown in FIG. 19. In the most preferred embodiment, the DSC-TGA pattern of the crystal form VII is substantially the same as that shown in FIG. 19.
  • the scanning electron micrograph of the crystal form VII is substantially the same as that shown in FIG. 20.
  • the present invention provides a method for preparing Form VII, which includes adding compound A to an ether solvent (for example, an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofuran) Type) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane), heat (for example, heating to 40-80°C, preferably 50°C or 60°C) to dissolve compound A, and then add Methanesulfonic acid is lowered to room temperature and stirred, filtered to obtain crystals, wherein the molar ratio of compound A to methanesulfonic acid is 1:(1-1.3), preferably about 1:1.
  • an ether solvent for example, an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofuran) Type
  • dioxanes preferably tetrahydrofuran, 2-methylt
  • the present invention provides a salt of compound A, which is the mesylate salt of compound A;
  • the molar ratio of compound A to methanesulfonic acid is 1:2;
  • the methanesulfonate salt of compound A is crystal form VIII;
  • the XRPD pattern of the crystalline form VIII includes diffraction angles (2 ⁇ ⁇ 0.2°, 2 ⁇ ) At the characteristic peak;
  • the XRPD pattern of Form VIII includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form VIII includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 21.
  • the XRPD peak position of the crystalline form VIII is substantially the same as that shown in FIG. 21.
  • the DSC spectrum of the crystal form VIII includes an endothermic peak at about 101°C.
  • the crystalline form VIII has a weight loss of about 7.5% when heated to about 150°C.
  • the DSC-TGA spectrum of the crystal form VIII includes the characteristic peaks substantially the same as those shown in FIG. 22. In the most preferred embodiment, the DSC-TGA spectrum of the crystal form VIII is substantially the same as that shown in FIG. 22.
  • the scanning electron micrograph of the crystal form VIII is substantially the same as that shown in FIG. 23.
  • the present invention provides a method for preparing Form VIII, which comprises adding compound A to an ether solvent (for example, an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofuran) Type) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane), heat (for example, heating to 40-80°C, preferably 50°C or 60°C) to dissolve compound A, and then add Methanesulfonic acid was lowered to room temperature and stirred, filtered to obtain crystals, wherein the molar ratio of compound A to methanesulfonic acid was 1:(2-2.5).
  • an ether solvent for example, an ether having 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofuran) Type
  • dioxanes preferably tetrahydrofuran, 2-methyltetrahydrofuran
  • the present invention provides a salt of compound A, which is the phosphate of compound A;
  • the molar ratio of compound A to phosphoric acid is 1:1;
  • the phosphate of compound A is crystal form IX;
  • the XRPD pattern of the crystal form IX includes characteristic peaks at diffraction angles (2 ⁇ ) of about 7.0 ⁇ 0.2°, 10.7 ⁇ 0.2°, 14.6 ⁇ 0.2°, and 26.7 ⁇ 0.2°;
  • the XRPD pattern of the crystal form IX includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form IX includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 24.
  • the XRPD peak position of the crystal form IX is substantially the same as that shown in FIG. 24.
  • the DSC chart of the crystalline form IX includes an endothermic peak at about 100°C.
  • the crystal form IX in the thermogravimetric analysis, has a weight loss of about 1.2% when heated to about 50°C and a weight loss of about 4.6% at about 50-120°C.
  • the DSC-TGA pattern of the crystal form IX includes the characteristic peaks substantially the same as those shown in FIG. 25. In the most preferred embodiment, the DSC-TGA pattern of the crystal form IX is substantially the same as that shown in FIG. 25.
  • the scanning electron micrograph of the crystal form IX is substantially the same as that shown in FIG. 26.
  • the present invention provides a method for preparing crystalline form IX, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1 to 6 carbon atoms, including but not limited to methanol, ethanol, 1-propane In alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heating (for example, heating to 40-80°C, preferably 55°C or 60°C) Compound A is dissolved, then phosphoric acid is added, cooled to room temperature and stirred, and filtered to obtain crystals, wherein the molar ratio of compound A to phosphoric acid is 1:(1-1.3), preferably about 1:1.
  • an alcohol solvent preferably an alcohol having 1 to 6 carbon atoms, including but not limited to methanol, ethanol, 1-propane In alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-
  • the present invention provides a salt of compound A, which is the maleate salt of compound A;
  • the molar ratio of compound A to maleic acid is 1:1;
  • the maleate of compound A is crystal form X;
  • the XRPD pattern of the crystal form X includes characteristic peaks at diffraction angles (2 ⁇ ) of about 5.4 ⁇ 0.2°, 5.8 ⁇ 0.2°, 13.7 ⁇ 0.2°, and 17.1 ⁇ 0.2°;
  • It preferably includes diffraction at about 5.4 ⁇ 0.2°, 5.8 ⁇ 0.2°, 8.9 ⁇ 0.2°, 10.0 ⁇ 0.2°, 13.7 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.1 ⁇ 0.2°, 21.7 ⁇ 0.2° and 21.9 ⁇ 0.2°
  • the XRPD pattern of the crystal form X includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form X includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 27.
  • the XRPD peak position of the crystal form X is substantially the same as that shown in FIG. 27.
  • the DSC spectrum of the crystalline form X includes an endothermic peak at about 29°C.
  • the crystal form X has a weight loss of about 1% when heated to about 100°C.
  • the DSC-TGA pattern of the crystal form X includes characteristic peaks substantially the same as those shown in FIG. 28. In the most preferred embodiment, the DSC-TGA pattern of the crystal form X is substantially the same as that shown in FIG. 28.
  • the scanning electron micrograph of the crystal form X is substantially the same as that shown in FIG. 29.
  • the present invention provides a method for preparing crystalline form X, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heating (for example, heating to 40-80 °C, preferably 55 °C or 60 °C) to Compound A is dissolved, then maleic acid (preferably a methanol or ethanol solution of maleic acid) is added, cooled to room temperature and stirred, filtered and optionally dried to obtain crystals, wherein the molar ratio of compound A and maleic acid is 1:( 1-1.3), preferably about 1:1.
  • an alcohol solvent preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (isopropanol),
  • the present invention provides a salt of compound A, which is the L-tartrate salt of compound A;
  • the molar ratio of compound A to L-tartaric acid is 1:1;
  • the L-tartrate salt of compound A is crystal form XI;
  • the XRPD pattern of the crystal form XI includes characteristic peaks at diffraction angles (2 ⁇ ) of about 6.5 ⁇ 0.2°, 14.3 ⁇ 0.2°, 20.8 ⁇ 0.2°, 21.5 ⁇ 0.2°, and 25.2 ⁇ 0.2°;
  • the XRPD pattern of the crystalline form XI includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystalline form XI includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 30.
  • the XRPD peak position of the crystalline form XI is substantially the same as that shown in FIG. 30.
  • the DSC spectrum of the crystalline form XI does not include an endothermic peak.
  • the crystalline form XI has a weight loss of about 0.7% when heated to about 170°C.
  • the DSC-TGA pattern of the crystal form XI is substantially the same as that shown in FIG. 31.
  • the scanning electron micrograph of the crystal form XI is substantially the same as that shown in FIG. 32.
  • the present invention provides a method for preparing crystalline form XI, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heating (for example, heating to 40-80 °C, preferably 55 °C or 60 °C) to Compound A is dissolved, then L-tartaric acid (preferably a methanol or ethanol solution of L-tartaric acid) is added, cooled to room temperature and stirred, filtered and optionally dried to obtain crystals, wherein the molar ratio of compound A and L-tartaric acid is 1:( 1-1.3), preferably about 1:1.
  • an alcohol solvent preferably an alcohol having 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propan
  • the present invention provides a salt of compound A, which is the fumarate salt of compound A;
  • the molar ratio of compound A to fumaric acid is 1:1;
  • the fumarate of compound A is crystal form XII;
  • the XRPD pattern of the crystal form XII includes characteristic peaks at diffraction angles (2 ⁇ ) of about 7.2 ⁇ 0.2°, 10.9 ⁇ 0.2°, 20.9 ⁇ 0.2°, and 27.5 ⁇ 0.2°;
  • the XRPD pattern of the crystal form XII includes peaks at the following diffraction angles (2 ⁇ ):
  • the XRPD pattern of the crystal form XII includes a peak at the diffraction angle (2 ⁇ ) substantially the same as that shown in FIG. 33.
  • the XRPD peak position of the crystalline form XII is substantially the same as that shown in FIG. 33.
  • the DSC spectrum of the crystalline form XII includes an endothermic peak at about 102°C.
  • the crystal form XII has a weight loss of about 1.1% when heated to about 60°C and a weight loss of about 4.1% when heated to about 60-150°C.
  • the DSC-TGA pattern of the crystal form XII includes the characteristic peaks substantially the same as those shown in FIG. 34. In the most preferred embodiment, the DSC-TGA pattern of the crystalline form XII is substantially the same as that shown in FIG. 34.
  • the present invention provides a method for preparing crystalline form XII, which includes adding compound A to an alcohol solvent (preferably an alcohol having 1 to 6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol), heating (for example, heating to 40-80 °C, preferably 55 °C or 60 °C) to Compound A is dissolved, then fumaric acid (preferably a methanol or ethanol solution of fumaric acid) is added, cooled to room temperature and stirred, filtered and optionally dried to obtain crystals, wherein the molar ratio of compound A to fumaric acid is 1:( 1-1.3), preferably about 1:1.
  • an alcohol solvent preferably an alcohol having 1 to 6 carbon atoms, including but not limited to methanol, ethanol, 1-propane Alcohol (n-propanol), 2-propanol (
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a salt of Compound A of the present invention or a crystal form thereof, and one or more pharmaceutically acceptable carriers.
  • the present invention provides the use of the salt or crystal form of Compound A of the present invention in the preparation of a medicament for preventing or treating diseases modulated by P2X3 and/or P2X2/3 receptor antagonists.
  • the present invention provides a salt or crystalline form of Compound A of the present invention, which is 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 salt of compound A of the invention or its crystal form.
  • 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 the salt of Compound A 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 A salt 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 salt of compound A 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, for example 1.5mg, 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.).
  • 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°.
  • the anode target material is copper
  • the light tube is set to (40KV 40mA)
  • the 2 ⁇ scanning angle of the sample is from 4° to 50°
  • 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.
  • Test conditions using gradient mode, the humidity range is 0% to 90%, the humidity increment of each gradient is 10%, and the holding time of each gradient is 1h
  • the compound A hydrochloride crystal form Ia and citrate crystal form III samples together with compound A free base were subjected to a solubility experiment at 37°C in FaSSIF (fasting intestinal simulant fluid). See the table below for solubility data.
  • FaSSIF fasting intestinal simulant fluid
  • the solubility of the two salt crystal forms in FaSSIF is significantly improved compared with the free base.
  • the hydrochloride crystal form Ia is increased by about 30 times, and the citrate crystal form III is increased by about 4 times.

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Abstract

本发明涉及5-((2-乙炔基-5-异丙基吡啶-4-基)氧基)嘧啶-2，4-二胺的盐及其固体形式，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的盐、其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”)的盐及其固体形式，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)的盐
Figure PCTCN2020087688-appb-000001
在另一方面中，本发明提供化合物A的盐的晶型。
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盐酸盐(摩尔比1∶1)晶型Ia的X射线粉末衍射图谱。
图2为化合物A盐酸盐(摩尔比1∶1)晶型Ia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盐酸盐(摩尔比1∶1)晶型Ia的扫描电子显微镜照片。
图4为化合物A盐酸盐(摩尔比1∶1)晶型Ib的X射线粉末衍射图谱。
图5为化合物A盐酸盐(摩尔比1∶1)晶型Ib的差示扫描量热(DSC)图谱。
图6为化合物A盐酸盐(摩尔比1∶1)晶型Ib的热重分析(TGA)图谱。
图7为化合物A盐酸盐(摩尔比1∶2)晶型II的X射线粉末衍射图谱。
图8为化合物A盐酸盐(摩尔比1∶2)晶型II的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图9为化合物A柠檬酸盐(摩尔比1∶0.5)晶型III的X射线粉末衍射图谱。
图10为化合物A柠檬酸盐(摩尔比1∶0.5)晶型III的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图11为化合物A柠檬酸盐(摩尔比1∶0.5)晶型III的扫描电子显微镜照片。
图12为化合物A硫酸盐(摩尔比1∶0.5)晶型IV的X射线粉末衍射图谱。
图13为化合物A硫酸盐(摩尔比1∶0.5)晶型IV的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图14为化合物A硫酸盐(摩尔比1∶1)晶型V的X射线粉末衍射图谱。
图15为化合物A硫酸盐(摩尔比1∶1)晶型V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对甲苯磺酸盐(摩尔比1∶1)晶型VI的X射线粉末衍射图谱。
图17为化合物A对甲苯磺酸盐(摩尔比1∶1)晶型VI的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图18为化合物A甲磺酸盐(摩尔比1∶1)晶型VII的X射线粉末衍射图谱。
图19为化合物A甲磺酸盐(摩尔比1∶1)晶型VII的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图20为化合物A甲磺酸盐(摩尔比1∶1)晶型VII的扫描电子显微镜照片。
图21为化合物A甲磺酸盐(摩尔比1∶2)晶型VIII的X射线粉末衍射图谱。
图22为化合物A甲磺酸盐(摩尔比1∶2)晶型VIII的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图23为化合物A甲磺酸盐(摩尔比1∶2)晶型VIII的扫描电子显微镜照片。
图24为化合物A磷酸盐(摩尔比1∶1)晶型IX的X射线粉末衍射图谱。
图25为化合物A磷酸盐(摩尔比1∶1)晶型IX的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图26为化合物A磷酸盐(摩尔比1∶1)晶型IX的扫描电子显微镜照片。
图27为化合物A马来酸盐(摩尔比1∶1)晶型X的X射线粉末衍射图谱。
图28为化合物A马来酸盐(摩尔比1∶1)晶型X的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图29为化合物A马来酸盐(摩尔比1∶1)晶型X的扫描电子显微镜照片。
图30为化合物A L-酒石酸盐(摩尔比1∶1)晶型XI的X射线粉末衍射图谱。
图31为化合物A L-酒石酸盐(摩尔比1∶1)晶型XI的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图32为化合物A L-酒石酸盐(摩尔比1∶1)晶型XI的扫描电子显微镜照片。
图33为化合物A富马酸盐(摩尔比1∶1)晶型XII的X射线粉末衍射图谱。
图34为化合物A富马酸盐(摩尔比1∶1)晶型XII的差示扫描量热(DSC)图谱和热重分析(TGA)图谱。
图35为高温稳定性实验前后化合物A盐酸盐(摩尔比1∶1)晶型Ia的X射线粉末衍射图谱对比。
图36为高温稳定性实验前后化合物A柠檬酸盐(摩尔比1∶0.5)晶型III的X射线粉末衍射图谱对比。
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的盐的所有固态形式，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 PCTCN2020087688-appb-000002
：1.540598和Kα2
Figure PCTCN2020087688-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 Advance 300核磁共振仪上采集，除非另外说明，以DMSO-d 6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)。
化合物A的盐、其晶型及其制备方法
在一些实施方案中，本发明提供化合物A的盐，
Figure PCTCN2020087688-appb-000004
Figure PCTCN2020087688-appb-000005
其为无机酸盐或有机酸盐，其中
所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸、硼酸、磷酸及其任意组合；
所述有机酸选自甲酸、乙酸、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、丙二酸、琥珀酸、戊二酸、己二酸、马来酸、富马酸、乳酸、L-苹果酸、柠檬酸、L-酒石酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙二磺酸、羟乙基磺酸、对甲苯磺酸、苯磺酸、1，5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸及其任意组合。
在优选的实施方案中，所述化合物A的盐选自L-酒石酸盐、磷酸盐、甲磺酸盐、马来酸盐、盐酸盐、富马酸盐、柠檬酸盐、对甲苯磺酸盐和硫酸盐。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的盐酸盐；
优选地，化合物A与盐酸的摩尔比为1∶1；
优选地，所述化合物A的盐酸盐为晶型Ia；
所述晶型Ia的XRPD图谱包括在约7.8±0.2°、10.4±0.2°、15.7±0.2°、20.0±0.2°、20.7±0.2°、22.3±0.2°和26.0±0.2°的衍射角(2θ)处的特征峰；
优选包括在约7.8±0.2°、10.4±0.2°、11.1±0.2°、15.7±0.2°、16.2±0.2°、20.0±0.2°、20.7±0.2°、22.3±0.2°、23.7±0.2°、24.7±0.2°、26.0±0.2°和28.8±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约7.8±0.2°、10.4±0.2°、11.1±0.2°、14.5±0.2°、14.7±0.2°、15.7±0.2°、16.2±0.2°、18.0±0.2°、20.0±0.2°、20.7±0.2°、22.3±0.2°、23.0±0.2°、23.7±0.2°、24.7±0.2°、25.3±0.2°、26.0±0.2°、26.4±0.2°、27.0±0.2°、28.8±0.2°、29.7±0.2°、33.9±0.2°和38.3±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Ia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 7.8° 100 17 23.5° 19.5 33 32.0° 10.9
2 10.4° 68.4 18 23.7° 31.9 34 32.3° 8.7
3 11.1° 41.5 19 24.3° 9.8 35 32.8° 7.8
4 13.1° 11.1 20 24.7° 30.3 36 33.5° 10.3
5 14.5° 18.4 21 25.3° 14.7 37 33.9° 14.3
6 14.7° 16.6 22 26.0° 96.7 38 34.5° 11.6
7 15.7° 82.7 23 26.4° 20.7 39 35.1° 7.2
8 16.2° 47.2 24 26.5° 16.4 40 36.0° 6.8
9 18.0° 12.0 25 27.0° 18.5 41 36.3° 7.6
10 18.9° 10.0 26 27.7° 6.5 42 36.6° 6.5
11 19.3° 8.0 27 28.8° 28.5 43 37.3° 8.5
12 20.0° 58.8 28 29.2° 13.6 44 37.7° 9.0
13 20.7° 51.9 29 29.7° 26.0 45 38.3° 13.9
14 22.3° 69.7 30 30.5° 11.9 46 39.3° 6.6
15 22.6° 20.4 31 30.8° 8.1      
16 23.0° 23.5 32 31.4° 8.2      
在更优选的实施方案中，所述晶型Ia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Ia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Ia的DSC图谱包括在约108℃的吸热峰以及在约190℃的放热峰。
在更优选的实施方案中，在热重分析中，所述晶型Ia在加热至约130℃时有约5.6％的失重。
在更优选的实施方案中，所述晶型Ia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Ia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Ia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Ia的方法，其包括将化合物A加入至醇类溶剂(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)或者酮类溶剂(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)中，加热(例如加热至40-80℃，优选50℃或60℃)使化合物A溶解，然后加入盐酸(盐酸浓度为2-15mol/L，优选4mol/L或12mol/L)，降至室温并搅拌，过滤并任选地干燥 得到晶体，其中化合物A和HCl的摩尔比为1∶(1-1.3)。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的盐酸盐；
优选地，化合物A与盐酸的摩尔比为1∶1；
优选地，所述化合物A的盐酸盐为晶型Ib；
所述晶型Ib的XRPD图谱包括在约5.4±0.2°、11.2±0.2°和20.0±0.2°的衍射角(2θ)处的特征峰；
优选包括在约5.4±0.2°、9.5±0.2°、11.2±0.2°、13.6±0.2°、20.0±0.2°、20.8±0.2°、24.9±0.2°和25.5±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约5.4±0.2°、9.5±0.2°、11.2±0.2°、13.6±0.2°、15.7±0.2°、17.6±0.2°、20.0±0.2°、20.8±0.2°、22.1±0.2°、23.2±0.2°、23.6±0.2°、24.1±0.2°、24.6±0.2°、24.9±0.2°、25.5±0.2°和30.5±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Ib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 5.4 100 11 20.0 20.6 21 27.3 1.6
2 9.5 11.1 12 20.8 10.0 22 27.5 1.6
3 11.2 22.7 13 22.1 4.6 23 29.5 3.7
4 12.5 2.8 14 22.6 1.6 24 30.0 1.7
5 13.6 16.1 15 23.2 3.4 25 30.5 5.4
6 14.5 1.5 16 23.6 6.6 26 31.8 1.5
7 15.7 4.1 17 24.1 6.9 27 34.2 2.0
8 16.6 1.7 18 24.6 4.1 28 34.6 1.6
9 17.6 3.3 19 24.9 10.7 29 36.7 1.1
10 19.1 3.0 20 25.5 16.3      
在更优选的实施方案中，所述晶型Ib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Ib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Ib的DSC图谱包括在约207℃的放热峰。
在更优选的实施方案中，所述晶型Ib的DSC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Ib的DSC图谱与图5所示基本上相同。
在更优选的实施方案中，在热重分析中，所述晶型Ib在加热至约167℃时有约2.6％的失重。
在更优选的实施方案中，所述晶型Ib的TGA图谱与图6所示基本上相同。
在一些实施方案中，本发明提供制备晶型Ib的方法，其包括将化合物A加入至酯类溶剂(优选具有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)中，加热(例如加热至40-80℃，优选50℃或60℃)使化合物A溶解，然后加入盐酸(盐酸浓度为2-15mol/L，优选4mol/L或12mol/L)，降至室温并搅拌，过滤并任选地干燥得到晶体，其中化合物A和HCl的摩尔比为1∶(1-1.3)。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的盐酸盐；
优选地，化合物A与盐酸的摩尔比为1∶2；
优选地，所述化合物A的盐酸盐为晶型II；
所述晶型II的XRPD图谱包括在约13.3±0.2°、14.2±0.2°、21.9±0.2°和27.4±0.2°的衍射角(2θ)处的特征峰；
优选包括在约8.2±0.2°、11.9±0.2°、13.3±0.2°、14.2±0.2°、16.0±0.2°、18.3±0.2°、19.4±0.2°、20.0±0.2°、21.2±0.2°、21.9±0.2°、22.9±0.2°、24.6±0.2°、26.6±0.2°、27.4±0.2°和28.0±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约8.2±0.2°、11.9±0.2°、13.3±0.2°、14.2±0.2°、14.8±0.2°、16.0±0.2°、17.8±0.2°、18.3±0.2°、19.4±0.2°、20.0±0.2°、21.2±0.2°、21.9±0.2°、22.6±0.2°、22.9±0.2°、23.5±0.2°、24.6±0.2°、25.6±0.2°、26.6±0.2°、27.4±0.2°、28.0±0.2°、29.7±0.2°、31.8±0.2°和34.0±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 7.2° 15.1 18 21.6° 19.2 35 29.4° 21.4
2 8.2° 32.7 19 21.9° 100 36 29.7° 23.6
3 9.1° 15.0 20 22.6° 25.5 37 30.0° 13.3
4 10.5° 16.2 21 22.9° 34.5 38 30.7° 13.1
5 11.9° 30.3 22 23.5° 29.4 39 30.9° 13.4
6 13.3° 67.9 23 23.8° 25.3 40 31.8° 28.1
7 14.2° 51.1 24 24.0° 18.9 41 32.5° 14.6
8 14.8° 18.5 25 24.6° 35.0 42 32.9° 14.4
9 15.6° 10.4 26 24.9° 14.9 43 33.4° 10.6
10 16.0° 32.3 27 25.6° 20.4 44 34.0° 23.4
11 16.6° 9.5 28 26.3° 26.3 45 34.6° 10.2
12 17.8° 15.0 29 26.6° 49.3 46 35.0° 12.2
13 18.3° 33.8 30 27.0° 33.6 47 35.7° 11.8
14 19.4° 44.8 31 27.4° 72.9 48 36.1° 11.6
15 20.0° 36.1 32 28.0° 32.4 49 37.0° 13.4
16 20.6° 14.1 33 28.4° 14.9 50 38.6° 8.8
17 21.2° 35.4 34 28.7° 12.7 51 39.5° 7.8
在更优选的实施方案中，所述晶型II的XRPD图谱包括与图7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7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40℃处的吸热峰。
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180℃时有约0.9％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8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8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加入至醇类溶剂(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，加热(例如加热至40-80℃，优选50℃或60℃)使化合物A溶解，然后加入盐酸(盐酸浓度为2-15mol/L，优选4mol/L或12mol/L)，降至室温并搅拌，过滤并任选地干燥得到晶体，其中化合物A和HCl的摩尔比为1∶(2-2.5)。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的柠檬酸盐；
优选地，化合物A与柠檬酸的摩尔比为1∶0.5；
优选地，所述化合物A的柠檬酸盐为晶型III；
所述晶型III的XRPD图谱包括在约6.9±0.2°、10.8±0.2°、14.6±0.2°、20.3±0.2°和22.5±0.2°的衍射角(2θ)处的特征峰；
优选包括在约6.9±0.2°、10.8±0.2°、14.6±0.2°、16.3±0.2°、20.3±0.2°、22.5±0.2°、23.4±0.2°和26.6±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约6.9±0.2°、10.8±0.2°、12.7±0.2°、14.6±0.2°、16.3±0.2°、17.6±0.2°、18.1±0.2°、20.3±0.2°、21.4±0.2°、22.5±0.2°、23.4±0.2°、24.2±0.2°、25.5±0.2°、26.0±0.2°、26.6±0.2°和27.1±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 6.9° 100 10 16.3° 29.2 19 25.5° 16.8
2 10.2° 13.3 11 17.6° 10.9 20 26.0° 18.9
3 10.8° 87.2 12 18.1° 15.1 21 26.6° 31.5
4 12.4° 15.0 13 18.7° 7.9 22 27.1° 12.9
5 12.7° 22.1 14 20.3° 58.0 23 30.7° 8.6
6 13.9° 11.3 15 21.4° 19.9 24 34.0° 7.3
7 14.6° 46.3 16 22.5° 48.1 25 35.1° 9.4
8 14.8° 26.1 17 23.4° 39.4 26 37.1° 8.9
9 15.1° 13.0 18 24.2° 18.1 27 38.8° 7.6
在更优选的实施方案中，所述晶型III的XRPD图谱包括与图9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9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117℃处的吸热峰。
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150℃时有约2.9％的失重。
在更优选的实施方案中，所述晶型III的DSC-TGA图谱包括与图10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-TGA图谱与图10所示基本上相同。
在更优选的实施方案中，所述晶型III的扫描电子显微镜照片与图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III的方法，其包括将化合物A加入至醇类溶剂(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，加热(例如加热至40-80℃，优选50℃或60℃)使化合物A溶解，然后加入柠檬酸(优选柠檬酸的甲醇或乙醇溶液)，降至室温并搅拌，过滤并任选地干燥得到晶体，其中化合物A和柠檬酸的摩尔比为1∶(1-1.3)。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的硫酸盐；
优选地，化合物A与硫酸的摩尔比为1∶0.5；
优选地，所述化合物A的硫酸盐为晶型IV；
所述晶型IV的XRPD图谱包括在约8.0±0.2°、11.2±0.2°、20.9±0.2°、21.8±0.2°和26.3±0.2°的衍射角(2θ)处的特征峰；
优选包括在约8.0±0.2°、10.5±0.2°、11.2±0.2°、20.9±0.2°、21.8±0.2°、22.5±0.2°、23.8±0.2°和26.3±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约8.0±0.2°、10.5±0.2°、11.2±0.2°、13.2±0.2°、15.3±0.2°、15.9±0.2°、16.8±0.2°、19.0±0.2°、20.9±0.2°、21.8±0.2°、22.5±0.2°、23.8±0.2°、24.9±0.2°、26.3±0.2°、28.3±0.2°、29.1±0.2°、30.1±0.2°和37.9±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 8.0° 85.1 10 21.8° 100 19 31.0° 8.7
2 10.5° 33.4 11 22.5° 38.7 20 31.9° 10.3
3 11.2° 65.7 12 23.5° 18.2 21 32.2° 9.4
4 13.2° 15.9 13 23.8° 37.3 22 33.9° 11.3
5 15.3° 16.9 14 24.9° 30.0 23 35.6° 6.5
6 15.9° 14.7 15 26.3° 41.2 24 37.3° 7.1
7 16.8° 13.7 16 28.3° 14.8 25 37.9° 12.0
8 19.0° 13.7 17 29.1° 14.1 26 38.7° 6.2
9 20.9° 39.9 18 30.1° 29.0      
在更优选的实施方案中，所述晶型IV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IV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IV的DSC图谱包括在约41℃处的吸热峰。
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150℃时有约2.1％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IV的DSC-TGA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IV的方法，其包括将化合物A加入至醇类溶剂(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，加热(例如加热至40-80℃，优选55℃或60℃)使化合物A溶解，然后加入硫酸(例如硫酸的甲醇或乙醇溶液)，降至室温并搅拌，过滤并任选地干燥得到晶体，其中化合物A和硫酸的摩尔比为1∶(0.4-0.6)，优选1∶0.5。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的硫酸盐；
优选地，化合物A与硫酸的摩尔比为1∶1；
优选地，所述化合物A的硫酸盐为晶型V；
所述晶型V的XRPD图谱包括在约7.9±0.2°、11.2±0.2°、20.3±0.2°、21.7±0.2°和26.3±0.2°的衍射角(2θ)处的特征峰；
优选包括在约7.9±0.2°、11.2±0.2°、20.3±0.2°、21.7±0.2°、22.5±0.2°、23.7±0.2°、24.8±0.2°和26.3±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约7.9±0.2°、10.4±0.2°、11.2±0.2°、13.1±0.2°、15.1±0.2°、15.7±0.2°、15.9±0.2°、16.6±0.2°、18.9±0.2°、20.3±0.2°、21.0±0.2°、21.7±0.2°、22.5±0.2°、23.7±0.2°、24.3±0.2°、24.8±0.2°、26.3±0.2°、28.2±0.2°、29.1±0.2°、30.1±0.2°和37.9±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 7.9° 100 11 20.3° 35.8 21 29.1° 10.6
2 10.4° 18.4 12 21.0° 14.6 22 30.1° 26.0
3 11.2° 50.6 13 21.7° 94.8 23 31.8° 8.9
4 12.7° 6.5 14 22.5° 28.1 24 32.3° 11.2
5 13.1° 10.4 15 23.3° 14.2 25 34.0° 8.7
6 15.1° 10.2 16 23.7° 22.7 26 35.5° 7.1
7 15.7° 11.0 17 24.3° 14.2 27 37.3° 5.6
8 15.9° 10.5 18 24.8° 24.3 28 37.9° 10.3
9 16.6° 15.9 19 26.3° 39.7      
10 18.9° 10.0 20 28.2° 14.7      
在更优选的实施方案中，所述晶型V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V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V的DSC图谱包括在约35℃处的吸热峰。
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150℃时有约0.8％的失重。
在更优选的实施方案中，所述晶型V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V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V的方法，其包括将化合物A加入至醇类溶剂(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，加热(例如加热至40-80℃，优选55℃或60℃)使化合物A溶解，然后加入硫酸(例如硫酸的甲醇或乙醇溶液)，降至室温并搅拌，过滤并任选地干燥得到晶体，其中化合物A和硫酸的摩尔比为1∶(1-1.3)，优选约1∶1。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的对甲苯磺酸盐；
优选地，化合物A与对甲苯磺酸的摩尔比为1∶1；
优选地，所述化合物A的对甲苯磺酸盐为晶型VI；
所述晶型VI的XRPD图谱包括在约9.2±0.2°、10.8±0.2°、18.0±0.2°和19.5±0.2°的衍射角(2θ)处的特征峰；
优选包括在约9.2±0.2°、10.8±0.2°、17.7±0.2°、18.0±0.2°、18.5±0.2°、19.5±0.2°、20.4±0.2°、21.7±0.2°、21.9±0.2°、23.6±0.2°和28.6±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约9.2±0.2°、10.8±0.2°、14.9±0.2°、15.4±0.2°、17.7±0.2°、18.0±0.2°、18.5±0.2°、19.5±0.2°、20.4±0.2°、21.2±0.2°、21.7±0.2°、21.9±0.2°、23.6±0.2°、24.5±0.2°、26.2±0.2°、28.6±0.2°、32.1±0.2°和32.7±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 5.1° 12.6 14 21.7° 35.8 27 30.8° 6.5
2 9.2° 41.7 15 21.9° 34.8 28 31.6° 6.5
3 10.8° 51.5 16 23.1° 11.0 29 32.1° 10.1
4 14.9° 25.7 17 23.6° 33.9 30 32.7° 11.0
5 15.4° 25.9 18 24.0° 14.9 31 33.3° 7.2
6 15.7° 8.8 19 24.5° 26.6 32 33.7° 6.5
7 16.3° 8.8 20 25.8° 10.0 33 34.6° 4.3
8 17.7° 34.1 21 26.2° 23.0 34 35.9° 5.4
9 18.0° 46.5 22 27.6° 10.7 35 36.6° 5.6
10 18.5° 28.5 23 28.0° 12.6 36 37.9° 6.5
11 19.5° 100 24 28.6° 45.0 37 39.0° 5.0
12 20.4° 28.2 25 29.6° 8.1 38 39.6° 6.5
13 21.2° 25.5 26 30.4° 7.2      
在更优选的实施方案中，所述晶型VI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VI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VI的DSC图谱包括在约36℃处的吸热峰。
在更优选的实施方案中，在热重分析中，所述晶型VI在加热至约180℃时有约3％的失重。
在更优选的实施方案中，所述晶型VI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VI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VI的方法，其包括将化合物A加入至酮类溶剂(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)中，加热(例如加热至40-80℃，优选50℃或60℃)使化合物A溶解，然后加入对甲苯磺酸(例如对甲苯磺酸的甲醇或乙醇溶液)得到反应物溶液，任选地将反应物溶液浓缩至干并再次加入上述酮类溶剂，将所得溶液降至室温并搅拌，过滤得到晶体，其中化合物A和对甲苯磺酸的摩尔比为1∶(1-1.3)，优选约1∶1。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的甲磺酸盐；
优选地，化合物A与甲磺酸的摩尔比为1∶1；
优选地，所述化合物A的甲磺酸盐为晶型VII；
所述晶型VII的XRPD图谱包括在约7.7±0.2°、10.5±0.2°、19.0±0.2°、20.1±0.2°和20.5±0.2°的衍射角(2θ)处的特征峰；
优选包括在约7.7±0.2°、10.5±0.2°、16.2±0.2°、16.8±0.2°、19.0±0.2°、19.9±0.2°、20.1±0.2°、20.5±0.2°、21.0±0.2°、22.6±0.2°、24.0±0.2°、25.5±0.2°和26.5±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约6.0±0.2°、7.7±0.2°、10.5±0.2°、11.0±0.2°、12.3±0.2°、13.5±0.2°、14.0±0.2°、14.3±0.2°、14.9±0.2°、15.5±0.2°、16.2±0.2°、16.8±0.2°、19.0±0.2°、19.9±0.2°、20.1±0.2°、20.5±0.2°、21.0±0.2°、21.4±0.2°、22.6±0.2°、23.2±0.2°、24.0±0.2°、24.9±0.2°、25.5±0.2°、25.8±0.2°、26.5±0.2°、27.6±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 6.0° 23.4 16 17.8° 9.6 31 25.8° 23.0
2 7.7° 51.5 17 18.2° 10.2 32 26.5° 31.7
3 10.0° 14.3 18 19.0° 62.0 33 27.6° 16.0
4 10.5° 81.9 19 19.9° 45.4 34 28.2° 11.7
5 11.0° 22.2 20 20.1° 100 35 29.1° 13.6
6 12.3° 23.0 21 20.5° 73.4 36 29.6° 18.4
7 12.6° 13.6 22 21.0° 40.7 37 30.0° 9.5
8 13.5° 18.7 23 21.4° 18.8 38 30.5° 10.6
9 14.0° 26.2 24 21.9° 10.6 39 31.9° 12.2
10 14.3° 20.3 25 22.6° 37.8 40 32.6° 7.1
11 14.9° 17.3 26 23.2° 33.0 41 33.2° 10.3
12 15.5° 21.4 27 23.4° 23.8 42 34.4° 9.6
13 15.8° 14.1 28 24.0° 33.2 43 35.2° 8.3
14 16.2° 39.6 29 24.9° 22.0 44 35.9° 6.9
15 16.8° 33.5 30 25.5° 29.2 45 37.4° 8.5
在更优选的实施方案中，所述晶型VII的XRPD图谱包括与图18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18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99℃处的吸热峰。
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150℃时有约0.9％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19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19所示基本上相同。
在更优选的实施方案中，所述晶型VII的扫描电子显微镜照片与图20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加入至醚类溶剂(例如具有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)中，加热(例如加热至40-80℃，优选50℃或60℃)使化合物A溶解，然后加入甲磺酸，降至室温并搅拌，过滤得到晶体，其中化合物A和甲磺酸的摩尔比为1∶(1-1.3)，优选约1∶1。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的甲磺酸盐；
优选地，化合物A与甲磺酸的摩尔比为1∶2；
优选地，所述化合物A的甲磺酸盐为晶型VIII；
所述晶型VIII的XRPD图谱包括在约11.0±0.2°、12.2±0.2°、13.4±0.2°、19.9±0.2°、20.2±0.2°、 21.4±0.2°和25.8±0.2°的衍射角(2θ)处的特征峰；
优选包括在约3.2±0.2°、6.0±0.2°、11.0±0.2°、12.2±0.2°、13.4±0.2°、19.9±0.2°、20.2±0.2°、21.0±0.2°、21.4±0.2°、23.0±0.2°、23.4±0.2°、24.9±0.2°和25.8±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约3.2±0.2°、6.0±0.2°、9.4±0.2°、11.0±0.2°、12.2±0.2°、13.4±0.2°、14.9±0.2°、15.5±0.2°、15.7±0.2°、17.7±0.2°、18.1±0.2°、18.9±0.2°、19.9±0.2°、20.2±0.2°、21.0±0.2°、21.4±0.2°、21.9±0.2°、22.4±0.2°、23.0±0.2°、23.4±0.2°、23.9±0.2°、24.9±0.2°、25.2±0.2°、25.8±0.2°、26.5±0.2°、27.4±0.2°、28.9±0.2°、30.8±0.2°和31.5±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 3.2° 41.4 16 20.2° 100 31 27.4° 24.0
2 6.0° 35.5 17 21.0° 61.2 32 28.3° 15.3
3 9.4° 19.6 18 21.4° 79.6 33 28.7° 24.8
4 11.0° 72.1 19 21.9° 23.9 34 28.9° 32.0
5 12.2° 84.1 20 22.4° 29.7 35 29.6° 14.8
6 13.4° 67.7 21 23.0° 62.7 36 30.2° 18.9
7 14.9° 17.8 22 23.4° 55.4 37 30.8° 23.8
8 15.5° 27.6 23 23.9° 28.5 38 31.1° 16.1
9 15.7° 28.3 24 24.3° 17.1 39 31.5° 23.4
10 17.1° 11.0 25 24.6° 22.3 40 33.1° 10.2
11 17.7° 28.8 26 24.9° 38.9 41 33.2° 9.4
12 18.1° 29.5 27 25.2° 29.7 42 34.7° 12.8
13 18.9° 14.9 28 25.8° 99.5 43 35.2° 14.1
14 19.6° 19.3 29 26.5° 19.1 44 37.9° 12.2
15 19.9° 69.8 30 27.1° 14.8      
在更优选的实施方案中，所述晶型VIII的XRPD图谱包括与图21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21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101℃处的吸热峰。
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150℃时有约7.5％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22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22所示基本上相同。
在更优选的实施方案中，所述晶型VIII的扫描电子显微镜照片与图23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加入至醚类溶剂(例如具有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)中，加热(例如加热至40-80℃，优选50℃或60℃)使化合物A溶解，然后加入甲磺酸，降至室温并搅拌，过滤得到晶体，其中化合物A和甲磺酸的摩尔比为1∶(2-2.5)。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的磷酸盐；
优选地，化合物A与磷酸的摩尔比为1∶1；
优选地，所述化合物A的磷酸盐为晶型IX；
所述晶型IX的XRPD图谱包括在约7.0±0.2°、10.7±0.2°、14.6±0.2°和26.7±0.2°的衍射角(2θ)处的特征峰；
优选包括在约7.0±0.2°、10.7±0.2°、14.6±0.2°、15.3±0.2°、18.4±0.2°、22.3±0.2°、23.4±0.2°和26.7±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约7.0±0.2°、10.7±0.2°、14.0±0.2°、14.6±0.2°、15.3±0.2°、16.2±0.2°、18.4±0.2°、20.3±0.2°、21.5±0.2°、22.3±0.2°、23.4±0.2°、24.3±0.2°、25.7±0.2°、26.7±0.2°和29.5±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IX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 7.0° 100 9 17.3° 7.1 17 25.7° 14.6
2 10.2° 8.4 10 18.4° 20.9 18 26.7° 33.9
3 10.7° 46.8 11 20.3° 18.8 19 28.2° 6.8
4 12.3° 7.3 12 21.5° 15.2 20 29.5° 9.1
5 14.0° 14.5 13 22.3° 30.7 21 30.1° 9.0
6 14.6° 47.9 14 23.4° 27.6 22 30.9° 6.6
7 15.3° 20.1 15 24.3° 18.1 23 32.6° 5.4
8 16.2° 11.5 16 24.9° 11.0 24 35.1° 6.2
在更优选的实施方案中，所述晶型IX的XRPD图谱包括与图24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IX的XRPD峰位与图24所示基本上相同。
在更优选的实施方案中，所述晶型IX的DSC图谱包括在约100℃处的吸热峰。
在更优选的实施方案中，在热重分析中，所述晶型IX在加热至约50℃时有约1.2％的失重，在约50-120℃有约4.6％的失重。
在更优选的实施方案中，所述晶型IX的DSC-TGA图谱包括与图25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IX的DSC-TGA图谱与图25所示基本上相同。
在更优选的实施方案中，所述晶型IX的扫描电子显微镜照片与图26所示基本上相同。
在一些实施方案中，本发明提供制备晶型IX的方法，其包括将化合物A加入至醇类溶剂(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，加热(例如加热至40-80℃，优选55℃或60℃)使化合物A溶解，然后加入磷酸，降至室温并搅拌，过滤得到晶体，其中化合物A和磷酸的摩尔比为1∶(1-1.3)，优选约1∶1。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的马来酸盐；
优选地，化合物A与马来酸的摩尔比为1∶1；
优选地，所述化合物A的马来酸盐为晶型X；
所述晶型X的XRPD图谱包括在约5.4±0.2°、5.8±0.2°、13.7±0.2°和17.1±0.2°的衍射角(2θ)处的特征峰；
优选包括在约5.4±0.2°、5.8±0.2°、8.9±0.2°、10.0±0.2°、13.7±0.2°、16.0±0.2°、17.1±0.2°、21.7±0.2°和21.9±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约5.4±0.2°、5.8±0.2°、8.9±0.2°、10.0±0.2°、13.7±0.2°、16.0±0.2°、17.1±0.2°、21.7±0.2°、21.9±0.2°、24.1±0.2°、25.8±0.2°和27.6±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X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 5.4° 100 12 17.9° 2.4 23 25.1° 3.7
2 5.8° 13.5 13 18.6° 4.5 24 25.8° 8.8
3 8.5° 2.6 14 19.2° 4.2 25 26.7° 4.2
4 8.9° 11.3 15 19.8° 6.5 26 27.6° 9.3
5 10.0° 13.0 16 20.7° 3.5 27 28.9° 2.0
6 10.8° 3.4 17 21.7° 13.5 28 31.7° 3.3
7 13.7° 19.3 18 21.9° 14.0 29 33.9° 2.4
8 14.3° 3.3 19 22.2° 5.9 30 34.8° 1.5
9 15.0° 2.7 20 22.7° 4.2 31 35.8° 1.6
10 16.0° 10.2 21 23.4° 4.3 32 38.8° 1.6
11 17.1° 13.5 22 24.1° 7.3      
在更优选的实施方案中，所述晶型X的XRPD图谱包括与图27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X的XRPD峰位与图27所示基本上相同。
在更优选的实施方案中，所述晶型X的DSC图谱包括在约29℃处的吸热峰。
在更优选的实施方案中，在热重分析中，所述晶型X在加热至约100℃时有约1％的失重。
在更优选的实施方案中，所述晶型X的DSC-TGA图谱包括与图28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X的DSC-TGA图谱与图28所示基本上相同。
在更优选的实施方案中，所述晶型X的扫描电子显微镜照片与图29所示基本上相同。
在一些实施方案中，本发明提供制备晶型X的方法，其包括将化合物A加入至醇类溶剂(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，加热(例如加热至40-80℃，优选55℃或60℃)使化合物A溶解，然后加入马来酸(优选马来酸的甲醇或乙醇溶液)，降至室温并搅拌，过滤并任选地干燥得到晶体，其中化合物A和马来酸的摩尔比为1∶(1-1.3)，优选约1∶1。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的L-酒石酸盐；
优选地，化合物A与L-酒石酸的摩尔比为1∶1；
优选地，所述化合物A的L-酒石酸盐为晶型XI；
所述晶型XI的XRPD图谱包括在约6.5±0.2°、14.3±0.2°、20.8±0.2°、21.5±0.2°和25.2±0.2°的衍射角(2θ)处的特征峰；
优选包括在约6.5±0.2°、10.9±0.2°、12.6±0.2°、14.3±0.2°、16.1±0.2°、17.3±0.2°、18.0±0.2°、20.8±0.2°、21.5±0.2°、22.5±0.2°和25.2±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约6.5±0.2°、10.3±0.2°、10.9±0.2°、12.6±0.2°、14.3±0.2°、15.2±0.2°、16.1±0.2°、17.3±0.2°、18.0±0.2°、19.4±0.2°、20.8±0.2°、21.5±0.2°、22.0±0.2°、22.5±0.2°、23.4±0.2°、23.8±0.2°、24.2±0.2°、24.8±0.2°、25.2±0.2°、25.8±0.2°、26.7±0.2°、27.8±0.2°、28.8±0.2°、30.1±0.2°、31.4±0.2°、33.8±0.2°和35.2±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XI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 6.5° 76.8 15 22.5° 27.1 29 31.4° 13.0
2 10.3° 12.3 16 23.4° 21.4 30 31.9° 8.1
3 10.9° 31.4 17 23.8° 12.6 31 32.5° 9.5
4 12.6° 27.4 18 24.2° 18.6 32 32.9° 7.2
5 14.3° 45.0 19 24.5° 15.7 33 33.8° 17.1
6 14.9° 10.1 20 24.8° 20.9 34 34.7° 6.8
7 15.2° 14.9 21 25.2° 40.4 35 35.2° 9.6
8 16.1° 25.3 22 25.8° 10.3 36 35.9° 7.7
9 17.3° 30.1 23 26.7° 11.3 37 36.2° 5.3
10 18.0° 36.9 24 27.2° 7.0 38 36.8° 5.1
11 19.4° 19.7 25 27.8° 12.6 39 37.8° 7.0
12 20.8° 43.1 26 28.8° 11.9 40 38.2° 7.0
13 21.5° 100 27 29.3° 9.5 41 39.3° 8.9
14 22.0° 18.8 28 30.1° 12.0      
在更优选的实施方案中，所述晶型XI的XRPD图谱包括与图30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XI的XRPD峰位与图30所示基本上相同。
在更优选的实施方案中，所述晶型XI的DSC图谱不包含吸热峰。
在更优选的实施方案中，在热重分析中，所述晶型XI在加热至约170℃时有约0.7％的失重。
在更优选的实施方案中，所述晶型XI的DSC-TGA图谱与图31所示基本上相同。
在更优选的实施方案中，所述晶型XI的扫描电子显微镜照片与图32所示基本上相同。
在一些实施方案中，本发明提供制备晶型XI的方法，其包括将化合物A加入至醇类溶剂(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，加热(例如加热至40-80℃，优选55℃或60℃)使化合物A溶解，然后加入L-酒石酸(优选L-酒石酸的甲醇或乙醇溶液)，降至室温并搅拌，过滤并任选地干燥得到晶体，其中化合物A和L-酒石酸的摩尔比为1∶(1-1.3)，优选约1∶1。
在优选的实施方案中，本发明提供化合物A的盐，其为化合物A的富马酸盐；
优选地，化合物A与富马酸的摩尔比为1∶1；
优选地，所述化合物A的富马酸盐为晶型XII；
所述晶型XII的XRPD图谱包括在约7.2±0.2°、10.9±0.2°、20.9±0.2°和27.5±0.2°的衍射角(2θ)处的特征峰；
优选包括在约7.2±0.2°、10.3±0.2°、10.9±0.2°、15.0±0.2°、20.9±0.2°、21.6±0.2°、24.2±0.2°和27.5±0.2°的衍射角(2θ)处的特征峰；
最优选包括在约7.2±0.2°、7.8±0.2°、10.3±0.2°、10.9±0.2°、13.0±0.2°、14.5±0.2°、15.0±0.2°、17.6±0.2°、20.9±0.2°、21.6±0.2°、22.9±0.2°、24.2±0.2°、25.9±0.2°、27.5±0.2°和31.0±0.2°的衍射角(2θ)处的特征峰。
在更优选的实施方案中，所述晶型XII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 I％
1 7.2° 100 7 15.0° 55.4 13 22.9° 44.3
2 7.8° 38.2 8 17.6° 22.8 14 24.2° 71.4
3 10.3° 51.0 9 20.3° 51.6 15 25.9° 36.1
4 10.9° 90.2 10 20.9° 93.6 16 27.5° 86.3
5 13.0° 48.2 11 21.6° 55.8 17 31.0° 20.5
6 14.5° 31.9 12 22.7° 40.6      
在更优选的实施方案中，所述晶型XII的XRPD图谱包括与图33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XII的XRPD峰位与图33所示基本上相同。
在更优选的实施方案中，所述晶型XII的DSC图谱包括在约102℃处的吸热峰。
在更优选的实施方案中，在热重分析中，所述晶型XII在加热至约60℃时有约1.1％的失重，在约60-150℃有约4.1％的失重。
在更优选的实施方案中，所述晶型XII的DSC-TGA图谱包括与图34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XII的DSC-TGA图谱与图34所示基本上相同。
在一些实施方案中，本发明提供制备晶型XII的方法，其包括将化合物A加入至醇类溶剂(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，加热(例如加热至40-80℃，优选55℃或60℃)使化合物A溶解，然后加入富马酸(优选富马酸的甲醇或乙醇溶液)，降至室温并搅拌，过滤并任选地干燥得到晶体，其中化合物A和富马酸的摩尔比为1∶(1-1.3)，优选约1∶1。
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，其包含本发明的化合物A的盐或其晶型，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化合物A的盐或其晶型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化合物A的盐或其晶型，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化合物A的盐或其晶型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、良性前列腺肥大、前列腺炎、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、前列腺痛、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；心血管系统疾病，所述心血管系统疾病优选为高血压；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A的盐的量。
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A的盐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A的盐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)。
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)
(a)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°。
(b)仪器型号：Bruker D2 phaser
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4°到50°，扫描步长为0.02°。
(2)差示扫描量热分析(DSC)
仪器型号：(a)TA Discovery DSC 250(TA Instruments，US)；(b)TA Discovery DSC 25(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：(a)Discovery TGA 55(TA Instruments，US)；(b)TGA 4000(PerkinElmer，Germany)
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)
(5)核磁共振( 1H NMR)
仪器型号：Bruker Advance 300，配备有B-ACS 120自动进样系统
(6)动态水分吸脱附分析(DVS)
仪器型号：DVS Intrinsic(SMS，UK)
测试条件：采用梯度模式，湿度范围为0％至90％，各梯度的湿度增量为10％，各梯度的保持 时间为1h
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 PCTCN2020087688-appb-000006
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 x3)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(20mLx3)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盐酸盐(摩尔比1∶1)晶型Ia的制备(方法一)
将5.0g化合物A加入到100mL无水乙醇中，加热至60℃，并在此温度下搅拌至固体完全溶解。缓慢滴加1.6mL浓盐酸，将反应液缓慢降至室温后继续搅拌1h。过滤收集固体，在40℃下真空干燥过夜，得到晶体。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；将样品在扫描电子显微镜下观察，晶体形貌如图3所示。
1H NMR(300MHz，DMSO-d 6)δ：1.29(d，6H)，3.33(m，1H)，4.29(s，1H)，7.17(s，1H)，7.71(br d，2H)，7.96(s，1H)，8.10(br d，1H)，8.42(s，2H)，12.35(br d，1H).
实施例3：化合物A盐酸盐(摩尔比1∶1)晶型Ia的制备(方法二)
将1.0g化合物A加入到100mL丙酮中，加热至50℃，并在此温度下搅拌30min。缓慢滴加0.93mL 4N盐酸，将反应液缓慢降至室温后继续搅拌过夜。过滤收集固体，在50℃下真空干燥过夜，得到晶体。经X-射线粉末衍射检测，其XRPD图谱与图1相同。
1H NMR(300MHz，DMSO-d 6)δ：1.29(d，6H)，3.33(m，1H)，4.29(s，1H)，7.17(s，1H)，7.71(br d，2H)，7.96(s，1H)，8.10(br d，1H)，8.42(s，2H)，12.35(br d，1H).
实施例4：化合物A盐酸盐(摩尔比1∶1)晶型Ib的制备
将1.0g化合物A加入到200mL乙酸乙酯中，加热至50℃，并在此温度下搅拌30min。缓慢滴加0.93mL 4N盐酸，将反应液缓慢降至室温后继续搅拌过夜。过滤收集固体，在50℃下真空干燥过夜，得到晶体。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图谱和TGA图谱分别如图5和图6所示。
1H NMR(300MHz，DMSO-d 6)δ：1.29(d，6H)，3.33(m，1H)，4.29(s，1H)，7.17(s，1H)，7.71(br d，2H)，7.96(s，1H)，8.10(br d，1H)，8.42(s，2H)，12.35(br d，1H).
实施例5：化合物A盐酸盐(摩尔比1∶2)晶型II的制备
将5.0g化合物A加入到100mL无水乙醇中，加热至60℃，并在此温度下搅拌至固体完全溶解，缓慢滴加3.2mL浓盐酸，将反应液缓慢降至室温后继续搅拌1h。过滤收集固体，在40℃下真空干燥过夜，得到晶体。经X-射线粉末衍射检测，其XRPD图谱如图7所示；经DSC和TGA分析，其DSC和TGA图谱如图8所示。
1H NMR(300MHz，DMSO-d 6)δ：1.30(d，6H)，3.41(m，1H)，4.67(s，1H)，7.46(s，1H)，7.83(br d，2H)，8.06(d，2H)，8.52(d，2H)，12.57(br d，1H).
实施例6：化合物A柠檬酸盐(摩尔比1∶0.5)晶型III的制备
将5.0g化合物A加入到280mL无水乙醇中，加热至60℃，并在此温度下搅拌至固体完全溶解。缓慢滴加37.2mL 0.5M柠檬酸甲醇溶液，将反应液缓慢降至室温后继续搅拌1.5h。过滤收集固体，在50℃下真空干燥过夜，得到晶体。经X-射线粉末衍射检测，其XRPD图谱如图9所示；经DSC和TGA分析，其DSC和TGA图谱如图10所示；样品在扫描电子显微镜下观察，晶体形貌如图11所示。
1H NMR(300MHz，DMSO-d 6)δ：1.30(d，6H)，2.64(dd，2H)，3.35(m，1H)，4.24(s，1H)，6.33(s，2H)，6.64(s，1H)，6.76(br d，2H)，7.65(s，1H)，8.38(s，1H)，10.93(br d，2H).
实施例7：化合物A硫酸盐(摩尔比1∶0.5)晶型IV的制备
将5.0g化合物A加入到280mL无水乙醇中，加热至55℃，并在此温度下搅拌至固体完全溶解。缓慢滴加5.2mL 1.8M硫酸乙醇溶液，将反应液缓慢降至室温后继续搅拌6.5h。过滤收集固体，在50℃下真空干燥过夜，得到晶体。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。
1H NMR(300MHz，DMSO-d 6)δ：1.31(d，6H)，3.38(m，1H)，4.30(s，1H)，7.06(s，1H)，7.31(s，2H)，7.88(s，3H)，8.44(s，1H)，10.79(br d，1H).
实施例8：化合物A硫酸盐(摩尔比1∶1)晶型V的制备
将5.0g化合物A加入到280mL无水乙醇中，加热至55℃，并在此温度下搅拌至固体完全溶解，缓慢滴加10.5mL 1.8M硫酸乙醇溶液，将反应液缓慢降至室温后继续搅拌6.5h。过滤收集固体，在50℃下真空干燥过夜，得到晶体。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。
1H NMR(300MHz，DMSO-d 6)δ：1.31(d，6H)，3.34(m，1H)，4.32(s，1H)，7.20(s，1H)，7.64(s，2H)，7.95(s，1H)，8.10(s，1H)，8.44(s，1H)，8.49(s，1H)，11.99(br d，1H).
实施例9：化合物A对甲苯磺酸盐(摩尔比1∶1)晶型VI的制备
将5.0g化合物A加入到290mL丙酮中，加热至50℃，并在此温度下搅拌1h，缓慢滴加37.2mL 0.5M对甲苯磺酸甲醇溶液，将反应液减压浓缩至干后加入95mL丙酮，室温下继续搅拌48h。过滤收集固体，得到晶体。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。
1H NMR(300MHz，DMSO-d 6)δ：1.30(d，6H)，2.29(s，3H)，3.33(m，1H)，4.31(s，1H)，7.12(d，2H)，7.18(s，1H)，7.47(d，2H)，7.63(br d，2H)，7.94(s，1H)，8.09(br d，1H)，8.43(s，1H)，8.49(br d，1H)，11.97(br d，1H).
实施例10：化合物A甲磺酸盐(摩尔比1∶1)晶型VII的制备
将5.0g化合物A加入到190mL四氢呋喃中，加热至50℃，并在此温度下搅拌1h，缓慢滴加1.2mL甲磺酸，将反应液缓慢降至室温后继续搅拌过夜。过滤收集固体，得到晶体。经X-射线粉末衍射检测，其XRPD图谱如图18所示；经DSC和TGA分析，其DSC和TGA图谱如图19所示；样品在扫描电子显微镜下观察，晶体形貌如图20所示。
1H NMR(300MHz，DMSO-d 6)δ：1.32(d，6H)，2.38(s，3H)，3.35(m，1H)，4.39(s，1H)，7.26(s，1H)，7.70(br d，2H)，7.98(s，1H)，8.10(s，1H)，8.49(d，2H)，12.10(br d，1H).
实施例11：化合物A甲磺酸盐(摩尔比1∶2)晶型VIII的制备
将5.0g化合物A加入到190mL四氢呋喃中，加热至50℃，并在此温度下搅拌1h，缓慢滴加2.4mL甲磺酸，将反应液缓慢降至室温后继续搅拌过夜。过滤收集固体，得到晶体。经X-射线粉末衍射检测，其XRPD图谱如图21所示；经DSC和TGA分析，其DSC和TGA图谱如图22所示；样品在扫描电子显微镜下观察，晶体形貌如图23所示。
1H NMR(300MHz，DMSO-d 6)δ：1.32(d，6H)，2.38(s，6H)，3.38(m，1H)，4.54(s，1H)，7.37(s，1H)，7.70(br d，2H)，8.00(s，1H)，8.11(s，1H)，8.51(d，2H)，12.08(br d，1H).
实施例12：化合物A磷酸盐(摩尔比1∶1)晶型IX的制备
将5.0g化合物A加入到150mL无水乙醇中，加热至55℃，并在此温度下搅拌1h，缓慢滴加1.3mL 85％磷酸(14.5mol/L)，将反应液缓慢降至室温后继续搅拌2h。过滤收集固体，在40℃下真空干燥过夜，得到晶体。经X-射线粉末衍射检测，其XRPD图谱如图24所示；经DSC和TGA分析，其DSC和TGA图谱如图25所示；样品在扫描电子显微镜下观察，晶体形貌如图26所示。
1H NMR(300MHz，DMSO-d 6)δ：1.30(d，6H)，3.35(m，1H)，4.23(s，1H)，6.25(s，2H)，6.60(s，1H)，6.63(s，2H)，7.62(s，1H)，8.38(s，1H).
实施例13：化合物A马来酸盐(摩尔比1∶1)晶型X的制备
将5.0g化合物A加入到185mL无水乙醇中，加热至60℃，并在此温度下搅拌1h，缓慢滴加18.6mL 1M马来酸乙醇溶液，将反应液缓慢降至室温后继续搅拌2h。过滤收集固体，在40℃下真空干燥过夜，得到晶体。经X-射线粉末衍射检测，其XRPD图谱如图27所示；经DSC和TGA分析，其DSC和TGA图谱如图28所示；样品在扫描电子显微镜下观察，晶体形貌如图29所示。
1H NMR(300MHz，DMSO-d 6)δ：1.30(d，6H)，3.33(m，1H)，4.28(s，1H)，6.07(s，2H)，7.06(s，1H)，7.34(br d，2H)，7.87(s，1H)，7.95(br d，2H)，8.42(s，1H).
实施例14：化合物A L-酒石酸盐(摩尔比1∶1)晶型XI的制备
将5.0g化合物A加入到190mL无水乙醇中，加热至60℃，并在此温度下搅拌1h，缓慢滴加37.2mL 0.5M L-酒石酸甲醇溶液，将反应液缓慢降至室温后继续搅拌2h。过滤收集固体，在40℃下真空干燥过夜，得到晶体。经X-射线粉末衍射检测，其XRPD图谱如图30所示；经DSC和TGA分析，其DSC和TGA图谱如图31所示；样品在扫描电子显微镜下观察，晶体形貌如图32所示。
1H NMR(300MHz，DMSO-d 6)δ：1.32(d，6H)，3.36(m，1H)，4.25(s，1H)，4.28(d，2H)，6.21(s，2H)，6.61(s，3H)，7.64(s，1H)，8.40(s，1H).
实施例15：化合物A富马酸盐(摩尔比1∶1)晶型XII的制备
将5.0g化合物A加入到190mL无水乙醇中，加热至60℃，并在此温度下搅拌1h，缓慢滴加74.4mL 0.25M富马酸甲醇溶液，将反应液缓慢降至室温后继续搅拌2h。过滤收集固体，在40℃下真空干燥过夜，得到晶体。经X-射线粉末衍射检测，其XRPD图谱如图33所示；经DSC和TGA分析，其DSC和TGA图谱如图34所示。
1H NMR(300MHz，DMSO-d 6)δ：1.32(d，6H)，3.38(m，1H)，4.24(s，1H)，6.15(d，2H)，6.53(s，2H)，6.58(s，1H)，6.64(s，2H)，7.63(s，1H)，8.39(s，1H).
实验例
实验例1：引湿性实验
使用动态水分吸附分析法(DVS)对化合物A盐酸盐晶型Ia、柠檬酸盐晶型III和马来酸盐晶型X样品的引湿性进行研究，并对DVS测定前后的样品进行XRPD检测和谱图比较。盐酸盐晶型Ia样品在90％RH时的吸湿量为1.21％，DVS测定前后样品的XRPD图谱没有发生变化。柠檬酸盐晶型III样品在80％RH的吸湿量为1.69％，DVS测定前后样品的XRPD图谱没有发生变化。马来酸盐晶型X样品在90％RH时的吸湿量为3.69％，DVS测定前后样品的XRPD图谱没有发生变化。
实验例2：高温稳定性实验
将化合物A盐酸盐晶型Ia和柠檬酸盐晶型III样品在40℃/75％RH和60℃两个条件下进行稳定性考察2周。在实验进行1周和2周后用Bruker D8 advance X射线粉末衍射仪测定XRPD图谱(见图35和图36)，结果显示两种盐晶型在稳定性考察过程中晶型均无变化，稳定性优异。
实验例3：溶解性实验
将化合物A盐酸盐晶型Ia和柠檬酸盐晶型III样品与化合物A游离碱一起进行在FaSSIF(空腹肠模拟液)中37℃下的溶解性实验。溶解性数据见下表。两盐晶型在FaSSIF中的溶解性较游离碱均明显提高，其中盐酸盐晶型Ia提高约30倍，柠檬酸盐晶型III提高约4倍。
Figure PCTCN2020087688-appb-000007
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 (17)

  1. 化合物A的盐，
    Figure PCTCN2020087688-appb-100001
    其为无机酸盐或有机酸盐，其中
    所述无机酸选自盐酸、氢溴酸、氢碘酸、硫酸、硝酸、硼酸、磷酸及其任意组合；
    所述有机酸选自甲酸、乙酸、乙酰乙酸、三氟乙酸、丙酸、丙酮酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、硬脂酸、棕榈酸、草酸、丙二酸、琥珀酸、戊二酸、己二酸、马来酸、富马酸、乳酸、L-苹果酸、柠檬酸、L-酒石酸、苯甲酸、水杨酸、肉桂酸、萘甲酸、扑酸、烟酸、乳清酸、甲基硫酸、十二烷基硫酸、甲磺酸、三氟甲磺酸、乙二磺酸、羟乙基磺酸、对甲苯磺酸、苯磺酸、1，5-萘二磺酸、2-萘磺酸、樟脑磺酸、氨基磺酸、谷氨酸、天冬氨酸、葡糖酸、葡糖醛酸及其任意组合。
  2. 权利要求1的化合物A的盐，其中所述盐选自L-酒石酸盐、磷酸盐、甲磺酸盐、马来酸盐、盐酸盐、富马酸盐、柠檬酸盐、对甲苯磺酸盐和硫酸盐。
  3. 权利要求1的化合物A的盐，其为化合物A的盐酸盐；
    优选地，化合物A与盐酸的摩尔比为1∶1；
    优选地，所述化合物A的盐酸盐为晶型Ia；
    所述晶型Ia的XRPD图谱包括在约7.8±0.2°、10.4±0.2°、15.7±0.2°、20.0±0.2°、20.7±0.2°、22.3±0.2°和26.0±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约7.8±0.2°、10.4±0.2°、11.1±0.2°、15.7±0.2°、16.2±0.2°、20.0±0.2°、20.7±0.2°、22.3±0.2°、23.7±0.2°、24.7±0.2°、26.0±0.2°和28.8±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约7.8±0.2°、10.4±0.2°、11.1±0.2°、14.5±0.2°、14.7±0.2°、15.7±0.2°、16.2±0.2°、18.0±0.2°、20.0±0.2°、20.7±0.2°、22.3±0.2°、23.0±0.2°、23.7±0.2°、24.7±0.2°、25.3±0.2°、26.0±0.2°、26.4±0.2°、27.0±0.2°、28.8±0.2°、29.7±0.2°、33.9±0.2°和38.3±0.2°的衍射角(2θ)处的特征峰。
  4. 权利要求1的化合物A的盐，其为化合物A的盐酸盐；
    优选地，化合物A与盐酸的摩尔比为1∶1；
    优选地，所述化合物A的盐酸盐为晶型Ib；
    所述晶型Ib的XRPD图谱包括在约5.4±0.2°、11.2±0.2°和20.0±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约5.4±0.2°、9.5±0.2°、11.2±0.2°、13.6±0.2°、20.0±0.2°、20.8±0.2°、24.9±0.2°和25.5±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约5.4±0.2°、9.5±0.2°、11.2±0.2°、13.6±0.2°、15.7±0.2°、17.6±0.2°、20.0±0.2°、20.8±0.2°、22.1±0.2°、23.2±0.2°、23.6±0.2°、24.1±0.2°、24.6±0.2°、24.9±0.2°、25.5±0.2°和30.5±0.2°的衍射角(2θ)处的特征峰。
  5. 权利要求1的化合物A的盐，其为化合物A的盐酸盐；
    优选地，化合物A与盐酸的摩尔比为1∶2；
    优选地，所述化合物A的盐酸盐为晶型II；
    所述晶型II的XRPD图谱包括在约13.3±0.2°、14.2±0.2°、21.9±0.2°和27.4±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约8.2±0.2°、11.9±0.2°、13.3±0.2°、14.2±0.2°、16.0±0.2°、18.3±0.2°、19.4±0.2°、20.0±0.2°、21.2±0.2°、21.9±0.2°、22.9±0.2°、24.6±0.2°、26.6±0.2°、27.4±0.2°和28.0±0.2°的衍射角 (2θ)处的特征峰；
    最优选包括在约8.2±0.2°、11.9±0.2°、13.3±0.2°、14.2±0.2°、14.8±0.2°、16.0±0.2°、17.8±0.2°、18.3±0.2°、19.4±0.2°、20.0±0.2°、21.2±0.2°、21.9±0.2°、22.6±0.2°、22.9±0.2°、23.5±0.2°、24.6±0.2°、25.6±0.2°、26.6±0.2°、27.4±0.2°、28.0±0.2°、29.7±0.2°、31.8±0.2°和34.0±0.2°的衍射角(2θ)处的特征峰。
  6. 权利要求1的化合物A的盐，其为化合物A的柠檬酸盐；
    优选地，化合物A与柠檬酸的摩尔比为1∶0.5；
    优选地，所述化合物A的柠檬酸盐为晶型III；
    所述晶型III的XRPD图谱包括在约6.9±0.2°、10.8±0.2°、14.6±0.2°、20.3±0.2°和22.5±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约6.9±0.2°、10.8±0.2°、14.6±0.2°、16.3±0.2°、20.3±0.2°、22.5±0.2°、23.4±0.2°和26.6±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约6.9±0.2°、10.8±0.2°、12.7±0.2°、14.6±0.2°、16.3±0.2°、17.6±0.2°、18.1±0.2°、20.3±0.2°、21.4±0.2°、22.5±0.2°、23.4±0.2°、24.2±0.2°、25.5±0.2°、26.0±0.2°、26.6±0.2°和27.1±0.2°的衍射角(2θ)处的特征峰。
  7. 权利要求1的化合物A的盐，其为化合物A的硫酸盐；
    优选地，化合物A与硫酸的摩尔比为1∶0.5；
    优选地，所述化合物A的硫酸盐为晶型IV；
    所述晶型IV的XRPD图谱包括在约8.0±0.2°、11.2±0.2°、20.9±0.2°、21.8±0.2°和26.3±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约8.0±0.2°、10.5±0.2°、11.2±0.2°、20.9±0.2°、21.8±0.2°、22.5±0.2°、23.8±0.2°和26.3±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约8.0±0.2°、10.5±0.2°、11.2±0.2°、13.2±0.2°、15.3±0.2°、15.9±0.2°、16.8±0.2°、19.0±0.2°、20.9±0.2°、21.8±0.2°、22.5±0.2°、23.8±0.2°、24.9±0.2°、26.3±0.2°、28.3±0.2°、29.1±0.2°、30.1±0.2°和37.9±0.2°的衍射角(2θ)处的特征峰。
  8. 权利要求1的化合物A的盐，其为化合物A的硫酸盐；
    优选地，化合物A与硫酸的摩尔比为1∶1；
    优选地，所述化合物A的硫酸盐为晶型V；
    所述晶型V的XRPD图谱包括在约7.9±0.2°、11.2±0.2°、20.3±0.2°、21.7±0.2°和26.3±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约7.9±0.2°、11.2±0.2°、20.3±0.2°、21.7±0.2°、22.5±0.2°、23.7±0.2°、24.8±0.2°和26.3±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约7.9±0.2°、10.4±0.2°、11.2±0.2°、13.1±0.2°、15.1±0.2°、15.7±0.2°、15.9±0.2°、16.6±0.2°、18.9±0.2°、20.3±0.2°、21.0±0.2°、21.7±0.2°、22.5±0.2°、23.7±0.2°、24.3±0.2°、24.8±0.2°、26.3±0.2°、28.2±0.2°、29.1±0.2°、30.1±0.2°和37.9±0.2°的衍射角(2θ)处的特征峰。
  9. 权利要求1的化合物A的盐，其为化合物A的对甲苯磺酸盐；
    优选地，化合物A与对甲苯磺酸的摩尔比为1∶1；
    优选地，所述化合物A的对甲苯磺酸盐为晶型VI；
    所述晶型VI的XRPD图谱包括在约9.2±0.2°、10.8±0.2°、18.0±0.2°和19.5±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约9.2±0.2°、10.8±0.2°、17.7±0.2°、18.0±0.2°、18.5±0.2°、19.5±0.2°、20.4±0.2°、21.7±0.2°、21.9±0.2°、23.6±0.2°和28.6±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约9.2±0.2°、10.8±0.2°、14.9±0.2°、15.4±0.2°、17.7±0.2°、18.0±0.2°、18.5±0.2°、 19.5±0.2°、20.4±0.2°、21.2±0.2°、21./±0.2°、21.9±0.2°、23.6±0.2°、24.5±0.2°、26.2±0.2°、28.6±0.2°、32.1±0.2°和32.7±0.2°的衍射角(2θ)处的特征峰。
  10. 权利要求1的化合物A的盐，其为化合物A的甲磺酸盐；
    优选地，化合物A与甲磺酸的摩尔比为1∶1；
    优选地，所述化合物A的甲磺酸盐为晶型VII；
    所述晶型VII的XRPD图谱包括在约7.7±0.2°、10.5±0.2°、19.0±0.2°、20.1±0.2°和20.5±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约7.7±0.2°、10.5±0.2°、16.2±0.2°、16.8±0.2°、19.0±0.2°、19.9±0.2°、20.1±0.2°、20.5±0.2°、21.0±0.2°、22.6±0.2°、24.0±0.2°、25.5±0.2°和26.5±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约6.0±0.2°、7.7±0.2°、10.5±0.2°、11.0±0.2°、12.3±0.2°、13.5±0.2°、14.0±0.2°、14.3±0.2°、14.9±0.2°、15.5±0.2°、16.2±0.2°、16.8±0.2°、19.0±0.2°、19.9±0.2°、20.1±0.2°、20.5±0.2°、21.0±0.2°、21.4±0.2°、22.6±0.2°、23.2±0.2°、24.0±0.2°、24.9±0.2°、25.5±0.2°、25.8±0.2°、26.5±0.2°、27.6±0.2°和29.6±0.2°的衍射角(2θ)处的特征峰。
  11. 权利要求1的化合物A的盐，其为化合物A的甲磺酸盐；
    优选地，化合物A与甲磺酸的摩尔比为1∶2；
    优选地，所述化合物A的甲磺酸盐为晶型VIII；
    所述晶型VIII的XRPD图谱包括在约11.0±0.2°、12.2±0.2°、13.4±0.2°、19.9±0.2°、20.2±0.2°、21.4±0.2°和25.8±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约3.2±0.2°、6.0±0.2°、11.0±0.2°、12.2±0.2°、13.4±0.2°、19.9±0.2°、20.2±0.2°、21.0±0.2°、21.4±0.2°、23.0±0.2°、23.4±0.2°、24.9±0.2°和25.8±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约3.2±0.2°、6.0±0.2°、9.4±0.2°、11.0±0.2°、12.2±0.2°、13.4±0.2°、14.9±0.2°、15.5±0.2°、15.7±0.2°、17.7±0.2°、18.1±0.2°、18.9±0.2°、19.9±0.2°、20.2±0.2°、21.0±0.2°、21.4±0.2°、21.9±0.2°、22.4±0.2°、23.0±0.2°、23.4±0.2°、23.9±0.2°、24.9±0.2°、25.2±0.2°、25.8±0.2°、26.5±0.2°、27.4±0.2°、28.9±0.2°、30.8±0.2°和31.5±0.2°的衍射角(2θ)处的特征峰。
  12. 权利要求1的化合物A的盐，其为化合物A的磷酸盐；
    优选地，化合物A与磷酸的摩尔比为1∶1；
    优选地，所述化合物A的磷酸盐为晶型IX；
    所述晶型IX的XRPD图谱包括在约7.0±0.2°、10.7±0.2°、14.6±0.2°和26.7±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约7.0±0.2°、10.7±0.2°、14.6±0.2°、15.3±0.2°、18.4±0.2°、22.3±0.2°、23.4±0.2°和26.7±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约7.0±0.2°、10.7±0.2°、14.0±0.2°、14.6±0.2°、15.3±0.2°、16.2±0.2°、18.4±0.2°、20.3±0.2°、21.5±0.2°、22.3±0.2°、23.4±0.2°、24.3±0.2°、25.7±0.2°、26.7±0.2°和29.5±0.2°的衍射角(2θ)处的特征峰。
  13. 权利要求1的化合物A的盐，其为化合物A的马来酸盐；
    优选地，化合物A与马来酸的摩尔比为1∶1；
    优选地，所述化合物A的马来酸盐为晶型X；
    所述晶型X的XRPD图谱包括在约5.4±0.2°、5.8±0.2°、13.7±0.2°和17.1±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约5.4±0.2°、5.8±0.2°、8.9±0.2°、10.0±0.2°、13.7±0.2°、16.0±0.2°、17.1±0.2°、21.7±0.2°和21.9±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约5.4±0.2°、5.8±0.2°、8.9±0.2°、10.0±0.2°、13.7±0.2°、16.0±0.2°、17.1±0.2°、21.7±0.2°、21.9±0.2°、24.1±0.2°、25.8±0.2°和27.6±0.2°的衍射角(2θ)处的特征峰。
  14. 权利要求1的化合物A的盐，其为化合物A的L-酒石酸盐；
    优选地，化合物A与L-酒石酸的摩尔比为1∶1；
    优选地，所述化合物A的L-酒石酸盐为晶型XI；
    所述晶型XI的XRPD图谱包括在约6.5±0.2°、14.3±0.2°、20.8±0.2°、21.5±0.2°和25.2±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约6.5±0.2°、10.9±0.2°、12.6±0.2°、14.3±0.2°、16.1±0.2°、17.3±0.2°、18.0±0.2°、20.8±0.2°、21.5±0.2°、22.5±0.2°和25.2±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约6.5±0.2°、10.3±0.2°、10.9±0.2°、12.6±0.2°、14.3±0.2°、15.2±0.2°、16.1±0.2°、17.3±0.2°、18.0±0.2°、19.4±0.2°、20.8±0.2°、21.5±0.2°、22.0±0.2°、22.5±0.2°、23.4±0.2°、23.8±0.2°、24.2±0.2°、24.8±0.2°、25.2±0.2°、25.8±0.2°、26.7±0.2°、27.8±0.2°、28.8±0.2°、30.1±0.2°、31.4±0.2°、33.8±0.2°和35.2±0.2°的衍射角(2θ)处的特征峰。
  15. 权利要求1的化合物A的盐，其为化合物A的富马酸盐；
    优选地，化合物A与富马酸的摩尔比为1∶1；
    优选地，所述化合物A的富马酸盐为晶型XII；
    所述晶型XII的XRPD图谱包括在约7.2±0.2°、10.9±0.2°、20.9±0.2°和27.5±0.2°的衍射角(2θ)处的特征峰；
    优选包括在约7.2±0.2°、10.3±0.2°、10.9±0.2°、15.0±0.2°、20.9±0.2°、21.6±0.2°、24.2±0.2°和27.5±0.2°的衍射角(2θ)处的特征峰；
    最优选包括在约7.2±0.2°、7.8±0.2°、10.3±0.2°、10.9±0.2°、13.0±0.2°、14.5±0.2°、15.0±0.2°、17.6±0.2°、20.9±0.2°、21.6±0.2°、22.9±0.2°、24.2±0.2°、25.9±0.2°、27.5±0.2°和31.0±0.2°的衍射角(2θ)处的特征峰。
  16. 药物组合物，其包含权利要求1-15中任一项的盐，以及一种或多种药学上可接受的载体。
  17. 权利要求1-15中任一项的盐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、良性前列腺肥大、前列腺炎、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、前列腺痛、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；心血管系统疾病，所述心血管系统疾病优选为高血压；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。
PCT/CN2020/087688 2019-04-30 2020-04-29 二氨基嘧啶类化合物的盐、其固体形式及其制备方法和用途 WO2020221276A1 (zh)

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