Crystal form of compound containing benzene ring as well as preparation method and application of crystal form

Abstract

The invention discloses a crystal form of a benzene ring-containing compound as well as a preparation method and application of the crystal form. The invention provides a crystal form of a compound as shown in a formula A. The crystal form is selected from a crystal form I, a crystal form II, a crystal form III or a crystal form IV. The compound as shown in the formula A is high in crystal form purity, good in solubility and low in hygroscopicity, has good stability under the conditions of high temperature and high humidity, and has important value for optimization and development of drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a crystal form of a compound containing a benzene ring, a preparation method and an application thereof. Background Art

[0002] The compound represented by formula A has high P2X4 antagonistic activity, good selectivity, low toxicity and good metabolic stability.

[0003]

[0004] Polymorphism is common in compounds, and general drugs may exist in two or more different crystalline states. The existence form and quantity of polymorphic compounds are unpredictable. Different crystalline forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, uniformity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, in the process of new drug development, it is necessary to conduct comprehensive polymorph screening of compounds, and selecting crystalline forms suitable for drug formulation development has important clinical significance. Summary of the invention

[0005] The technical problem to be solved by the present invention is the defect that the compound of formula A in the prior art lacks a stable crystal form. The present invention provides a crystal form of a compound containing a benzene ring, a preparation method thereof, and an application thereof. The crystal form of compound A of the present invention has high purity, good solubility, low hygroscopicity, and good stability under high temperature and high humidity conditions, which is of great value to the optimization and development of drugs.

[0006] The present invention provides a crystalline form I of a compound represented by formula A:

[0007]

[0008] Its X-ray powder diffraction pattern (XRPD) expressed in 2θ using Cu-Kα radiation has characteristic peaks at 6.10°±0.20°, 15.55±0.20°, 19.41°±0.20° and 25.25°±0.20°.

[0009] In certain preferred embodiments of the present invention, the crystalline form I has characteristic peaks at 6.10°±0.20°, 15.55°±0.20°, 18.45°±0.20°, 19.41°±0.20°, 21.67°±0.20°, 24.07°±0.20°, and 25.25°±0.20° using Cu-Kα radiation and expressed in 2θ angle; more preferably, at 6.10°±0.20°, 14.16°±0.20°, 15 There are characteristic peaks at .55±0.20°, 15.80°±0.20°, 17.23°±0.20°, 18.45°±0.20°, 19.41°±0.20°, 20.22°±0.20°, 21.67°±0.20°, 23.26°±0.20°, 24.07°±0.20°, 24.29°±0.20°, 25.25°±0.20°, 27.86°±0.20° and 28.62°±0.20°.

[0010] In certain preferred embodiments of the present invention, the characteristic peaks and relative intensities of the XRPD of the crystalline form I using Cu-Kα radiation and expressed at 2θ angles are shown in the following table. More preferably, the XRPD pattern of the crystalline form I using Cu-Kα radiation and expressed at 2θ angles is substantially as follows: Figure 1 shown.

[0011]

[0012]

[0013] In certain preferred embodiments of the present invention, the thermogravimetric analysis (TGA) spectrum of the crystalline form I shows no weight loss before 200° C., and its TGA spectrum is preferably as follows: Figure 2 shown.

[0014] In certain preferred embodiments of the present invention, the differential scanning calorimetry (DSC) spectrum of the crystalline form I has an endothermic peak at 231.7±4°C, a melting enthalpy of 134.32±5 J / g, and its DSC spectrum is preferably as follows: Figure 2 shown.

[0015] In certain preferred embodiments of the present invention, the XRPD spectrum of the crystalline form I before and after the DVS test has no obvious change, and the XRPD comparison spectrum before and after the DVS test is preferably as follows: Figure 2 shown.

[0016] In certain preferred embodiments of the present invention, in the polarized light microscope (PLM) spectrum of the crystal form I, the crystal form is an irregular crystal of about 2 μm, with an agglomeration of 20-50 μm, and its PLM diagram is preferably substantially as follows Figure 4 shown.

[0017] In certain preferred embodiments of the present invention, the purity of the crystalline form I is generally above 95%, preferably above 98%.

[0018] In certain preferred embodiments of the present invention, in the stability study experiment of the crystal form I, it was placed at 80°C for 24 hours or at 60°C, 25°C / 60%RH, 40°C / 75%RH, 25°C / 90(±5)%RH for 14 days, and the main peak purity did not change significantly, the crystal form did not change, and the crystallinity did not decrease significantly. Combined with the DSC and TGA graphs, it can be seen that the product is anhydrous crystalline form.

[0019] In certain preferred embodiments of the present invention, in the hygroscopicity test of the crystal form I, the weight of the crystal form I increased by 0.158% from 0-80% RH, and it was almost non-hygroscopic. After the DVS test, the crystal form did not change.

[0020] In certain preferred embodiments of the present invention, in the grinding, crystal conversion and tableting experiments of the crystal form I, the crystal form of the crystal form I did not change before and after dry grinding, and the crystallinity gradually decreased with the increase of grinding time. When grinding to 10 minutes, it was close to amorphous. After grinding the crystal form I in water for 10 minutes, the crystal form did not change, and the crystallinity did not decrease significantly; after grinding in ethanol for 2 minutes, it was converted into an ethanol solvate. The crystal form I was tableted at a pressure of 40Mpa, and the crystal form did not change, and the crystallinity did not decrease significantly.

[0021] The present invention provides a crystalline form II of the compound of formula A, which has characteristic peaks at 17.75°±0.20°, 21.13°±0.20°, 22.42°±0.20° and 24.78°±0.20° in an X-ray powder diffraction pattern (XRPD) expressed in 2θ using Cu-Kα radiation.

[0022] In certain preferred embodiments of the present invention, the crystalline form II has characteristic peaks at 13.43°±0.20°, 17.75°±0.20°, 22.42°±0.20°, 21.13°±0.20°, 23.43°±0.20°, 24.78°±0.20°, 25.18°±0.20° and 25.99°±0.20° in an XRPD pattern expressed in 2θ angle using Cu-Kα radiation; more preferably, at 12.35°±0.20°, 12.88°±0.20°, 13.43°±0.20°, 24.78°±0.20°, 25.18°±0.20° and 25.99°±0.20° .... There are characteristic peaks at 0.20°, 13.43°±0.20°, 14.18°±0.20°, 18.17°±0.20°, 17.75°±0.20°, 21.13°±0.20°, 22.42°±0.20°, 23.43°±0.20°, 24.26°±0.20°, 24.78°±0.20°, 25.18°±0.20°, 25.99°±0.20°, 27.08°±0.20° and 31.17°±0.20°.

[0023] In certain preferred embodiments of the present invention, the characteristic peaks and relative intensities of XRPD expressed at 2θ angle using Cu-Kα radiation of the crystalline form II are shown in the following table. More preferably, the XRPD pattern of the crystalline form II expressed at 2θ angle is substantially as follows: Figure 5 shown.

[0024]

[0025]

[0026] In certain preferred embodiments of the present invention, the TGA spectrum of the crystal form II shows a weight loss of 1.1% in the temperature range of RT-80°C. The TGA spectrum is preferably as follows: Figure 6 shown.

[0027] In certain preferred embodiments of the present invention, the DSC spectrum of the crystalline form II has a first endothermic peak at 66.7±4°C, a melting enthalpy of 15.19±5 J / g, a second endothermic peak at 234.6±4°C, and a melting enthalpy of 116.82±5 J / g. The DSC spectrum is preferably as follows Figure 6 shown.

[0028] The present invention provides a crystalline form III of the compound of formula A, which has characteristic peaks at 9.49°±0.20°, 12.19±0.20°, 18.66°±0.20° and 23.45°±0.20° in an X-ray powder diffraction pattern (XRPD) expressed in 2θ using Cu-Kα radiation.

[0029] In certain preferred embodiments of the present invention, the crystalline form III has characteristic peaks at 9.49°±0.20°, 12.19°±0.20°, 17.81°±0.20°, 18.66°±0.20°, 20.64°±0.20°, 23.14°±0.20°, 23.45°±0.20°, 24.43°±0.20° and 26.54°±0.20° in its XRPD pattern expressed in 2θ angle using Cu-Kα radiation; more preferably, at 8.59°±0.20°, 9.49°±0.20°, 11.46°±0.20°, There are characteristic peaks at 12.19°±0.20°, 15.03°±0.20°, 16.6°±0.20°, 17.81°±0.20°, 18.28°±0.20°, 18.66°±0.20°, 20.02°±0.20°, 20.64°±0.20°, 22.16°±0.20°, 23.14°±0.20°, 23.45°±0.20°, 24.43°±0.20°, 25.12°±0.20°, 26.54°±0.20°, 27.03°±0.20° and 29.00°±0.20°.

[0030] In certain preferred embodiments of the present invention, the characteristic peaks and relative intensities of XRPD using Cu-Kα radiation and expressed at 2θ angles of the crystalline form III are shown in the following table. More preferably, the XRPD pattern of the crystalline form III expressed at 2θ angles is substantially as follows: Fig. 9 shown.

[0031]

[0032]

[0033] In certain preferred embodiments of the present invention, the DSC graph of the crystalline form III has a first endothermic peak at 76.5±4°C, a melting enthalpy of 43.12±5 J / g, a second endothermic peak at 112.3°C±4, a melting enthalpy of 15.84±5 J / g, and a third endothermic peak at 233.0±4°C, a melting enthalpy of 105.05±5 J / g. The DSC spectrum is preferably substantially as follows Fig.10 shown.

[0034] In certain preferred embodiments of the present invention, the TGA graph of the crystalline form III shows a weight loss of 0.49% in the range of room temperature to 90°C and a weight loss of 0.45% in the range of 90-120°C. The TGA graph is preferably substantially as follows: Fig.10 shown.

[0035] The present invention provides a crystalline form IV of the compound of formula A, which has characteristic peaks at 7.84°±0.20°, 15.80°±0.20°, 17.24°±0.20° and 23.88°±0.20° in an X-ray powder diffraction pattern (XRPD) expressed in 2θ using Cu-Kα radiation.

[0036] In certain preferred embodiments of the present invention, the XRPD of the crystalline form IV using Cu-Kα radiation and expressed in 2θ angle is 7.84°±0.20°, 12.85°±0.20°, 15.80°±0.20°, 17.24°±0.20°, 18.38°±0.20°, 18.97°±0.20°, 22.02°±0.20° and 23.88°±0.20°. having characteristic peaks; more preferably, having characteristic peaks at 7.84°±0.20°, 12.85°±0.20°, 15.80°±0.20°, 17.24°±0.20°, 18.38°±0.20°, 18.97°±0.20°, 20.15°±0.20°, 22.02°±0.20°, 23.88°±0.20° and 27.27°±0.20°.

[0037] In certain preferred embodiments of the present invention, the characteristic peaks and relative intensities of XRPD expressed at 2θ angle using Cu-Kα radiation of the crystalline form IV are shown in the following table. More preferably, the XRPD pattern of the crystalline form IV expressed at 2θ angle is substantially as follows: Fig.12 shown.

[0038]

[0039]

[0040] In certain preferred embodiments of the present invention, the TGA spectrum of the crystalline form IV has no weight loss before 200° C., and its TGA spectrum is preferably as follows: Fig.13 shown.

[0041] In certain preferred embodiments of the present invention, the DSC spectrum of the crystalline form IV has a first endothermic peak in the range of 224.0±4°C, a melting enthalpy of 114.93±5 J / g, a second endothermic peak in the range of 233.4±4°C, a melting enthalpy of 25.30±5 J / g, and an exothermic peak at 229.3°C, an enthalpy of 2.36±5 J / g, and its DSC spectrum is preferably as follows Fig.13 shown.

[0042] The present invention also provides a method for preparing the crystalline form I of the compound as shown in formula A, wherein the preparation method is scheme 1, scheme 2, scheme 3 or scheme 4; wherein,

[0043] Scheme 1: After dissolving the compound represented by formula A in acetone, the solution is added dropwise into water, stirred for 2-4 hours and then filtered, and the filter cake is collected and dried to obtain Form I;

[0044] Scheme 2: After heating Form II to 200°C, Form II is transformed into Form I, or after placing Form II at room temperature (about 22-25°C) for 15 days, Form II is transformed into Form I;

[0045] Scheme 3, after heating Form IV to the exothermic peak, Form IV is transformed into Form I;

[0046] In scheme 4, at room temperature and 50°C, Form I and Form II were competitively slurried in water and n-heptane for 3 days and 7 days, and the obtained solids were all Form I.

[0047] The present invention also provides a method for preparing the crystal form II of the compound shown in formula A, which comprises the following steps: using the crystal form I as a raw material, and obtaining it by cooling crystallization method (for example, 22 to 30° C.) in acetonitrile, acetonitrile-toluene, acetonitrile-methyl tert-butyl ether, acetonitrile-water, acetonitrile-isopropyl acetate, acetonitrile-ethyl acetate and acetonitrile-methanol solvent systems.

[0048] The present invention also provides a method for preparing the crystalline form III of the compound shown in formula A, the preparation method comprising the following steps: using the crystalline form I as a raw material, suspending and slurrying in an ethanol-ethyl acetate (e.g., v:v=1:1) or ethanol-isopropyl acetate (e.g., v:v=1:1) system under room temperature to obtain it.

[0049] The present invention also provides a method for preparing the crystalline form IV of the compound shown in formula A, the preparation method comprising the following steps: using the crystalline form I as a raw material (for example, 18° C.), obtaining it in an acetone-methyl tert-butyl ether (for example, v:v=1:6) system by an anti-solvent crystallization method (positive drop).

[0050] The present invention provides a pharmaceutical composition, which comprises a crystalline form (e.g., one or more of crystalline form I, crystalline form II, crystalline form III, and crystalline form IV) of the compound as described above in formula A and a pharmaceutical excipient. The dosage of the crystalline form can be a therapeutically effective amount.

[0051] The pharmaceutical excipients can be those widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the effective absorption of the active ingredient after the subject receives the composition. The pharmaceutical excipients can be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipients can include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.

[0052] Substances that can be used as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl cellulose. sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffered solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants.

[0053] The pharmaceutical composition of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or lyophilizing processes.

[0054] The present invention also provides a use of a crystalline form (e.g., one or more of crystalline form I, crystalline form II, crystalline form III, and crystalline form IV) of the compound as described above as shown in formula A in the preparation of a P2X4 inhibitor. In the application, the P2X4 inhibitor can be used in mammals; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the inhibitory effect of P2X4.

[0055] The present invention also provides a use of the above-mentioned crystalline form of the compound shown in formula A (for example, one or more of crystalline form I, crystalline form II, crystalline form III, and crystalline form IV) or the pharmaceutical composition as described above in the preparation of a drug; the drug is a drug for protecting, treating, curing or alleviating a P2X4-mediated or activity-related disease in an animal; or, the drug is a drug for treating cardiovascular and cerebrovascular diseases, urinary tract diseases, respiratory diseases, cardiovascular and cerebrovascular diseases, pain, ophthalmic diseases, autoimmune diseases, endometriosis, chronic itching, itching, inflammation, sleep disorders, epilepsy, mental illness, neurodegeneration, traumatic brain injury, colon syndrome, inflammatory bowel disease, digestive tract diseases, gastrointestinal dysfunction, sexual dysfunction, arthritis, rheumatoid arthritis, blood diseases, musculoskeletal and connective tissue development disorders.

[0056] The present invention provides a use of a crystalline form of the compound as shown in formula A (e.g., one or more of crystalline form I, crystalline form II, crystalline form III, and crystalline form IV) or a pharmaceutical composition as described above for protecting, treating, curing, or alleviating a disease mediated by P2X4 or activity-related in an animal (e.g., a human).

[0057] The diseases include, but are not limited to, cardiovascular and cerebrovascular diseases, urinary tract diseases, respiratory diseases, pain, ophthalmic diseases, autoimmune diseases, endometriosis, chronic pruritus, pruritus, inflammation, sleep disorders, epilepsy, mental illness, neurodegeneration, traumatic brain injury, colon syndrome, inflammatory bowel disease, digestive tract diseases, gastrointestinal disorders, sexual dysfunction, arthritis, rheumatoid arthritis, blood diseases, musculoskeletal and connective tissue development disorders;

[0058] In some embodiments, the cardiovascular and cerebrovascular diseases are selected from heart failure, chronic heart failure, hypertension, myocardial infarction, stroke, thrombosis and atherosclerosis,

[0059] In some embodiments, the urinary tract disorder is selected from urinary incontinence, cystitis, overactive bladder, dysuria or cystitis, interstitial cystitis, and painful bladder syndrome;

[0060] In some embodiments, the respiratory disease is selected from a respiratory disorder including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, respiratory failure, cough (e.g., acute cough or chronic cough), and bronchiolitis obliterans syndrome;

[0061] In some embodiments, the pain is selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache or chronic pain, pain syndromes (acute and chronic), neuropathic pain, diabetic neuropathic pain, diabetic neuropathy, cancer-related pain, chemotherapy- or poisoning-induced pain, pelvic pain and endometriosis-related pain;

[0062] In some embodiments, the ophthalmic disease is selected from dry eye, ocular neuropathic pain, ocular trauma, and postoperative ocular pain.

[0063] In some embodiments, the acute cough or chronic cough comprises a cough caused by a coronavirus infection.

[0064] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0065] In the present invention, RT means 15-30°C, for example 20-25°C.

[0066] In the present invention, the term "substantially" means that with slight changes in measuring equipment, measuring conditions, and batches of products to be measured, the positions of the peaks in the graph may vary slightly and are not regarded as absolute values.

[0067] The reagents and raw materials used in the present invention are commercially available.

[0068] The positive and progressive effects of the present invention are:

[0069] 1. The prior art has not reported the crystal form of this type of compound, and this application first discovered multiple new crystal forms of this compound. Through a large number of experiments and screening, the present invention first prepared crystal form I, crystal form II, crystal form III, and crystal form IV and used them as candidate objects.

[0070] 2. The crystal forms I-IV prepared by the present invention have high purity, good solubility, low hygroscopicity, good crystal stability under high temperature and high humidity conditions, and are easy to store. They can avoid the risk of crystal transformation during drug development or production, and avoid changes in bioavailability and efficacy. They can be developed into dosage forms suitable for clinical use and have strong economic value.

[0071] 3. The present invention also provides a preparation method of Form I, Form II, Form III and Form IV, which is simple to operate and has high reproducibility, does not easily leave solvent residues, is environmentally friendly, and is suitable for production on different scales. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 is the XRPD pattern of Form I;

[0073] Figure 2 It is the TGA / DSC overlay of Form I;

[0074] Figure 3 For the crystal form I 1 H NMR spectrum;

[0075] Figure 4 is the PLM diagram of Form I;

[0076] Figure 5 is the XRPD pattern of Form II;

[0077] Figure 6 It is the TGA / DSC overlay of Form II;

[0078] Figure 7 For the crystal form II 1 H NMR spectrum;

[0079] Figure 8 This is an XRPD overlay of Form II after heating to 100°C using DSC;

[0080] Fig. 9 is the XRPD pattern of Form III;

[0081] Fig.10 It is the TGA / DSC overlay of Form III;

[0082] Fig.11 For the crystal form III 1 H NMR spectrum;

[0083] Fig.12 is the XRPD pattern of Form IV;

[0084] Fig.13 is a TGA / DSC overlay of Form IV;

[0085] Fig.14 For the crystal form IV 1 H NMR spectrum;

[0086] Fig.15 The XRPD spectrum of Form IV after being heated to the exothermic peak by DSC;

[0087] Fig.16This is a comparison diagram of the crystal form I before and after the crystal form under the condition of 80℃ / 24h;

[0088] Fig.17 This is a crystal form overlay diagram of Form I on the third day of stability testing;

[0089] Fig.18 This is a crystal form overlay diagram of Form I on the 7th day of stability testing;

[0090] Fig.19 This is a crystal form overlay diagram of Form I on the 14th day of stability testing;

[0091] Fig. 20 This is the DVS spectrum of the hygroscopicity experiment of Form I;

[0092] Fig.21 This is a comparison of XRPD images of Form I before and after the hygroscopicity experiment. DETAILED DESCRIPTION

[0093] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0094] The present invention is further described in detail below in conjunction with specific examples. It should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited by the following examples. The implementation conditions adopted in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in routine experiments.

[0095] In the following examples, the experimental methods are usually carried out under conventional conditions or conventional test conditions, and the compounds can be obtained by organic synthesis or by commercially available methods.

[0096] The abbreviations used in the present invention are explained as follows:

[0097] XRPD—X-ray Powder Diffraction

[0098] TGA—Thermogravimetric analysis

[0099] DSC—Differential Scanning Calorimetry

[0100] DVS—Dynamic Water Sorption and Desorption Analysis

[0101] PLM - Polarized Light Microscopy Analysis

[0102] The test conditions are as follows:

[0103] XRPD

[0104] The solids were characterized using an X-ray powder diffractometer (Bruker D8 advance or D2 Phase).

[0105] Scanning angle: 3°(2θ)-40°(2θ).

[0106] Step size: 0.02°(2θ).

[0107] Scan speed: 0.3sec / step (D8), 0.2sec / step (D2).

[0108] Light tube voltage: 40KV (D8), 30KV (D2).

[0109] Light tube current: 40mA (D8), 10mA (D2).

[0110] Rotation: On.

[0111] Sample pan: Zero background sample pan.

[0112] TGA

[0113] Thermogravimetric analysis of solid samples was performed using a TA Instrument Thermogravimetric Analysis Q500 or Discovery TGA 55. After balancing the sample pan, the sample was hung on a hanging wire and raised to the furnace. After stabilization, the sample was heated at a rate of 10°C / min to different endpoint temperatures.

[0114] DSC

[0115] DSC analysis of solid samples was performed using TA Instrument Differential Scanning Calorimeter Q200 and Discovery DSC 250. The sample was weighed and the value was recorded, and then the sample was placed in the sample chamber. The sample was heated from 25°C to different end-point temperatures at a rate of 10°C / min.

[0116] DVS

[0117] DVS analysis of solids was performed using an IGAsorp dynamic water sorption instrument.

[0118] Temperature: 25℃.

[0119] Air flow: 250mL / min.

[0120] Scanning cycles:2.

[0121] Minimum test time: 30 minutes.

[0122] Maximum test time: 2h.

[0123] Waiting for balance: 98%.

[0124] PLM

[0125] The samples were observed using a Nikon Eclipse LV100N POL polarizing microscope.

[0126] Example 1 Preparation of Compound A,

[0127] Reference is made to the preparation method of Example 1 of published PCT patent application WO2021104486A1, the contents of which are incorporated herein by reference in their entirety.

[0128] Example 2 Preparation of Form I of Compound A

[0129] 1. Add ethanol and water to a reaction vessel, stir, add the product obtained in Example 1 to the reaction vessel, heat to 75-85°C, continue stirring for 4-8h, then cool to 20-30°C, continue stirring for 4-7h, filter, rinse the filter cake with water, and collect the filter cake;

[0130] After dissolving the filter cake with acetone at room temperature, the reaction solution was added dropwise to water for 1-3 hours. Stirring was continued for 2-4 hours and then filtered to collect the filter cake.

[0131] The filter cake was temperature controlled at 20-30°C and vacuum dried for 2-12 h, then temperature controlled at 40-50°C and vacuum dried for 2-12 h to obtain Form I.

[0132] Crystalline characterization:

[0133] The XRPD pattern of Form I using Cu-Kα radiation and expressed in 2θ angles is as follows Figure 1 The specific data are shown in the following table. The DSC and TGA analysis results of Form I are shown in Figure 2 As shown, the results show that Form I has an endothermic peak at 231.7°C, with an enthalpy value of 134.32 J / g; Form I has no weight loss before 200°C. 1 H NMR spectrum Figure 3 As shown, no solvent residue is observed, and the crystal form I is an anhydrous crystal form. In the polarizing microscope (PLM) spectrum of the crystal form I, the crystal form is an irregular crystal of about 2 μm, with an agglomeration of 20-50 μm. The PLM diagram thereof is preferably substantially as follows: Figure 4 shown.

[0134]

[0135] Example 3: Crystal transformation experiment and characterization of Form I of Formula A compound

[0136] In order to verify the stability of Form I and screen more forms, Form I obtained in Example 2 was subjected to a form screening experiment by the following method.

[0137] 3.1 Single solvent room temperature suspension method: Form I was placed in butanone, tetrahydrofuran, ethyl acetate, toluene, n-heptane, methyl tert-butyl ether, and water solvent, stirred at room temperature for 4 days, and filtered to obtain Form I.

[0138] 3.2 Single solvent high temperature suspension method: Stir Form I in a solvent such as butanone, isopropyl acetate, toluene, n-heptane, methyl tert-butyl ether, water, ethyl acetate, etc. at 50°C for 4 days, filter, and obtain Form I.

[0139] 3.3 Binary solvent evaporation method: Add 2-3 mL of the selected solvent to the crystal form I to prepare a suspension or a clear solution with a concentration of 20 mg / mL, take 2 mL for filtration, and the filtrate is used for the binary solvent evaporation method experiment. The experimental process is: take a well plate, add two filtrates to each well, 100 μL of each filtrate, cover the top of the well plate with a sealing film, pierce holes, and slowly evaporate at room temperature (about 17°C). When the solvent evaporates completely, the obtained solid is characterized as crystal form I. The binary solvent system is: acetone-water, tetrahydrofuran-water, butanone-water, tetrahydrofuran-n-heptane, acetonitrile-water, ethyl acetate-toluene, ethyl acetate-water, toluene-MTBE (methyl tert-butyl ether).

[0140] 3.4 Single solvent evaporation method: Form I is dissolved in a corresponding solvent to prepare a clear solution or saturated solution of Form I with a concentration of 20 mg / mL, and the solution is left open at room temperature (about 17°C). After the solvent evaporates slowly and completely, the obtained solid is characterized as Form I. The solvent used is methanol or tetrahydrofuran.

[0141] 3.5 Anti-solvent method: dissolve Form I in a good solvent, add a specified volume of anti-solvent at room temperature, continue to stir slowly, wait for solid to precipitate, filter, and dry the obtained solid in vacuum at 50°C for 4h. The obtained solid is characterized as Form I;

[0142] The good solvent / anti-solvent system is: THF / toluene, THF / MTBE, THF / n-heptane, acetone / toluene, acetone / water, butanone / toluene.

[0143] The characterization of the obtained Form I is the same as that of Example 2.

[0144] Example 4: Preparation and characterization of Form II of the compound of formula A

[0145] 4.1 Weigh about 50 mg of Form I prepared in Example 3.1 into a sample bottle, add 2.4 mL of acetonitrile and stir at 50°C until the solid is basically dissolved, then cool and crystallize at 22°C, filter, and dry the obtained solid in vacuo at 50°C to obtain Crystal II.

[0146] 4.2 Weigh 50 mg of Form I prepared in Example 3.1 into a sample bottle. At 50°C, first add 0.5 mL of anti-solvent and then add good solvent until the solid is basically dissolved. After filtering, place the filtrate at 22°C to cool and crystallize, filter, and dry the obtained solid in vacuo at 50°C to obtain Crystal II.

[0147] The good solvent is acetonitrile, and the anti-solvent is toluene, methyl tert-butyl ether, water, isopropyl acetate, ethyl acetate, and methanol. The material ratio is as follows:

[0148] experiment# Antisolvent / Good Solvent Volume ratio 2 Toluene / ACN 1 / 2 3 MTBE / ACN 1 / 1.8 4 Water / ACN 1 / 2 5 EtOH / ACN 1 / 2.2 6 IPAc / ACN 1 / 2 7 EtOAc / ACN 1 / 1.6 8 MeOH / ACN 1 / 2.8

[0149] Crystalline characterization:

[0150] The crystal form II was characterized by the above crystal form characterization method, and its XRPD pattern is as follows: Figure 5 The peak list is shown in the following table, and the DSC and TGA analysis results are shown in Figure 6 As shown, the DSC characterization results show that Form II has two endothermic peaks, with peak values ​​at 66.7°C and 234.6°C, and melting points of 15.19 J / g and 116.82 J / g, respectively. The TGA characterization results show that Form II loses 1.1% (0.26 mol water) before 80°C. 1 H NMR spectrum Figure 7 As shown, 1 No residual solvent was observed in the H NMR spectrum. After heating Form II to 100°C using DSC, the crystal form did not change. Figure 8 Form II is an anhydrous crystal with a melting point of 232.4-234.2°C.

[0151] Peak list of Form II:

[0152]

[0153] Example 5: Preparation and characterization of Form III of the compound of formula A

[0154] 5.1 Weigh about 90 mg of the crystal form I prepared in Example 3.1 into a sample bottle, add 0.5 mL of EtOH and IPAC (isopropyl acetate) respectively, and suspend and stir at room temperature (about 25°C). Stir for 2 days, filter and obtain crystal form III.

[0155] 5.2 About 90 mg of Form I prepared in Example 3.1 was weighed into a sample bottle, 0.5 mL of EtOH and 0.5 mL of EA (ethyl acetate) were added, and the mixture was suspended and stirred at room temperature (about 25° C.) for 3 days, filtered, and the obtained solid was vacuum dried at 50° C. for 1 day to obtain Form III.

[0156] 5.3 At room temperature, Form I and Form II prepared in Example 3.1 were competitively slurried in acetonitrile for 3 days to obtain Form III.

[0157] Crystalline characterization:

[0158] The crystal form III was characterized by the above-mentioned crystal characterization method, and its XRPD pattern is as follows: Fig. 9 The peak list is shown in the following table, and the DSC and TGA analysis results are shown in Fig.10 As shown, the DSC characterization results show that Form III has three endothermic peaks, with peak values ​​of 76.5°C, a melting point of 43.12 J / g, 112.3°C, a melting point of 15.84 J / g, and 233.0°C, a melting point of 105.05 J / g. The TGA results show that Form III loses 0.49% of its weight before 90°C and loses 0.45% of its weight between 90 and 120°C. 1 H NMR spectrum Fig.11 shown.

[0159] The peak list of Form III is:

[0160]

[0161] Example 6: Preparation and characterization of Form IV of the compound of formula A

[0162] Weigh about 350 mg of Form I prepared in Example 3.1 into a sample bottle, add 6.3 mL of acetone at room temperature (about 18°C) to dissolve Form I, filter and take the filtrate, add 37.8 mL of methyl tert-butyl ether at room temperature (about 18°C), continue to stir slowly, filter until solid precipitates, filter, and dry the resulting solid in vacuo at 50°C for 4 h to obtain Crystal IV.

[0163] Crystalline characterization:

[0164] The crystal form IV was characterized by the above characterization method, and its XRPD pattern is as follows: Fig.12 The peak list is shown in the following table, and the DSC and TGA analysis results are shown in Fig.13 As shown, the DSC characterization results show that Form IV has two endothermic peaks and one exothermic peak, with peak values ​​of 224.0°C, 233.4°C and 229.3°C respectively. The TGA characterization results show that Form IV has no weight loss before 200°C. Form IV is an anhydrous crystal. 1 H NMR spectrum Fig.14 shown.

[0165] The peak list of Form IV is:

[0166]

[0167] Example 7 Conversion between various crystal forms

[0168] 7.1 The crystal form IV obtained in Example 6 was heated to the exothermic peak (230°C) and then subjected to XRPD detection. The results are as follows: Fig.15 As shown, the obtained solid is Form I, and the characterization of Form I is the same as that of Example 2.

[0169] 7.2 After the crystal form II obtained in Example 4.1 is heated to 200°C, the crystal form II is transformed into the crystal form I, or after the crystal form II obtained in Example 4.1 is placed at room temperature (about 22-25°C) for 15 days, the crystal form II is transformed into the crystal form I; the characterization of the crystal form I is the same as that in Example 2.

[0170] 7.3 At room temperature and 50°C, Form I obtained in Example 3.1 and Form II obtained in Example 4.1 were competitively slurried in water and n-heptane for 3 days and 7 days, and the obtained solids were both Form I; the characterization of Form I was the same as that in Example 2.

[0171] Example 8 Stability Test of Form I

[0172] A certain amount of Form I prepared in Example 3.1 was weighed, and placed in an open state at 60°C, 25°C / 60%RH, 40°C / 75%RH, and 25°C / 90(±5)%RH, respectively. Samples were taken on the 3rd, 7th, and 14th days, and samples were taken after being placed in an open state at 80°C for 24 hours. The purity of Form I was detected by HPLC and its crystal form was detected by XRPD. The results showed that after Form I was placed at 80°C for 24 hours and at 60°C, 25°C / 60%RH, 40°C / 75%RH, and 25°C / 90(±5)%RH for 14 days, the main peak purity did not change significantly, the crystal form did not change, and the crystallinity did not decrease significantly. Specific experimental parameters and results are shown in the following table and Fig.16 , Fig.17 , Fig.18 and Fig.19 .

[0173]

[0174] Example 9 Solubility test of Form I in biological solvent and water

[0175] Weigh a certain amount of Form I prepared in Example 3.1, add SGF, FaSSIF, FeSSIF and water to prepare a 5 mg / mL suspension, stir thoroughly at 37°C for 0.5h, 2h and 24h, take out, filter, retain the filtrate, determine its solubility by HPLC, and detect the crystal form of the solid in the suspension by XRPD. The results show that the solubility of Form I in FaSSIF and FeSSIF is less than 0.015 mg / mL, and no main peak is detected in SGF and water. Form I is in a good suspension state in SGF, FaSSIF, FeSSIF and water. After stirring for 24h, the crystal form has not changed, and the crystallinity has not decreased significantly. See the table below for specific experimental conditions and results.

[0176]

[0177] Example 10 Stability test of Form I in biological solvent and water

[0178] Weigh a certain amount of Form I prepared in Example 3.1, add SGF, FaSSIF, FeSSIF and water to prepare a 5 mg / mL suspension. Stir thoroughly for 0.5 h, 2 h and 24 h at 37 ° C, take samples, dilute the suspension to 0.25 mg / mL and determine its purity by HPLC. The results show that after stirring Form I in SGF, FaSSIF, FeSSIF and water for 24 h at 37 ° C, the main peak purity does not change significantly. Specific experimental conditions and results are shown in the table below.

[0179]

[0180] Example 11 Hygroscopicity Experiment of Crystal Form I

[0181] The hygroscopicity of the crystal form I prepared in Example 3.1 was measured by DVS, and the solid after DVS test was tested by XRPD. The results showed that the weight of the crystal form I increased by 0.158% from 0-80% RH, and it was almost non-hygroscopic. After DVS test, the crystal form I did not change, and the results were as follows Fig. 20 and Fig.21 .

Claims

1. A crystalline form of a compound as shown in formula A: It is selected from Form I, Form II, Form III or Form IV; in, A crystalline form I of the compound of formula A, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.10°±0.20°, 15.55±0.20°, 19.41°±0.20° and 25.25°±0.20°; A crystalline form II of the compound of formula A, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 17.75°±0.20°, 21.13°±0.20°, 22.42°±0.20° and 24.78°±0.20°; A crystalline form III of the compound of formula A, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.49°±0.20°, 12.19±0.20°, 18.66°±0.20° and 23.45°±0.20°; The crystalline form IV of the compound of formula A has characteristic peaks at 2θ values ​​of 7.84°±0.20°, 15.80°±0.20°, 17.24°±0.20° and 23.88°±0.20° in its X-ray powder diffraction pattern using Cu-Kα radiation.

2. The crystalline form of the compound of formula A according to claim 1, characterized in that: It meets one or more of the following conditions: (1) Form I, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.10°±0.20°, 15.55°±0.20°, 18.45°±0.20°, 19.41°±0.20°, 21.67°±0.20°, 24.07°±0.20°, 25.25°±0.20° and 28.62°±0.20°; (2) Form II, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 13.43°±0.20°, 17.75°±0.20°, 22.42°±0.20°, 21.13°±0.20°, 23.43°±0.20°, 24.78°±0.20°, 25.18°±0.20° and 25.99°±0.20°; (3) Form III, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 9.49°±0.20°, 12.19°±0.20°, 17.81°±0.20°, 18.66°±0.20°, 20.64°±0.20°, 23.14°±0.20°, 23.45°±0.20°, 24.43°±0.20° and 26.54°±0.20°; (4) The crystalline form IV described above has characteristic peaks in its X-ray powder diffraction pattern using Cu-Kα radiation at 2θ values ​​of 7.84°±0.20°, 12.85°±0.20°, 15.80°±0.20°, 17.24°±0.20°, 18.38°±0.20°, 18.97°±0.20°, 22.02°±0.20° and 23.88°±0.20°.

3. The crystalline form of the compound of formula A according to claim 2, characterized in that: It meets one or more of the following conditions: (1) Form I, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 6.10°±0.20°, 14.16°±0.20°, 15.55±0.20°, 15.80°±0.20°, 17.23°±0.20°, 18.45°±0.20°, 19.41°±0.20°, 20.22°±0.20°, 21.67°±0.20°, 23.26°±0.20°, 24.07°±0.20°, 24.29°±0.20°, 25.25°±0.20°, 27.86°±0.20° and 28.62°±0.20°; (2) The DSC spectrum of the crystalline form I has an endothermic peak at 231.7±4°C, and a melting enthalpy of 134.32±5 J / g; (3) In the TGA spectrum of the crystalline form I, there is no weight loss before 200°C; (4) Form II, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 12.35°±0.20°, 12.88°±0.20°, 13.43°±0.20°, 14.18°±0.20°, 18.17°±0.20°, 17.75°±0.20°, 21.13°±0.20°, 22.42°±0.20°, 23.43°±0.20°, 24.26°±0.20°, 24.78°±0.20°, 25.18°±0.20°, 25.99°±0.20°, 27.08°±0.20° and 31.17°±0.20°; (5) In the DSC spectrum of the crystalline form II, there is a first endothermic peak at 66.7±4°C, a melting enthalpy of 15.19±5 J / g, and a second endothermic peak at 234.6±4°C, a melting enthalpy of 116.82±5 J / g; (6) In the TGA spectrum of the crystal form II, the weight loss is 1.1% in the temperature range of RT-80°C; (7) Form III, which uses Cu-Kα radiation, and its X-ray powder diffraction pattern has 2θ values ​​of 8.59°±0.20°, 9.49°±0.20°, 11.46°±0.20°, 12.19°±0.20°, 15.03°±0.20°, 16.6°±0.20°, 17.81°±0.20°, 18.28°±0.20°, 18.66 There are characteristic peaks at 20.02°±0.20°, 20.64°±0.20°, 22.16°±0.20°, 23.14°±0.20°, 23.45°±0.20°, 24.43°±0.20°, 25.12°±0.20°, 26.54°±0.20°, 27.03°±0.20°, and 29.00°±0.20°; (8) In the DSC spectrum of the crystalline form III, there is a first endothermic peak at 76.5±4°C, with a melting enthalpy of 43.12±5 J / g, a second endothermic peak at 112.3°C±4, with a melting enthalpy of 15.84±5 J / g, and a third endothermic peak at 233.0±4°C, with a melting enthalpy of 105.05±5 J / g; (9) In the TGA spectrum of the crystalline form III, the weight loss is 0.49% in the range of room temperature to 90°C, and the weight loss is 0.45% in the range of 90-120°C; (10) Form IV, which uses Cu-Kα radiation and its X-ray powder diffraction pattern has characteristic peaks at 2θ values ​​of 7.84°±0.20°, 12.85°±0.20°, 15.80°±0.20°, 17.24°±0.20°, 18.38°±0.20°, 18.97°±0.20°, 20.15°±0.20°, 22.02°±0.20°, 23.88°±0.20° and 27.27°±0.20°; (11) In the DSC spectrum of the crystalline form IV, there is a first endothermic peak in the range of 224.0±4°C, with a melting enthalpy of 114.93±5 J / g, a second endothermic peak in the range of 233.4±4°C, with a melting enthalpy of 25.30±5 J / g, and an exothermic peak at 229.3°C, with an enthalpy of 2.36±5 J / g; (12) In the TGA spectrum of Form IV, there is no weight loss before 200°C.

4. The crystalline form of the compound of formula A according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The characteristic peaks and relative intensities of the XRPD of Form I using Cu-Kα radiation and expressed in 2θ angle are as follows: (2) The characteristic peaks and relative intensities of the crystal form II using Cu-Kα radiation and XRPD expressed in 2θ angles are shown in the following table: (3) The characteristic peaks and relative intensities of the crystal form III using Cu-Kα radiation and XRPD expressed in 2θ angles are shown in the following table: ； (4) The characteristic peaks and relative intensities of the crystal form IV using Cu-Kα radiation and XRPD expressed in 2θ angles are shown in the following table:

5. The crystalline form of the compound of formula A according to claim 3, characterized in that: It meets one or more of the following conditions: (1) Form I, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG1 ; (2) The thermogravimetric analysis spectrum of the crystal form I is basically shown in Figure 2; (3) The differential scanning calorimetry spectrum of the crystalline form I is substantially as shown in FIG2 ; (4) The hydrogen nuclear magnetic resonance spectrum of the crystal form I is substantially as shown in FIG3 ; (5) The polarizing microscope spectrum of the crystal form I is basically as shown in Figure 4; (6) Form II, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG5 ; (7) The thermogravimetric analysis spectrum of the crystal form II is substantially as shown in FIG6 ; (8) The differential scanning calorimetry spectrum of Form II is substantially as shown in FIG6 ; (9) The hydrogen nuclear magnetic resonance spectrum of the crystal form II is substantially as shown in FIG7 ; (10) Form III, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG9 ; (11) The thermogravimetric analysis spectrum of Form III is substantially as shown in FIG10 ; (12) The differential scanning calorimetry spectrum of Form III is substantially as shown in FIG10 ; (13) The hydrogen nuclear magnetic resonance spectrum of the crystalline form III is substantially as shown in FIG11 ; (14) Form IV, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angles is substantially as shown in FIG12 ; (15) The thermogravimetric analysis spectrum of Form IV is substantially as shown in FIG13 ; (16) The differential scanning calorimetry spectrum of Form IV is substantially as shown in FIG13 ; (17) The hydrogen nuclear magnetic resonance spectrum of Form IV is basically as shown in Figure 14.

6. A method for preparing the crystalline form I of the compound of formula A according to any one of claims 1 to 5, characterized in that: The preparation method is scheme 1, scheme 2, scheme 3 or scheme 4; wherein, Scheme 1: After dissolving the compound represented by formula A in acetone, the solution is added dropwise into water, stirred for 2-4 hours and then filtered, and the filter cake is collected and dried to obtain Form I; Solution 2: After the crystal form II is heated to 200° C., the crystal form II is transformed into the crystal form I, or after the crystal form II is placed at room temperature (about 22-25° C.) for 15 days, the crystal form II is transformed into the crystal form I; Solution 3, after the crystal form IV is heated to the exothermic peak, the crystal form IV is transformed into the crystal form I; In scheme 4, at room temperature and 50°C, the crystal form I and crystal form II are competitively slurried in water and n-heptane for 3 days and 7 days, and the obtained solid is crystal form I.

7. A method for preparing the crystalline form II of the compound of formula A according to any one of claims 1 to 5, characterized in that: The preparation method comprises the following steps: using the crystal form I as a raw material, and obtaining it by cooling crystallization method (for example, 22 to 30° C.) in acetonitrile, acetonitrile-toluene, acetonitrile-methyl tert-butyl ether, acetonitrile-water, acetonitrile-isopropyl acetate, acetonitrile-ethyl acetate and acetonitrile-methanol solvent systems.

8. A method for preparing the crystalline form III of the compound of formula A according to any one of claims 1 to 5, characterized in that: The preparation method comprises the following steps: using the crystal form I as a raw material, suspending and slurrying in an ethanol-ethyl acetate (for example, v:v=1:1) or ethanol-isopropyl acetate (for example, v:v=1:1) system at room temperature to obtain the crystal form I.

9. A method for preparing the crystalline form IV of the compound of formula A according to any one of claims 1 to 5, characterized in that: The preparation method comprises the following steps: using the crystal form I as a raw material, obtaining it in an acetone-methyl tert-butyl ether (for example, v:v=1:6) system by anti-solvent crystallization (for example, 18°C).

10. A crystalline form of a compound represented by formula A, characterized in that: It is obtained by the preparation method according to any one of claims 6 to 9.

11. A pharmaceutical composition comprising the crystalline form of the compound represented by formula A as claimed in any one of claims 1 to 5 or the crystalline form of the compound represented by formula A as claimed in claim 10, and a pharmaceutical excipient.

12. A use of a substance X in the preparation of a P2X4 inhibitor or a drug; the drug can be a drug for protecting, treating, curing or alleviating a disease mediated by or associated with P2X4 activity; or, the drug can be a drug for treating cardiovascular and cerebrovascular diseases, urinary tract diseases, respiratory diseases, cardiovascular and cerebrovascular diseases, pain, ophthalmic diseases, autoimmune diseases, endometriosis, chronic itching, itching, inflammation, sleep disorders, epilepsy, mental illness, neurodegeneration, traumatic brain injury, colon syndrome, inflammatory bowel disease, digestive tract diseases, gastrointestinal dysfunction, sexual dysfunction, arthritis, rheumatoid arthritis, blood diseases, musculoskeletal and connective tissue development disorders; the substance X is a crystalline form of the compound of formula A as described in any one of claims 1 to 5 or a crystalline form of the compound of formula A as described in claim 10.

13. The use according to claim 12, characterized in that It meets one or more of the following conditions: (1) The cardiovascular and cerebrovascular diseases are selected from heart failure, chronic heart failure, hypertension, myocardial infarction, stroke, thrombosis and atherosclerosis; (2) The urinary tract disease is selected from urinary incontinence, cystitis, overactive bladder, dysuria or cystitis, interstitial cystitis and bladder pain syndrome; (3) The respiratory disease is selected from respiratory disorders, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, respiratory failure, cough (such as acute cough or chronic cough) and bronchiolitis obliterans syndrome; (4) The pain is selected from inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache or chronic pain, pain syndrome (acute and chronic), neuropathic pain, diabetic neuropathic pain, diabetic neuropathy, cancer-related pain, chemotherapy or poisoning-induced pain, pelvic pain and endometriosis-related pain; (5) The ophthalmic disease is selected from dry eye, ocular neuropathic pain, ocular trauma and postoperative ocular pain.

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