RU2844833C2 - Solid form of diaminopyrimidine or hydrate thereof, method for preparation thereof and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a crystalline form I of an anhydrate of compound A, having an X-ray powder diffraction pattern (XRPD) containing characteristic peaks located at diffraction angles (2θ), equal to 11.9 ± 0.2°, 12.3 ± 0.2°, 13.9 ± 0.2°, 19.8 ± 0.2° and 20.3 ± 0.2°. Invention relates to a method of producing crystalline form I of the anhydrate of compound A of the invention, involving the following steps: 1) adding compound A to water, then adding an acid, stirring to dissolve compound A and obtaining a solution that is filtered and a filtrate is obtained; 2) adding a base to the solution or filtrate obtained in step 1), and collecting the precipitated solid substance by filtering; and 3) adding the obtained solid substance to water and mixing, filtering to collect the solid substance, which is dried and crystalline form I is obtained. Invention relates to a process for the preparation of crystalline form I of the anhydrate of compound A of the invention, comprising dissolving compound A in a good solvent to obtain a solution, followed by adding an anti-solvent to the solution and stirring to ensure precipitation of a solid substance, which is filtered and a crystalline form is obtained; where a good solvent is a cyclic ether containing 3–10 carbon atoms; and the anti-solvent is hydrocarbon containing 5–10 carbon atoms or a linear ether containing 2–6 carbon atoms. Invention also relates to compound A. Invention refers to a pharmaceutical composition for preventing or treating a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist containing a crystalline form I of the anhydrate of compound A or compound A under the invention and one or more pharmaceutically acceptable carriers.

EFFECT: crystalline form I of the anhydrate of compound A or compound A is used to prepare a medicinal agent for preventing or treating diseases mediated by a P2X3 and/or P2X2/3 receptor antagonist.

19 cl, 21 dwg, 8 tbl, 16 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

The present invention relates to a solid form of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine (hereinafter referred to as "compound A" in the present invention) or a hydrate thereof, to a method for producing the solid form, to a pharmaceutical composition containing the solid form, and to the use of the solid form for the prevention or treatment of a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist.

LEVEL OF TECHNOLOGY

Purine compounds acting through cell surface purinergic receptors have been shown to play a role in various physiological and pathological processes. ATP (adenosine triphosphate) and, to a lesser extent, adenosine, can stimulate sensory nerve endings, causing severe pain and a marked increase in the degree of sensory nerve discharge. Based on the molecular structure, transduction mechanisms, and pharmacological characteristics of ATP receptors, they are divided into two main families, the P2Y and P2X purinergic receptors. The P2Y purinergic receptors are G protein-coupled receptors, while the P2X purinergic receptors belong to the family of ATP-gated cation channels. Purinergic receptors, in particular the P2X receptors, can form homomultimers or heteromultimers. Currently, cDNAs have been cloned for multiple P2X receptor subtypes (including 6 homologous receptors: P2X1, P2X2, P2X3, P2X4, P2X5, and P2X7; and 3 heterologous receptors: P2X2/3, P2X4/6, and P2X1/5). The structure and chromosomal map of the mouse P2X3 genomic receptor have also been described.

The results of the studies have shown that P2X3 and/or P2X2/3 receptor antagonists can be used to treat diseases such as pain, etc. The inventors of the present invention have identified diaminopyrimidine compounds, namely 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine, which can be used as effective P2X3 and/or P2X2/3 receptor antagonists (see publication PCT/CN 2018/112829, which is incorporated herein by reference in its entirety).

SUMMARY OF THE INVENTION

One object of the present invention are crystalline forms of compound A (5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine) given below, or a hydrate thereof:

The preferred crystalline forms of the present invention not only provide an excellent effect in preventing or treating a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist, but also have other advantages. For example, the preferred crystalline forms of the present invention have excellent physical characteristics (including solubility, dissolution rate, light stability, low hygroscopicity, high temperature stability, high humidity stability, flowability, etc.), and the preferred crystalline forms of the present invention can have such excellent characteristics as bioavailability, physical and/or chemical stability, and are easy to obtain. The preferred crystalline forms proposed in the present invention have good characteristics in powder form, are more suitable and suitable for mass production and preparation, can reduce irritation and improve absorption, overcome the difficulty associated with the metabolism rate, significantly reduce toxicity caused by accumulation of the drug, improve safety, and effectively ensure the quality and efficacy of pharmaceutical products.

Another object of the present invention is to provide methods for preparing the crystalline forms provided in the present invention.

Another object of the present invention is a pharmaceutical composition comprising any one or more of the crystalline forms provided in the present invention and one or more pharmaceutically acceptable carriers.

Another object of the present invention is the use of the crystalline form according to the present invention for the preparation of a medicament intended for the treatment of a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 shows the powder X-ray diffraction pattern of crystalline form I of the anhydrate of compound A.

Fig. 2 shows the dependence obtained using differential scanning calorimetry (DSC) and the dependence obtained using thermogravimetric analysis (TGA) for crystalline form I of the anhydrate of compound A.

Fig. 3 shows a scanning electron micrograph of crystalline form I of the anhydrate of compound A.

Fig. 4 shows the powder X-ray diffraction pattern of crystalline form II of the monohydrate of compound A.

Fig. 5 shows the dependence obtained using differential scanning calorimetry (DSC) and the dependence obtained using thermogravimetric analysis (TGA) for crystalline form II of the monohydrate of compound A.

Fig. 6 shows the powder X-ray diffraction pattern of crystalline form III of the hemihydrate of compound A.

Fig. 7 shows the dependence obtained using differential scanning calorimetry (DSC) for the crystalline form III of the hemihydrate of compound A.

Fig. 8 shows the powder X-ray diffraction pattern of crystalline form IV of the sesquihydrate of compound A.

Fig. 9 shows the dependence obtained using differential scanning calorimetry (DSC) and the dependence obtained using thermogravimetric analysis (TGA) for the crystalline form IV of the sesquihydrate of compound A.

Fig. 10 shows the powder X-ray diffraction pattern of crystalline form V of the monohydrate of compound A.

Fig. 11 shows the dependence obtained using differential scanning calorimetry (DSC) for the crystalline form V of the monohydrate of compound A.

Fig. 12 shows the powder X-ray diffraction pattern of crystalline form VI of the monohydrate of compound A.

Fig. 13 shows the dependence obtained using differential scanning calorimetry (DSC) for the crystalline form VI of the monohydrate of compound A.

Fig. 14 shows the powder X-ray diffraction pattern of crystalline form VII of the sesquihydrate of compound A.

Fig. 15 shows the dependence obtained using differential scanning calorimetry (DSC) and the dependence obtained using thermogravimetric analysis (TGA) for the crystalline form VII of the sesquihydrate of compound A.

Fig. 16 shows the powder X-ray diffraction pattern of the crystalline form VIII of the hemihydrate of compound A.

Fig. 17 shows the dependence obtained using differential scanning calorimetry (DSC) and the dependence obtained using thermogravimetric analysis (TGA) for the crystalline form VIII of the hemihydrate of compound A.

Fig. 18 shows a comparison of the X-ray powder diffraction patterns of crystalline form I of compound A anhydrate obtained before and after a stability study at room temperature.

Fig. 19 shows a comparison of the PRRGs of crystalline form I of compound A anhydrate obtained before and after the high temperature stability study.

Fig. 20 shows a comparison of the PRRGs of crystalline form I of compound A anhydrate obtained before and after the high humidity stability study.

Fig. 21 shows a comparison of the PRRGs of crystalline form I of compound A anhydrate obtained before and after a stability study during mechanical milling.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as commonly understood by a person skilled in the art. References to techniques used in the present invention mean references to techniques that are commonly known in the art, including variations of these techniques or replacements with equivalent techniques that are obvious to a person skilled in the art. Although it is obvious that most of the terms given below are easily understood by a person skilled in the art, nevertheless, the following definitions are given to better illustrate the present invention.

The terms "comprise", "include", "consist of", "have" or "relate", as well as other modifications thereof, as used in the present invention, are inclusive or allowable of modifications and do not exclude additional, unspecified elements or method steps.

The term "about" when used in the present invention, as will be apparent to one skilled in the art, means a range including an acceptable standard error of value, such as ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3, etc.

The term "solid form" as used in the present invention includes all solid forms of compound A or any hydrate thereof, such as a crystalline form or an amorphous form.

The term "amorphous" as used herein means any solid that does not possess three-dimensional order. In some cases, amorphous solids can be characterized by known techniques, including X-ray diffraction, solid-state nuclear magnetic resonance (SSNMR), DSC, or some combination of these techniques. As shown below, amorphous solids have diffuse X-ray spectra, typically containing one or two broad peaks (i.e., peaks having a base width of about 5°2θ or more).

The term "crystalline form" or "crystal" as used herein means any solid having three-dimensional order which, unlike an amorphous solid, has a characteristic XRD pattern containing well-defined peaks.

The term "powder X-ray diffraction pattern (XRD)" as used herein means an experimentally obtained diffractogram or parameters extracted therefrom. The XRD pattern typically depicts peak positions (abscissa axis) and peak intensities (ordinate axis).

The term "2θ" as used in the present invention means a peak position, expressed in degrees, obtained based on an experimental design for conducting an X-ray diffraction experiment, and is a common parameter of the abscissa axis in X-ray diffraction patterns. The experimental design requires that if the reflected beam is scattered when the incident beam forms an angle theta (θ) with a certain plane of the crystal lattice, then the reflected beam is recorded at an angle of 2-theta (2θ). It should be understood that in the present invention, reference to specific 2θ values for a particular solid form means reference to average 2θ values (expressed in degrees) determined using the experimental conditions for conducting an X-ray diffraction experiment described in the present invention. Thus, for example, as described in the present invention, Cu-Kα (Kα1 ( ): 1.540598, and Kα2 ( ): 1.544426 ).

As used herein, "I, %" means the peak intensity expressed as a percentage.

The term "differential scanning calorimetry (DSC) curve" as used herein means a curve obtained using a differential scanning calorimeter. Unless otherwise specified, a temperature specified in a description of a characteristic peak in a DSC curve means the temperature at which the peak begins.

The term "thermogravimetric analysis (TGA)-derived curve" as used herein means a curve obtained using a thermogravimetric analyzer.

As used herein, the term "substantially the same" with respect to peak positions in an X-ray diffraction pattern means that typical variations in peak position and intensity are taken into account. For example, it will be apparent to one skilled in the art that peak positions (2θ) may vary slightly, typically by an amount of 0.1-0.2 degrees, and also depend on the instrument on which the diffraction is analyzed. It will also be apparent to one skilled in the art that relative peak intensities vary with the instrument, and also vary with the degree of crystallinity, the preferred orientation, the surface preparation of the sample, and other factors known to those skilled in the art. Similarly, as used herein, the term "substantially the same" with respect to the DSC curve also includes all variations associated with these analytical techniques that are known to those skilled in the art. For example, in the dependence obtained using differential scanning calorimetry, the difference in the positions of well-defined peaks is up to ±0.2°C, and it is even more significant for broad peaks (for example, up to ±1°C).

In the context of the present application, unless otherwise stated, the liquid phase nuclear magnetic resonance spectrum is preferably recorded on a Bruker 400M nuclear magnetic resonance spectrometer using DMSO-d ₆ (DMSO = dimethyl sulfoxide) as a solvent.

In the context of the present application, the examination using polarization microscopy is preferably carried out using an ECLIPSE LV100POL polarization microscope (Nikon, Japan).

Numeric ranges (e.g., "1 to 10," "1 to 6," "2 to 10," "2 to 6," "3 to 10," "5 to 10," "3 to 6," etc.) when used herein include any value within the boundaries of the numerical range (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

The resulting salt or crystalline form thereof may be recovered by techniques including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique designed to recover solids using pressure or reduced pressure. The recovered solid may optionally be dried. In the present invention, "drying" is carried out under reduced pressure (preferably under vacuum) until the residual solvent content is reduced to within the range specified in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceutical Products for Human Use ("ICH") guidelines. The residual solvent content depends on the type of solvent, but does not exceed about 5,000 ppm, or preferably about 4,000 ppm, or more preferably about 3,000 ppm. Drying can be carried out in a centrifugal dryer, a vacuum drying oven, a forced draft drying oven, a conical vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a centrifugal spray dryer, a spray dryer, etc. Drying can be carried out at temperatures below about 100°C, below about 80°C, below about 60°C, below about 50°C, below about 30°C, or at any other suitable temperatures, at atmospheric pressure or under reduced pressure (preferably under vacuum) for any desired period of time (e.g., for about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) until the desired result is achieved, provided that the quality of the salt is not deteriorated. Drying can be carried out any number of times necessary until the desired quality of the product is achieved. Optionally, particle size reduction of the dried product can be carried out to obtain the desired particle size. Milling or micronization can be carried out before drying or after the drying of the product is completed. Techniques that can be used to reduce the particle size include, without limitation, ball milling, roller milling, hammer milling, and jet milling.

The term "anhydrate" when used in the present invention preferably means a crystalline form that does not contain a water molecule as a structural element.

Crystalline form and method of its production

In one embodiment, the present invention relates to crystalline Form I of the anhydrate of compound A:

Crystalline form I exhibits a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 19.8±0.2°, and 20.3±0.2°.

In a preferred embodiment, crystalline Form I has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2°, and 20.3±0.2°.

In a more preferred embodiment, crystalline Form I has a PRXP comprising characteristic peaks located at diffraction angles (2θ) of about 6.2±0.2°, 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 16.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.3±0.2°, 21.8±0.2°, 23.0±0.2°, 23.6±0.2°, 24.1±0.2°, 26.2±0.2°, 26.5±0.2°, 27.8±0.2°, 28.5±0.2°, 29.3±0.2° and 30.6±0.2°.

In a more preferred embodiment, crystalline form I has a PRRG containing peaks located at the following diffraction angles (2θ):

In a more preferred embodiment, crystalline Form I has a PRWG comprising peaks located at diffraction angles (2θ) substantially the same as those shown in Fig. 1. In a most preferred embodiment, the positions of the peaks observed in the PRWG of crystalline Form I are substantially the same as those shown in Fig. 1.

In a more preferred embodiment, crystalline Form I has a DSC pattern containing endothermic/exothermic peaks located at approximately 245/255°C.

In a more preferred embodiment, when crystalline Form I is subjected to thermogravimetric analysis, it exhibits a mass loss of about 0.1% when heated at about 100-150°C.

In a more preferred embodiment, crystalline Form I has a DSC-TGA pattern comprising characteristic peaks substantially the same as those shown in Fig. 2. In a most preferred embodiment, crystalline Form I has a DSC-TGA pattern substantially the same as those shown in Fig. 2.

In a more preferred embodiment, crystalline form I has a scanning electron microscopic image substantially the same as that shown in Fig. 3.

In some preferred embodiments, the present invention relates to a process for preparing crystalline Form I comprising the following steps:

1) adding compound A to water, then adding an acid (for example, an organic acid (such as acetic acid or trifluoroacetic acid) or an inorganic acid (such as hydrochloric acid or sulfuric acid), preferably hydrochloric acid), stirring to dissolve compound A and obtaining a solution, which is optionally filtered to obtain a filtrate;

2) adding a base (e.g. sodium hydroxide, potassium hydroxide or ammonia) to the solution or filtrate obtained in step 1) and collecting the precipitated solid by filtration; and

3) adding the resulting solid to water and stirring (e.g. for 0.5-5 h, preferably for 1-3 h), filtering to collect the solid, which is optionally dried to obtain crystalline form I.

In some preferred embodiments, the present invention relates to a process for preparing crystalline form I comprising dissolving compound A in a good solvent (at room temperature or under heating (e.g. under heating at 30-60°C, preferably at 50°C)) to obtain a solution (the mixture may be filtered if necessary to obtain the solution), then adding an antisolvent to the solution and stirring (the addition of the antisolvent and stirring may be carried out at room temperature or under cooling (e.g. under cooling to 0-10°C, preferably to 5°C)) to ensure precipitation of a solid, which is filtered to obtain the crystalline form.

In some preferred embodiments, the good solvent is an ether containing 3-10 carbon atoms, preferably a cyclic ether such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane; and the antisolvent is a hydrocarbon containing 5-10 carbon atoms (including alkanes, halogenated alkanes, alkenes, alkynes and aromatic hydrocarbons including but not limited to dichloromethane, trichloromethane (chloroform), n-hexane, n-heptane and toluene), or an ether containing 2-6 carbon atoms (preferably linear ethers such as diethyl ether, diisopropyl ether or methyl tert-butyl ether).

In some preferred embodiments, the ratio of mass of compound A/volume of good solvent (g/mL) is about 1:(30-120), preferably about 1:40 or 1:100.

In some preferred embodiments, the ratio of the volume of good solvent to the volume of antisolvent is from about 1:1 to 1:5.

In another embodiment, the present invention relates to crystalline Form II of the monohydrate of compound A:

Crystalline form II has a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 13.0±0.2°, 19.5±0.2° and 19.9±0.2°.

In a preferred embodiment, crystalline Form II has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 9.6±0.2°, 13.0±0.2°, 19.5±0.2°, 19.9±0.2°, and 22.7±0.2°.

In a more preferred embodiment, crystalline Form II has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 9.6±0.2°, 10.9±0.2°, 13.0±0.2°, 14.9±0.2°, 15.8±0.2°, 16.8±0.2°, 19.5±0.2°, 19.9±0.2°, 22.7±0.2°, 23.7±0.2°, 25.2±0.2°, 26.0±0.2°, 28.5±0.2°, 29.0±0.2°, 30.0±0.2° and 32.5±0.2°.

In a more preferred embodiment, crystalline form II has a PRRG containing peaks located at the following diffraction angles (2θ):

In a more preferred embodiment, crystalline Form II has a PRWG comprising peaks located at diffraction angles (2θ) substantially the same as those shown in Fig. 4. In a most preferred embodiment, the positions of the peaks observed in the PRWG of crystalline Form II are substantially the same as those shown in Fig. 4.

In a more preferred embodiment, crystalline Form II has a DSC pattern comprising an endothermic peak located at about 73.9°C and endothermic/exothermic peaks located at about 245/255°C.

In a more preferred embodiment, when crystalline Form II is subjected to thermogravimetric analysis, it exhibits a mass loss of about 6.2% when heated at about 100°C.

In a more preferred embodiment, crystalline Form II has a DSC-TGA pattern comprising characteristic peaks substantially the same as those shown in Fig. 5. In a most preferred embodiment, crystalline Form II has a DSC-TGA pattern substantially the same as those shown in Fig. 5.

In some preferred embodiments, the present invention relates to a method for preparing crystalline form II comprising suspending compound A in an aqueous alcoholic solvent (preferred is an alcohol containing 1-6 carbon atoms, including, but not limited to, methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol) and stirring (e.g., at room temperature) (e.g., for 1-5 days, such as for 3 days), filtering and obtaining the crystalline form.

In some preferred embodiments, the ratio of compound A mass/volume of aqueous alcoholic solvent (g/ml) is about 1:(30-100), preferably about 1:50.

In another embodiment, the present invention relates to crystalline form III of the hemihydrate of compound A:

Crystalline form III has a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 10.8±0.2° and 20.5±0.2°.

In a preferred embodiment, crystalline form III has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 10.8±0.2°, 19.3±0.2°, 20.5±0.2°, 21.7±0.2°, and 26.9±0.2°.

In a more preferred embodiment, crystalline Form III has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 10.8±0.2°, 13.0±0.2°, 15.0±0.2°, 15.4±0.2°, 16.5±0.2°, 17.3±0.2°, 19.3±0.2°, 19.9±0.2°, 20.5±0.2°, 21.7±0.2°, 23.3±0.2°, 25.1±0.2°, 26.5±0.2°, 26.9±0.2°, 28.7±0.2° and 32.2±0.2°.

In a more preferred embodiment, crystalline form III has a PRRG containing peaks located at the following diffraction angles (2θ):

In a more preferred embodiment, crystalline form III has a PRWG comprising peaks located at diffraction angles (2θ) substantially the same as those shown in Fig. 6. In a most preferred embodiment, the positions of the peaks observed in the PRWG of crystalline form III are substantially the same as those shown in Fig. 6.

In a more preferred embodiment, crystalline form III has a DSC pattern comprising an endothermic peak located at about 62.2°C and endothermic/exothermic peaks located at about 245/255°C.

In a more preferred embodiment, when crystalline Form III is subjected to thermogravimetric analysis, it exhibits a mass loss of about 3.6% when heated at about 80°C.

In a more preferred embodiment, crystalline form III has a DSC pattern comprising characteristic peaks substantially the same as those shown in Fig. 7. In a most preferred embodiment, crystalline form III has a DSC pattern substantially the same as those shown in Fig. 7.

In some preferred embodiments, the present invention relates to a method for preparing crystalline form III comprising dissolving compound A in a good solvent (e.g., at room temperature) to form a solution (the mixture may optionally be filtered to form the solution), then adding an antisolvent to the solution and stirring (the addition of the antisolvent and stirring are carried out, for example, at room temperature) to allow precipitation of a solid, which is filtered to form the crystalline form.

In some preferred embodiments, a good solvent is a sulfone or sulfoxide containing 2-10 carbon atoms, including, but not limited to, dimethyl sulfoxide; and the antisolvent is preferably water.

In some preferred embodiments, the ratio of mass of compound A to volume of good solvent (g/mL) is about 1:(1-20), preferably about 1:12.5.

In some preferred embodiments, the ratio of the volume of good solvent to the volume of antisolvent is from about 1:1 to 1:3.

In another embodiment, the present invention relates to crystalline form IV of the sesquihydrate of compound A:

Crystalline form IV has a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 12.3±0.2°, 21.3±0.2° and 24.1±0.2°.

In a preferred embodiment, crystalline form IV has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 12.3±0.2°, 12.6±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, and 27.9±0.2°.

In a more preferred embodiment, crystalline form IV has a PRXR comprising characteristic peaks located at diffraction angles (2θ) of about 12.3±0.2°, 12.6±0.2°, 14.3±0.2°, 17.2±0.2°, 20.0±0.2°, 20.6±0.2°, 21.3±0.2°, 23.2±0.2°, 23.8±0.2°, 24.1±0.2°, 25.0±0.2°, 25.7±0.2°, 27.9±0.2°, 31.2±0.2° and 31.7±0.2°.

In a more preferred embodiment, crystalline form IV has a PRRG containing peaks located at the following diffraction angles (2θ):

In a more preferred embodiment, crystalline form IV has a PRWG comprising peaks located at diffraction angles (2θ) substantially the same as those shown in Fig. 8. In a most preferred embodiment, the positions of the peaks observed in the PRWG of crystalline form IV are substantially the same as those shown in Fig. 8.

In a more preferred embodiment, crystalline form IV has a DSC pattern comprising an endothermic peak located at about 42.6°C, an endothermic peak located at about 66.9°C, and endothermic/exothermic peaks located at about 245/255°C.

In a more preferred embodiment, when crystalline form IV is subjected to thermogravimetric analysis, it exhibits a mass loss of about 9.4% when heated at about 100°C.

In a more preferred embodiment, crystalline form IV has a DSC-TGA pattern comprising characteristic peaks substantially the same as those shown in Fig. 9. In a most preferred embodiment, crystalline form IV has a DSC-TGA pattern substantially the same as those shown in Fig. 9.

In some preferred embodiments, the present invention relates to a method for preparing crystalline form IV comprising stirring compound A in water (e.g., at room temperature, such as for 1-5 days, preferably for 2-4 days) and filtering to obtain the crystalline form.

In some preferred embodiments, the ratio of compound A mass/water volume (g/ml) is about 1:(30-100), preferably about 1:50.

In some preferred embodiments, the present invention relates to a method for preparing crystalline form IV comprising dissolving compound A in a good solvent (e.g., at room temperature) to form a solution (the mixture may optionally be filtered to form the solution), then adding an antisolvent to the solution and stirring (the addition of the antisolvent and stirring are carried out, for example, at room temperature) to allow precipitation of a solid, which is filtered to form the crystalline form.

In some preferred embodiments, a good solvent is an ether containing 3-10 carbon atoms, preferably a cyclic ether, such as furans (including tetrahydrofurans) and dioxanes, preferably tetrahydrofuran, 2-methyltetrahydrofuran or dioxane; and the antisolvent is preferably water.

In some preferred embodiments, the ratio of mass of compound A to volume of good solvent (g/ml) is about 1:(50-120), preferably about 1:100.

In some preferred embodiments, the ratio of the volume of good solvent to the volume of antisolvent is from about 1:1 to 1:5.

In another embodiment, the present invention relates to crystalline form V of the monohydrate of compound A:

Crystalline form V has a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 14.1±0.2°, 21.0±0.2°, and 29.6±0.2°.

In a preferred embodiment, crystalline form V has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 8.7±0.2°, 9.4±0.2°, 11.9±0.2°, 14.1±0.2°, 15.8±0.2°, 16.8±0.2°, 18.9±0.2°, 19.9±0.2°, 20.6±0.2°, 21.0±0.2°, 22.5±0.2° and 29.6±0.2°.

In a more preferred embodiment, the crystalline form

V has a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 8.7±0.2°, 9.4±0.2°, 11.6±0.2°, 11.9±0.2°, 12.4±0.2°, 14.1±0.2°, 14.5±0.2°, 15.8±0.2°, 16.2±0.2°, 16.8±0.2°, 17.6±0.2°, 18.2±0.2°, 18.9±0.2°, 19.9±0.2°, 20.6±0.2°, 21.0±0.2°, 22.5±0.2°, 23.0±0.2°, 23.6±0.2°, 24.4±0.2°, 25.2±0.2°, 27.0±0.2° and 29.6±0.2°.

In a more preferred embodiment, crystalline form V has a PRRG containing peaks located at the following diffraction angles (2θ):

In a more preferred embodiment, crystalline form V has a PRWG comprising peaks located at diffraction angles (2θ) substantially the same as those shown in Fig. 10. In a most preferred embodiment, the positions of the peaks observed in the PRWG of crystalline form V are substantially the same as those shown in Fig. 10.

In a more preferred embodiment, crystalline form V has a DSC profile comprising an endothermic peak located at approximately 52.6°C and endothermic/exothermic peaks located at approximately 245/255°C.

In a more preferred embodiment, when crystalline form V is subjected to thermogravimetric analysis, it exhibits a mass loss of about 6.8% when heated at about 80°C.

In a more preferred embodiment, crystalline form V has a DSC pattern comprising characteristic peaks substantially the same as those shown in Fig. 11. In a most preferred embodiment, crystalline form V has a DSC pattern substantially the same as those shown in Fig. 11.

In some preferred embodiments, the present invention relates to a method for preparing crystalline form V comprising dissolving compound A in a good solvent (e.g., at room temperature) to form a solution (the mixture may optionally be filtered to form the solution), then adding an antisolvent to the solution and stirring (the addition of the antisolvent and stirring are carried out, for example, at room temperature) to allow precipitation of a solid, which is filtered to form the crystalline form.

In some preferred embodiments, a good solvent is a sulfone or sulfoxide containing 2-10 carbon atoms, including but not limited to dimethyl sulfoxide; and the antisolvent is preferably an aqueous alcoholic solvent (preferred is an alcohol containing 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol).

In some preferred embodiments, the ratio of mass of compound A to volume of good solvent (g/mL) is about 1:(1-20), preferably about 1:12.5.

In some preferred embodiments, the ratio of the volume of good solvent to the volume of antisolvent is from about 1:1 to 1:3.

In another embodiment, the present invention relates to crystalline form VI of the monohydrate of compound A:

Crystalline form VI has a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 10.4±0.2°, 12.1±0.2°, 16.6±0.2°, 20.7±0.2°, 22.8±0.2°, and 27.3±0.2°.

In a preferred embodiment, crystalline form VI has a PRWG comprising characteristic peaks located at diffraction angles (2θ) of about 8.7±0.2°, 10.4±0.2°, 12.1±0.2°, 15.4±0.2°, 16.6±0.2°, 19.5±0.2°, 20.7±0.2°, 21.2±0.2°, 22.8±0.2°, and 27.3±0.2°.

In a more preferred embodiment, crystalline Form VI has a PRXR comprising characteristic peaks located at diffraction angles (2θ) of about 8.7±0.2°, 10.4±0.2°, 12.1±0.2°, 13.4±0.2°, 14.7±0.2°, 15.4±0.2°, 16.6±0.2°, 17.4±0.2°, 19.5±0.2°, 20.7±0.2°, 21.2±0.2°, 22.1±0.2°, 22.8±0.2°, 23.6±0.2°, 26.0±0.2°, 27.3±0.2°, 28.0±0.2° and 30.4±0.2°.

In a more preferred embodiment, crystalline form VI has a PRRG containing peaks located at the following diffraction angles (2θ):

In a more preferred embodiment, crystalline form VI has a PRWG comprising peaks located at diffraction angles (2θ) substantially the same as those shown in Fig. 12. In a most preferred embodiment, the positions of the peaks observed in the PRWG of crystalline form VI are substantially the same as those shown in Fig. 12.

In a more preferred embodiment, crystalline form VI has a DSC pattern comprising an endothermic peak located at about 51.6°C, an endothermic peak located at about 77.5°C, and endothermic/exothermic peaks located at about 245/255°C.

In a more preferred embodiment, crystalline form VI has a DSC pattern comprising characteristic peaks substantially the same as those shown in Fig. 13. In a most preferred embodiment, crystalline form VI has a DSC pattern substantially the same as those shown in Fig. 13.

In some preferred embodiments, the present invention relates to a method for preparing crystalline form VI comprising stirring compound A (e.g., at room temperature) in a solvent mixture comprising a ketone (e.g., a ketone containing 3-6 carbon atoms, including, but not limited to, acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone) and water (e.g., for 1-5 days), and filtering to obtain the crystalline form.

In some preferred embodiments, the ratio of volume of ketone to volume of water is from about 10:1 to 1:1, preferably from about 5:1 to 2:1.

In some preferred embodiments, the ratio of compound A mass/solvent mixture volume (g/mL) is about 1:(1-30), preferably about 1:20.

In another embodiment, the present invention relates to crystalline form VII of the sesquihydrate of compound A:

Crystalline form VII has a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 13.1±0.2°, 19.9±0.2°, and 20.2±0.2°.

In a preferred embodiment, crystalline form VII has a PRRG containing characteristic peaks located at diffraction angles (2θ) of about 13.1±0.2°, 16.9±0.2°, 19.9±0.2°, 20.2±0.2°, 24.9±0.2°, and 28.8±0.2°.

In a more preferred embodiment, crystalline form VII has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 9.4±0.2°, 10.8±0.2°, 13.1±0.2°, 15.4±0.2°, 16.9±0.2°, 18.8±0.2°, 19.9±0.2°, 20.2±0.2°, 22.2±0.2°, 23.2±0.2°, 24.9±0.2°, 26.4±0.2°, and 28.8±0.2°.

In a more preferred embodiment, crystalline form VII has a PRRG containing peaks located at the following diffraction angles (2θ):

In a more preferred embodiment, crystalline Form VII has a PRWG comprising peaks located at diffraction angles (2θ) substantially the same as those shown in Fig. 14. In a most preferred embodiment, the positions of the peaks observed in the PRWG of crystalline Form VII are substantially the same as those shown in Fig. 14.

In a more preferred embodiment, crystalline form VII has a DSC pattern comprising an endothermic peak located at about 54.8°C and endothermic/exothermic peaks located at about 245/255°C.

In a more preferred embodiment, when crystalline Form VII is subjected to thermogravimetric analysis, it exhibits a mass loss of about 9.5% when heated at about 75°C.

In a more preferred embodiment, crystalline Form VII has a DSC-TGA pattern comprising characteristic peaks substantially the same as those shown in Fig. 15. In a most preferred embodiment, crystalline Form VII has a DSC-TGA pattern substantially the same as those shown in Fig. 15.

In some preferred embodiments, the present invention relates to a method for preparing crystalline form VII comprising stirring compound A in a solvent mixture comprising an alcohol (e.g., an alcohol containing 1-6 carbon atoms, including but not limited to methanol, ethanol, 1-propanol, 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol) and water, while heating (e.g., heating at 30-60°C, preferably at 50°C) to obtain a solution (the mixture may optionally be filtered to obtain a solution), cooling the solution (e.g., cooling to 0-10°C, preferably to 5°C) to allow precipitation of the solid, and filtering to obtain the crystalline form.

In some preferred embodiments, the ratio of volume of alcohol to volume of water is from about 5:1 to 0.5:1, preferably from about 3:1 to 1:1.

In some preferred embodiments, the ratio of compound A mass/solvent mixture volume (g/ml) is about 1:(20-80), preferably about 1:50.

In another embodiment, the present invention relates to crystalline form VIII of the hemihydrate of compound A:

Crystalline form VIII has a PRRG containing characteristic peaks located at diffraction angles (2θ) of approximately 13.0±0.2°, 16.8±0.2°, 19.4±0.2°, 21.7±0.2°, 22.9±0.2°, and 27.4±0.2°.

In a preferred embodiment, crystalline Form VIII has a PRRG comprising characteristic peaks located at diffraction angles (2θ) of about 10.3±0.2°, 13.0±0.2°, 16.8±0.2°, 19.1±0.2°, 19.4±0.2°, 21.1±0.2°, 21.7±0.2°, 22.9±0.2°, 25.8±0.2°, and 27.4±0.2°.

In a more preferred embodiment, crystalline Form VIII has a PRXP comprising characteristic peaks located at diffraction angles (2θ) of about 8.7±0.2°, 10.3±0.2°, 10.8±0.2°, 13.0±0.2°, 14.1±0.2°, 14.8±0.2°, 16.8±0.2°, 17.5±0.2°, 19.1±0.2°, 19.4±0.2°, 21.1±0.2°, 21.7±0.2°, 22.3±0.2°, 22.9±0.2°, 25.8±0.2°, 27.4±0.2°, 27.8±0.2°, 30.4±0.2° and 31.6±0.2°.

In a more preferred embodiment, crystalline form VIII has a PRRG containing peaks located at the following diffraction angles (2θ):

In a more preferred embodiment, crystalline Form VIII has a PRWG comprising peaks located at diffraction angles (2θ) substantially the same as those shown in Fig. 16. In a most preferred embodiment, the positions of the peaks observed in the PRWG of crystalline Form VIII are substantially the same as those shown in Fig. 16.

In a more preferred embodiment, crystalline form VIII has a DSC pattern comprising an endothermic peak located at about 50.9°C, an endothermic peak located at about 79.1°C, an endothermic peak located at about 124.9°C, and endothermic/exothermic peaks located at about 245/255°C.

In a more preferred embodiment, when crystalline Form VIII is subjected to thermogravimetric analysis, it exhibits a mass loss of about 3.6% when heated at about 105°C.

In a more preferred embodiment, crystalline form VIII has a DSC-TGA pattern comprising characteristic peaks substantially the same as those shown in Fig. 17. In a most preferred embodiment, crystalline form VIII has a DSC-TGA pattern substantially the same as those shown in Fig. 17.

In some preferred embodiments, the present invention relates to a method for preparing crystalline form VIII comprising stirring compound A in a solvent mixture comprising a ketone (e.g., a ketone having 3-6 carbon atoms, including, but not limited to, acetone, butanone, methyl ethyl ketone, methyl isobutyl ketone, and diethyl ketone) and water, while heating (e.g., heating at 30-60°C, preferably at 50°C) to obtain a solution (the mixture may optionally be filtered to obtain the solution), cooling the solution (e.g., cooling to 0-10°C, preferably to 5°C) to allow the solid to precipitate, and filtering to obtain the crystalline form.

In some preferred embodiments, the ratio of volume of ketone to volume of water is from about 5:1 to 0.5:1, preferably from about 3:1 to 1:1.

In some preferred embodiments, the ratio of compound A mass/solvent mixture volume (g/ml) is about 1:(20-80), preferably about 1:50.

Pharmaceutical composition, method of treatment and its application

In another embodiment, the present invention relates to a pharmaceutical composition comprising any one or more of crystalline forms I, II, III, IV, V, VI, VII or VIII of the present invention and one or more pharmaceutically acceptable carriers.

In another embodiment, the present invention relates to the use of crystalline form I, II, III, IV, V, VI, VII or VIII according to the present invention for the preparation of a medicament for the prevention or treatment of a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist.

In another embodiment, the present invention relates to crystalline form I, II, III, IV, V, VI, VII or VIII of the present invention, intended for use in the prevention or treatment of a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist.

In another embodiment, the present invention relates to a method for preventing or treating a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist, comprising administering to a subject in need thereof, preferably a mammal, any one or more of the crystalline forms I, II, III, IV, V, VI, VII or VIII of the present invention, in a prophylactically or therapeutically effective amount.

In a preferred embodiment, the disease mediated by the P2X3 and/or P2X2/3 receptor antagonist is selected from the group consisting of the following: a urinary tract disease selected from the following: reduced bladder capacity, urinary frequency, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis and idiopathic bladder hypersensitivity; pain selected from the following: inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain caused by burns, migraine and severe paroxysmal headache with periodic relapses, pain due to neuritis; neuralgia; pain due to poisoning; pain due to ischemic injury; pain due to interstitial cystitis; pain due to cancer; pain due to viral, parasitic or bacterial infection; post-traumatic pain and pain associated with irritable bowel syndrome; cardiovascular disease, preferably hypertension; a respiratory disease selected from the following: chronic obstructive pulmonary disease, asthma and bronchospasm; a gastrointestinal disease selected from the following: irritable bowel syndrome (preferably diarrhea-dominant irritable bowel syndrome), inflammatory bowel disease, biliary colic, renal colic, and pain associated with gastrointestinal distension.

As used herein, the term "pharmaceutically acceptable carrier" as used herein means a diluent, excipient, excipient, or vehicle with which a drug is administered and which, in accordance with sound medical judgment, is suitable for use in contact with the tissues of humans and animals without causing excessive toxicity, irritation, allergic reaction, or other difficulties or complications in accordance with a reasonable benefit/risk ratio.

A pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present invention includes, but is not limited to, sterile liquids such as water and oils, including those derived from petroleum and animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a typical carrier in case the pharmaceutical composition is administered intravenously. Physiological solutions, as well as aqueous dextrose solutions and glycerol can also be used as liquid carriers, especially for injection solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dry skim milk, glycerol, propylene glycol, water, ethanol, and the like. If desired, the composition may also contain minor amounts of wetting or emulsifying agents, or buffering agents for pH adjustment. 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 pharmaceutical carriers are described, for example, in Remington's Pharmaceutical Sciences (1990).

The composition proposed in the present invention can act systemically and/or locally. For this purpose, it can be administered by a suitable route, for example by injection, by intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration, or they can be administered orally, buccally, nasally, through the mucous membrane, topically, as an ophthalmic preparation, or by inhalation.

When using these routes of administration, the composition of the present invention can be administered in a suitable dosage form.

The dosage form may be a solid, semi-liquid, liquid or gaseous preparation, including, but not limited to, tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, salves, aqueous suspensions, injection solutions, suspensions, elixirs and syrups.

The pharmaceutical composition proposed in the present invention can be prepared by any technique well known in the art, for example, by mixing, dissolving, granulating, coating, trituration, emulsification, lyophilization, etc.

As used herein, the term "therapeutically effective amount" means an amount of a compound administered that alleviates to some extent one or more symptoms of the disorder being treated.

The modes of administration can also be adjusted to provide the optimal desired response. For example, a single bolus dose can be administered, several divided doses can be administered over a certain period of time, or the dose can be proportionally reduced or increased according to the requirements of the treatment. It should be noted that the doses can vary depending on the type and severity of the pathological condition that needs to be alleviated, and they can include one or more doses. It should also be understood that for each specific subject, specific dosage regimens should be adjusted over time in accordance with the individual need and the professional judgment of the person prescribing or supervising the administration of the compositions.

The amount of the compound of the present invention administered depends on the subject being treated, the severity of the disorder or condition, the rate of administration, the nature of the compound and the judgment of the attending physician. An effective dose is generally in the range of from about 0.0001 to about 50 mg/(kg body weight)/day, for example from about 0.01 to about 10 mg/kg/day, in a single dose or in divided doses. For a 70 kg human, it is from about 0.007 to about 3500 mg/day, for example from about 0.7 to about 700 mg/day. In some cases, doses less than the lower limit of the above range may be more than sufficient, while in other cases, larger doses may be used without any adverse side effect, provided that such larger doses are first divided into several smaller doses to be administered throughout the day.

The content or dose of the compound according to the present invention in the pharmaceutical composition is from about 0.01 to about 1000 mg, preferably 0.1-500 mg, more preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2 mg, 4 mg, 10 mg and 25 mg, etc.

Unless otherwise specified, the term "treat" or "treatment" as used herein means reversing, alleviating, or inhibiting the progress of, or preventing, the disorder, condition, or disease to which such term refers, or one or more symptoms of such disorder, condition, or disease.

As used herein, the term "subject" includes a human and a non-human animal. A typical human subject includes a human subject suffering from a disease (such as one described herein) (referred to as a patient) or a healthy subject. The term "non-human animal" as used herein includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

Advantageous characteristics of the crystalline form proposed in the present invention

1) The preferred crystalline forms of the present invention have good stability and their color and characteristics remain unchanged after storage at ambient temperature for a long period of time (for example, after storage for 180 days). In addition, the preferred crystalline forms of the present invention also have good stability under high temperature and high humidity conditions. For example, after storing crystalline form I under high temperature conditions (such as 60°C) for 30 days, there is no change in its crystalline form.

2) The preferred crystalline forms proposed in the present invention have good flowability, are easy to grind into powder and are suitable for the preparation of a pharmaceutical composition.

3) The methods for producing the preferred crystalline forms proposed in the present invention are simple and easy to carry out, and the reaction conditions are mild. In addition, there is no need for repeated purification and the procedures are safe and environmentally friendly, which can simplify the industrial production of the crystalline forms.

EXAMPLES

The present invention is explained in more detail below with reference to examples, which are used only to illustrate the technical solutions proposed in the present invention and are not intended to limit its scope. Those skilled in the art can make some minor improvements and changes that are still within the scope of the present invention.

Unless otherwise stated, all starting materials and reagents used in the examples below are commercially available or can be prepared by known procedures.

The test equipment and conditions used in the examples below were as follows:

(1) Powder X-ray diffraction (PRX)

Instrument model: Bruker D8 Advance equipped with LynxEye detector

The conditions of the study: the anode mirror material was copper, the parameters of the light guide were set as follows: 40 kV, 40 mA, the range of scanning angles 2θ for the sample was from 3 to 40°, the scanning step was 0.02°.

(2) Analysis by differential scanning calorimetry (DSC)

Device model: TA Discovery DSC 250 (TA Instruments, US)

The conditions of the study were as follows: the heating rate was 10°C/min, dry nitrogen was used as a purge gas.

(3) Thermogravimetric analysis (TGA)

Device model: Discovery TGA 55 (TA Instruments, US)

The conditions of the study were as follows: automatic weighing in a heating furnace, the heating rate was 10°C/min, dry nitrogen was used as a purge gas.

(4) Polarizing Microscope (PLM) Analysis

Device model: polarizing microscope ECLIPSE LV100POL (Nikon, JPN)

Example 1: Preparation of 5-((2-ethynyl-5-isopropylpyridin-4-yl)oxy)pyrimidine-2,4-diamine (compound A) (see publication PCT/CN 2018/112829, which is incorporated herein by reference in its entirety)

Stage 1:

Compound A-1 (100 g, 0.54 mol) was dissolved in 1,4-dioxane (700 mL), starting material IV1 (136 g, 0.81 mol), K ₂ CO ₃ (149 g, 1.08 mol) and Pd(PPh ₃ ) ₄ (6.2 g, 5.4 mmol) were added successively, then purified water (35 mL) was added and nitrogen was purged 3 times. The reaction was carried out under a protective nitrogen atmosphere at 100 °C for 18 h. LC-MS (liquid chromatography - mass spectrometry) showed that the conversion of the starting materials was mainly complete. The reaction solution was cooled to room temperature, filtered and the filter cake was washed with 1,4-dioxane (200 mL). The filtrate was concentrated under reduced pressure to remove 1,4-dioxane, then purified water (200 mL) was added and extracted with ethyl acetate (400 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate (100 g) for 30 min, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1-10:1), and compound A-2 (79 g, yellow oil, yield: 99.75%) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.37 (d, J=5.6 Hz, 1H), 8.22 (s, 1H), 7.04 (d, J=5.6 Hz, 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] ⁺ .

Stage 2:

Compound A-2 (79 g, 0.53 mol) was dissolved in anhydrous methanol (700 mL), 10% palladium on carbon (16 g) was added, and the reaction was carried out under hydrogen atmosphere (0.4 MPa) at room temperature for 18 h. LCMS showed that a small amount of starting material remained. Palladium on carbon (4 g) was added, and the reaction was continued under hydrogen atmosphere (0.4 MPa) at room temperature for 18 h. LCMS showed that the conversion of starting materials was complete. The reaction mixture solution was filtered, the filter cake was washed with methanol (100 mL), and the filtrate was concentrated under reduced pressure to give the crude product, compound A-3 (80 g, orange oily liquid, yield: 99.96%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.31 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 6.98 (d, J=5.6 Hz, 1H), 3.86 (s, 3H), 3.21-3.09 (m, 1H), 1.21 (d, J=7.2 Hz, 6H); MC m/z (IER): 152.1 [M+H] ⁺ .

Stage 3:

N,N-Dimethylethanolamine (46.3 g, 0.52 mol) was dissolved in n-hexane (400 ml). The reaction mixture was cooled under a protective nitrogen atmosphere to -15 ~ -20 °C, and a 2.4 mol/L solution of n-butyl lithium (434 ml, 1.04 mol) was slowly added dropwise. After completion of the dropwise addition, the reaction mixture was maintained at this temperature for 30 min, and then a solution of compound A-3 (40 g, 0.26 mol) in toluene (200 ml) was slowly added dropwise at -15 ~ -20 °C. After completion of the dropwise addition, the reaction mixture was maintained at this temperature for 30 min. The reaction mixture solution was cooled to -70 °C, a solution of carbon tetrabromide (172.4 g, 0.52 mol) in toluene (500 mL) was slowly added dropwise and the temperature was maintained at -70 ~ -75 °C. After the completion of the dropwise addition, the reaction mixture was maintained at this temperature for 1 h. LC-MS showed that the conversion of the starting materials was complete. The reaction was quenched by adding water (500 mL) and the mixture was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, washed once with saturated brine (500 mL), dried over anhydrous sodium sulfate (400 g) for 0.5 h, filtered and concentrated. The crude product was isolated by silica gel column chromatography (petroleum ether : ethyl acetate = 200:1 ~ 50:1) to give compound A-4 (25 g, light yellow oily liquid, yield: 41.81%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.20 (s, 1H), 3.89 (s, 3H), 3.13-3.05 (m, 1H), 1.18 (d, J=6.8 Hz, 6H); MS m/z (ESI): 229.9 [M+H] ⁺ .

Stage 4:

Compound A-4 (25 g, 0.11 mol) was dissolved in dichloromethane (300 mL). The reaction mixture was cooled under nitrogen blanket to 0~5 °C, and boron tribromide solution (140.3 g, 0.55 mol) was slowly added. After the addition was complete, the reaction solution was refluxed and reacted for 18 h. LC-MS showed that the conversion of the starting materials was complete. The reaction solution was cooled to room temperature and slowly added dropwise to 500 g of ice. After the dropwise addition was complete, saturated sodium bicarbonate solution was added dropwise to adjust the pH to 7~8. The reaction mixture was filtered, the filter cake was washed three times with ethyl acetate (400 ml), the filtrate was separated and the aqueous phase was re-extracted with ethyl acetate (400 ml × 3). All organic phases were combined, dried over anhydrous sodium sulfate (500 g) for 0.5 h, filtered and the filtrate was concentrated under reduced pressure to obtain compound A-5 (20 g, light yellow solid, yield: 84.17%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 7.99 (s, 1H), 6.90 (s, 1H), 3.10-3.02 (m, 1H), 1.18 (d, J=6.8 Hz, 6H); MC m/z (IER): 215.9 [M+H] ⁺ .

Stage 5:

Compound A-5 (10 g, 0.047 mol) was dissolved in DMF (N,N-dimethylformamide, 50 mL). Under a protective nitrogen atmosphere, potassium carbonate (12.8 g, 0.093 mol) and bromoacetonitrile (8.4 g, 0.07 mol) were added successively and the reaction mixture was stirred at room temperature for 2 h. LCMS showed that the conversion of the starting materials was complete. The reaction was quenched by adding water (50 mL) and the mixture was extracted with ethyl acetate (50 mL × 4). The combined organic phases were washed with saturated brine (50 mL × 3), anhydrous sodium sulfate was added, dried for 0.5 h and filtered. The filtrate was concentrated under reduced pressure and the crude product was isolated by silica gel column chromatography (petroleum ether : ethyl acetate = 20:1 - 5:1) to give compound A-6 (4 g, light yellow solid, yield: 33.38%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 7.40 (s, 1H), 5.37 (s, 2H), 3.14-3.06 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H); MS m/z (ESI): 254.8 [M+H] ⁺ .

Stage 6:

Compound A-6 (4 g, 0.016 mol) was dissolved in DMF (50 mL). Under a protective nitrogen atmosphere, tert-butoxybis(dimethylamino)methane (8.2 g, 0.048 mol) was added, the reaction mixture was heated to 100 °C and stirred for 2 h. LC-MS showed that the conversion of the starting materials was complete. The reaction solution was cooled to room temperature, the reaction was quenched by adding water (50 mL), and then the mixture was extracted with ethyl acetate (50 mL × 3). Then, the organic phase was washed with saturated brine (50 mL × 3), anhydrous sodium sulfate was added, dried for 0.5 h, and filtered. The filtrate was concentrated under reduced pressure and the crude product was isolated by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to give compound A-7 (3.8 g, light yellow solid, yield: 66.90%). MS m/z (ESI): 309.7 [M-45+H] ⁺ .

Stage 7:

Compound A-7 (3.54 g, 0.01 mol) was dissolved in DMF (25 mL). Aniline hydrobromide (2.08 g, 0.012 mol) was added under nitrogen blanket, the reaction mixture was heated to 100 °C and stirred for 2 h. LC-MS showed that the conversion of the starting materials was complete. The reaction solution was cooled to room temperature, the reaction was quenched by adding water (25 mL), and the mixture was extracted with ethyl acetate (20 mL × 3). Then, the organic phase was washed with saturated brine (20 mL × 3), anhydrous sodium sulfate was added, dried for 0.5 h, and filtered. The filtrate was concentrated under reduced pressure and the crude product was isolated by silica gel column chromatography (petroleum ether : ethyl acetate = 20:1 - 5:1) to give compound A-8 (3.1 g, light yellow solid, yield: 86.59%). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.36 (d, J = 12.8 Hz, 1H), 8.28 (s, 1H), 7.95 (d, J = 12.8 Hz, 1H), 7.32-7.24 (m, 4H), 7.20 (s, 1H), 6.99 (t, J = 7.2 Hz, 1H), 3.31-3.26 (m, 1H), 1.28 (d, J = 6.8 Hz, 6H); MC m/z (IER): 357.7 [M+H] ⁺ .

Stage 8:

Guanidine hydrochloride (2.4 g, 25.2 mmol) was added to anhydrous ethanol (50 mL). Sodium methoxide (2.4 g, 25.2 mmol) was added under a protective nitrogen atmosphere, the reaction mixture was stirred at room temperature for 0.5 h, then compound A-8 (3 g, 8.4 mmol) was added. After complete addition, the reaction solution was refluxed and the reaction was carried out for 18 h. LC-MS showed that the conversion of the starting materials was complete. The reaction mixture solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (DCM:MeOH = 50:1-20:1, DCM = dichloromethane) to obtain compound A-9 (900 mg, light yellow solid, yield: 33.17%, compound 2).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (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=6.8 Hz, 6H); MS m/z (ESI): 323.7 [M+H] ⁺ .

Stage 9:

Compound A-9 (3 g, 9.29 mmol) was dissolved in 1,4-dioxane (40 mL), trimethylsilylacetylene (9 g, 92.9 mmol), DIEA (12 g, 92.9 mmol), CuI (0.6 g), and Pd( _PPh3 ) _2Cl2 (0.6 g) were added _sequentially , and nitrogen was purged 3 times. The reaction was carried out under a protective nitrogen atmosphere at 50 °C for 2 h. LC-MS showed that the conversion of the starting materials was mostly complete. The reaction mixture solution was cooled to room temperature, filtered, the filter cake was washed with 1,4-dioxane (10 mL), the filtrate was concentrated under reduced pressure to remove dioxane, then purified water (100 mL) was added and extracted with ethyl acetate (100 mL × 3). The organic phases were combined, anhydrous sodium sulfate (20 g) was added, dried for 30 min, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1-5:1) to give compound A-10 (2 g, yield: 63.1%). MS m/z (ESI): 341.9 [M+H] ⁺ .

Stage 10:

Compound A-10 (2 g, 5.87 mmol) was dissolved in THF (tetrahydrofuran, 20 mL) and TBAF (tetrabutylammonium fluoride, 1.53 g, 5.87 mmol) was added. The reaction was carried out at room temperature for 10 min. LC-MS showed that the conversion of the starting materials was complete. The reaction mixture solution was evaporated to dryness in a rotary evaporator to obtain an oily residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:3) to obtain compound A (0.7 g, yellow solid, yield: 44.6%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.33 (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=6.8 Hz, 6H). MS m/z (ESI): 269.8 [M+H] ⁺ .

Example 2: Preparation of crystalline form I of anhydrate of compound A (method 1)

10.0 g of Compound A was added to 100 ml of water, 6 M hydrochloric acid solution was added dropwise at 0°C until the solid was completely dissolved, and the mixture was stirred at room temperature for 1 h. The solution was filtered, then the filtrate was collected and 1 M aqueous NaOH solution was added dropwise at 0°C until the pH value was 12, and a white solid was precipitated. The solid was collected by filtration. The resulting solid was stirred in 100 ml of water for 2 h, and the solid was collected by filtration. The solid was dried in vacuo at 50°C for 6 h, and the resulting solid was the desired crystalline form. The X-ray powder diffraction pattern is shown in Fig. 1; that obtained by DSC and TGA analysis is shown in Fig. 2 and the sample was examined using a scanning electron microscope and the crystal morphology is shown in Fig. 3.

Thermogravimetric analysis (TGA) results show that the crystalline form sample has a mass loss of 0.1% at 25-150°C, indicating that this crystalline form does not contain water of crystallization.

Example 3: Preparation of crystalline form I of anhydrate of compound A (method 2)

1.3 g of Compound A was added to 100 ml of tetrahydrofuran and stirred at room temperature until completely dissolved, the resulting solution was filtered and the filtrate was collected. To the filtrate was slowly added dropwise 300 ml of n-heptane and the mixture was stirred at room temperature overnight to ensure precipitation of the solid and the suspension was filtered and a crystalline form was obtained. The X-ray powder diffraction pattern obtained was the same as that shown in Fig. 1.

Example 4: Preparation of crystalline form I of compound A anhydrate (method 3)

2.0 g of Compound A was added to 80 ml of tetrahydrofuran and stirred at 50°C until completely dissolved and filtered while hot. The filtrate was cooled to 5°C, 100 ml of methyl tert-butyl ether were slowly added dropwise and the mixture was stirred at 5°C for 30 min. A solid precipitated and the suspension was filtered to obtain a crystalline form. The X-ray powder diffraction pattern was the same as that shown in Fig. 1.

Example 5: Preparation of crystalline form II of the monohydrate of compound A

2.0 g of Compound A were suspended in 100 ml of methanol (containing 1 wt % water) and stirred at room temperature for 3 days, and the solid was collected by filtration. The X-ray powder diffraction pattern obtained by X-ray powder diffraction is shown in Fig. 4; and the plot obtained by DSC and TGA analysis is shown in Fig. 5. The results of thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 6.2% at 25-100°C, which indicated that this crystalline form contained 1 molecule of crystallization water, since the theoretical water content of the sample containing 1 molecule of crystallization water was 6.27%.

Example 6: Preparation of crystalline form III of the hemihydrate of compound A

4.0 g of Compound A was added to 50 ml of dimethyl sulfoxide and stirred at room temperature until completely dissolved. The resulting solution was filtered and the filtrate was collected. 100 ml of water was slowly added dropwise to the filtrate, the resulting mixture was stirred at room temperature overnight and a solid was precipitated. The suspension was filtered and a crystalline form was obtained. The X-ray powder diffraction pattern obtained by powder X-ray diffraction is shown in Fig. 6; and the curve obtained by DSC and TGA analysis is shown in Fig. 7. The results of thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 3.6% at 25-80°C, which indicated that this crystalline form contained 0.5 molecules of crystallization water, since the theoretical water content of a sample containing 0.5 molecules of crystallization water was 3.24%.

Example 7: Preparation of crystalline form IV of the sesquihydrate of compound A (method 1)

2.0 g of Compound A was suspended in 100 ml of water and stirred at room temperature for 3 days, and the solid was collected by filtration. The X-ray powder diffraction pattern obtained by powder X-ray diffraction is shown in Fig. 8; and the plot obtained by DSC and TGA analysis is shown in Fig. 9. The results of thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 9.4% at 25-100°C, which indicated that this crystalline form contained 1.5 molecules of crystallization water, since the theoretical water content of the sample containing 1.5 molecules of crystallization water was 9.12%.

Example 8: Preparation of crystalline form IV of the sesquihydrate of compound A (method 2)

1.3 g of Compound A was added to 100 ml of tetrahydrofuran and stirred at room temperature until completely dissolved. The resulting solution was filtered and the filtrate was collected. 300 ml of water was slowly added dropwise to the filtrate and the mixture was stirred at room temperature overnight to ensure precipitation of the solid. The suspension was filtered and the crystalline form was obtained. The X-ray powder diffraction pattern is shown in Fig. 8.

Example 9: Preparation of crystalline form V of monohydrate of compound A

4.0 g of Compound A was added to 50 ml of dimethyl sulfoxide and stirred at room temperature until completely dissolved, and after filtration, the filtrate was collected. 100 ml of methanol (containing 1 wt % of water) was slowly added dropwise to the filtrate and stirred at room temperature overnight to ensure precipitation of the solid. The suspension was filtered and a crystalline form was obtained. The X-ray powder diffraction pattern obtained by powder X-ray diffraction is shown in Fig. 10; and the curve obtained by DSC and TGA analysis is shown in Fig. 11. The results of thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 6.8% at 25-80°C, which indicated that this crystalline form contained 1 molecule of crystallization water, since the theoretical water content of the sample containing 1 molecule of crystallization water was 6.27%.

Example 10: Preparation of crystalline form VI of monohydrate of compound A

5.0 g of Compound A was added to 100 ml of a solvent mixture containing acetone and water (4/1) to obtain a suspension, which was stirred at room temperature for 3 days and the solid was collected by filtration. The X-ray powder diffraction pattern is shown in Fig. 12; and the plot obtained by DSC and TGA analysis is shown in Fig. 13.

The water content determined using the V20 Karl Fischer moisture titration apparatus was 6.3%, indicating that this crystalline form contains 1 molecule of crystallization water, since the theoretical water content of a sample containing 1 molecule of crystallization water is 6.27%.

Example 11: Preparation of crystalline form VII of the sesquihydrate of compound A

2.0 g of Compound A was added to 100 ml of a solvent mixture containing ethanol and water (1/1), stirred at 50°C until completely dissolved, and filtered while hot. The filtrate was slowly cooled to 5°C, and the solid was collected by filtration. The X-ray powder diffraction pattern obtained by X-ray powder diffraction is shown in Fig. 14; and the plot obtained by DSC and TGA analysis is shown in Fig. 15. The results of thermogravimetric analysis (TGA) showed that the crystalline form sample had a weight loss of 9.5% at 25-75°C, which indicated that this crystalline form contained 1.5 molecules of crystallization water, since the theoretical water content of the sample containing 1.5 molecules of crystallization water was 9.12%.

Example 12: Preparation of crystalline form VIII of the hemihydrate of compound A

2.0 g of Compound A was added to 100 ml of a solvent mixture containing acetone and water (1/1), stirred at 50°C until completely dissolved, and filtered while hot. The filtrate was slowly cooled to 5°C, and the solid was collected by filtration. The X-ray powder diffraction pattern obtained by powder X-ray diffraction is shown in Fig. 16; and the plot obtained by DSC and TGA analysis is shown in Fig. 17. The thermogravimetric analysis (TGA) results showed that the crystalline form sample had a weight loss of 3.6% at 25-105°C, which indicates that this crystalline form contains 0.5 molecule of crystallization water, since the theoretical water content of the sample containing 0.5 molecule of crystallization water is 3.24%.

Experimental examples

Experimental Example 1: Stability Study at Room Temperature

Crystalline form I obtained in Example 2, crystalline form II obtained in Example 5, crystalline form III obtained in Example 6, crystalline form IV obtained in Example 7, crystalline form V obtained in Example 9, crystalline form VI obtained in Example 10, crystalline form VII obtained in Example 11, and crystalline form VIII obtained in Example 12 were respectively placed in medical bags made of low-density polyethylene, and the bags were sealed and kept at room temperature for 180 days. X-ray powder diffractometer Bruker D8 Advance was used to measure the X-ray powder diffractometer. The results showed that the samples of crystalline forms I, II, III, IV, V, VI, VII, and VIII did not change crystal form after 180 days, and the stability was good. Fig. 18 shows a comparison of X-ray powder diffractometers of crystalline form I obtained before and after keeping at room temperature for 180 days.

Experimental Example 2: High Temperature Stability Study

The stability of the crystalline form I obtained in Example 2 was investigated at 60°C and the X-ray powder diffractometer (XRPD) was measured using a Bruker D8 Advance powder X-ray diffractometer (see Fig. 19). The results showed that the sample of crystalline form I did not undergo a change in crystal form after 5, 10 and 30 days and its stability was excellent.

Experimental Example 3: Stability Study at High Humidity

The stability of the crystalline form I obtained in Example 2 was investigated under the following conditions: RH = 92.5%/25°C, and the X-ray powder diffractometer (see Fig. 20) was used to measure the X-ray powder diffractometer stability. The results showed that the sample of crystalline form I did not undergo a change in crystal form after 5, 10 and 30 days, and its stability was excellent.

Experimental Example 4: Stability Study under Mechanical Milling

The crystalline form I obtained in Example 2 was mechanically milled for 2 min and then X-ray powder diffractometer (see Fig. 21) was used to measure the X-ray powder diffractometer. The results showed that the sample of crystalline form I did not undergo a change in crystal form and its stability was excellent.

From the foregoing description, various modifications of the present invention in addition to those described herein will be apparent to those skilled in the art. Such modifications are intended to be within the scope of the appended claims. All literature cited in this application, including all patents, applications, journal articles, books, and any other publications, are incorporated herein by reference in their entirety.

Claims (29)

1. Crystalline form I of the anhydrate of compound A , having a PRXRD (powder X-ray diffraction pattern) containing characteristic peaks located at diffraction angles (2θ) equal to 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 19.8±0.2° and 20.3±0.2°. 2. Crystalline form I of the anhydrate of compound A according to claim 1, wherein crystalline form I has a PRRG containing characteristic peaks located at diffraction angles (2θ) equal to 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2° and 20.3±0.2°. 3. Crystalline form I of the anhydrate of compound A according to claim 1 or 2, wherein crystalline form I has a PRRG containing characteristic peaks located at diffraction angles (2θ) equal to 6.2±0.2°, 10.1±0.2°, 11.9±0.2°, 12.3±0.2°, 13.9±0.2°, 16.9±0.2°, 17.8±0.2°, 18.6±0.2°, 19.8±0.2°, 20.3±0.2°, 21.8±0.2°, 23.0±0.2°, 23.6±0.2°, 24.1±0.2°, 26.2±0.2°, 26.5±0.2°, 27.8±0.2°, 28.5±0.2°, 29.3±0.2° and 30.6±0.2°. 4. Crystalline form I of the anhydrate of compound A according to any one of claims 1 to 3, wherein crystalline form I has a differential scanning calorimetry (DSC) pattern containing endothermic/exothermic peaks located at 245/255°C. 5. Crystalline form I of the anhydrate of compound A according to any one of claims 1 to 4, wherein in thermogravimetric analysis, crystalline form I has a mass loss of 0.1% when heated to 100-150°C. 6. A method for obtaining crystalline form I of the anhydrate of compound A according to any one of paragraphs 1-5, comprising the following stages: 1) adding compound A to water, then adding acid, stirring to dissolve compound A and obtaining a solution, which is filtered to obtain a filtrate; 2) adding a base to the solution or filtrate obtained in step 1) and collecting the precipitated solid by filtration; and 3) adding the obtained solid to water and stirring, filtering to collect the solid, which is dried and crystalline form I is obtained. 7. The method according to claim 6, wherein the acid is acetic acid, trifluoroacetic acid, hydrochloric acid or sulfuric acid. 8. The method according to claim 6, wherein the base is sodium hydroxide, potassium hydroxide or ammonia. 9. A method for obtaining crystalline form I of the anhydrate of compound A according to any one of claims 1 to 5, comprising dissolving compound A in a good solvent to obtain a solution, then adding an antisolvent to the solution and stirring to ensure precipitation of a solid, which is filtered and the crystalline form is obtained; where the good solvent is a cyclic ether containing 3-10 carbon atoms; and The antisolvent is a hydrocarbon containing 5-10 carbon atoms or a simple linear ether containing 2-6 carbon atoms. 10. A method for obtaining crystalline form I of the anhydrate of compound A according to any one of claims 1 to 5, comprising dissolving compound A in a good solvent to obtain a solution, then adding an antisolvent to the solution and stirring to ensure precipitation of a solid, which is filtered and the crystalline form is obtained; where the good solvent is tetrahydrofuran, 2-methyltetrahydrofuran or dioxane; and The antisolvent is n-hexane, n-heptane, diethyl ether, diisopropyl ether or methyl tert-butyl ether. 11. The method of claim 10, wherein the good solvent is tetrahydrofuran; and the antisolvent is n-heptane or methyl tert-butyl ether. 12. The method according to claim 10, wherein the ratio of the mass of compound A/volume of good solvent (g/ml) is 1:(30-120). 13. The method according to claim 10, wherein the ratio of the mass of compound A/volume of good solvent (g/ml) is 1:40 or 1:100. 14. The method according to claim 10, wherein the ratio of the volume of the good solvent to the volume of the antisolvent is from 1:1 to 1:5. 15. Compound A, which has the following structure: 16. A pharmaceutical composition for the prevention or treatment of a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist, comprising crystalline form I according to claim 1 or compound A according to claim 15 and one or more pharmaceutically acceptable carriers. 17. Use of crystalline form I according to claim 1 or compound A according to claim 15 for the preparation of a medicinal product for the prevention or treatment of a disease mediated by a P2X3 and/or P2X2/3 receptor antagonist. 18. The use according to claim 17, wherein the disease is selected from the group consisting of the following: a urinary tract disease selected from the following: reduced bladder capacity, frequent urination, urge incontinence, stress incontinence, bladder hyperreactivity, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, nocturia, urinary urgency, pelvic hypersensitivity, urethritis, pelvic pain syndrome, prostatodynia, cystitis and idiopathic bladder hypersensitivity; pain selected from the following: inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, central pain, pain caused by burns, migraine and severe paroxysmal headache with periodic relapses, pain due to nerve damage; pain due to neuritis; neuralgia; pain due to poisoning; pain due to ischemic damage; pain due to interstitial cystitis; pain due to cancer; pain due to viral, parasitic or bacterial infection; post-traumatic pain and pain associated with irritable bowel syndrome; cardiovascular disease; respiratory disease selected from the following: chronic obstructive pulmonary disease, asthma and bronchospasm; gastrointestinal disease selected from the following: irritable bowel syndrome, inflammatory bowel disease, biliary colic, renal colic and pain associated with gastrointestinal distension. 19. The use according to claim 18, wherein the cardiovascular disease is hypertension; and the irritable bowel syndrome is diarrhea-dominant irritable bowel syndrome.