Crystals of neurokinin-1 antagonist prodrug compounds

Abstract

The present disclosure relates to a crystal of a neurokinin-1 antagonist prodrug compound. Specifically, the present disclosure relates to a novel crystal and preparation method of the compound of formula I. The novel crystal of the present disclosure has good physicochemical properties and is more advantageous for clinical treatment. [Formula 1] TIFF2025502261000016.tif64168

Description

[Technical field]

[0001] This application claims priority to: CN202210033685.4, application date is January 12, 2022.

[0002] (Technical field) The present disclosure relates to crystals of neurokinin-1 antagonist prodrug compounds, and in particular to novel crystals and methods of preparation of the compound of formula I: [Background technology]

[0003] Tachykinins are peptide ligands of neurokinin receptors. Neurokinin receptors, such as NK1, NK2 and NK3, are involved in various biological processes. They are found in the nervous and circulatory systems of mammals, as well as in peripheral tissues. Thus, modulation of such receptors has been investigated for the potential treatment or prevention of various physiological disorders, conditions, or diseases in mammals.

[0004] On the other hand, drug-induced hemolysis occurs when red blood cells are destroyed in large quantities by immune factors after a drug enters the body, and is clinically manifested as hemolysis, such as anemia, jaundice, and soy-sauce-like urine. Drug-induced hemolytic anemia is classified into three types: (1) drug-induced immunity causing antibody-mediated hemolysis, (2) drug action on red blood cells with genetic enzyme deficiency (e.g., G6PD deficiency), and (3) drug-induced hemolysis on abnormal hemoglobin. The key to treating such diseases is to discontinue the use of related drugs and control the occurrence of hemolysis to prevent complications.

[0005] WO2020259675 provides novel NK1 antagonist prodrug compounds (formula I) that are effective in treating various physiological disorders, symptoms and diseases with minimal side effects, and the compounds have good pharmaceutical activity. [ka] [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2020259675 Summary of the Invention [Problem to be solved by the invention]

[0007] The crystal structure of an active pharmaceutical ingredient often affects the chemical stability of the drug, and different crystallization and storage conditions may cause the crystal structure of the compound to change, and sometimes the formation of other crystals. In general, amorphous drugs do not have a regular crystal structure and often suffer from defects such as low product stability, fine crystals, difficulty in filtration, prone to aggregation, and poor flowability. Therefore, it is necessary to improve all aspects of the properties of the compound represented by formula I, and thorough research must be carried out to find new crystal forms with higher crystal purity and better chemical stability. [Means for solving the problem]

[0008] (Summary of the invention) The present disclosure provides a novel crystalline form of the compound of formula I, which has good stability and good clinical applicability. [ka]

[0009] The type I crystal of the compound represented by formula I provided by the present disclosure has characteristic diffraction peaks at 2θ angles of 4.1, 10.3, 11.6, 12.3, 17.8, 20.6, and 20.8 in its powder X-ray diffraction spectrum.

[0010] The type I crystal of the compound represented by formula I provided by the present disclosure has characteristic diffraction peaks at 2θ angles of 4.1, 10.3, 10.6, 11.6, 12.3, 13.1, 14.0, 15.0, 16.0, 16.4, 17.1, 17.8, 18.0, 18.3, 18.6, 19.1, 19.4, 19.6, 20.2, 20.6, 20.8, 21.0, 21.7, 22.2, 22.5, 23.0, 23.4, 24.0, 24.3, 24.7, 27.4, and 30.7 in its powder X-ray diffraction spectrum.

[0011] The type I crystal of the compound represented by formula I provided by the present disclosure has an X-ray powder diffraction spectrum as shown in FIG.

[0012] The crystal form II of the compound represented by formula I provided by the present disclosure has characteristic peaks at 2θ angles of 5.4, 8.4, 13.6, 17.2, 17.8, 20.6, and 21.5 in its powder X-ray diffraction spectrum.

[0013] The type II crystal of the compound represented by formula I provided by the present disclosure has characteristic peaks at 2θ angles of 5.4, 7.8, 8.4, 9.5, 10.7, 11.4, 11.6, 13.6, 13.8, 14.0, 14.5, 14.8, 15.6, 15.8, 16.2, 16.7, 17.2, 17.8, 18.6, 19.0, 19.6, 20.1, 20.6, 21.0, 21.5, 21.8, 22.3, 22.8, 23.3, 23.5, 23.8, 24.1, 24.7, 25.0, 25.4, and 25.7 in its powder X-ray diffraction spectrum.

[0014] The powder X-ray diffraction spectrum of the type II crystal of the compound represented by formula I provided by the present disclosure is as shown in Figure 3. The powder X-ray diffraction spectrum of the type III crystal of the compound represented by formula I provided by the present disclosure has characteristic peaks at 2θ angles of 10.0, 17.6, 18.0, 18.7, 19.5, 20.4, and 20.9.

[0015] The type III crystal of the compound represented by formula I provided by the present disclosure has characteristic peaks at 2θ angles of 4.8, 10.0, 10.3, 10.6, 11.2, 11.7, 13.4, 14.0, 14.6, 16.5, 17.3, 17.6, 18.0, 18.7, 19.3, 19.5, 20.0, 20.4, 20.9, 21.5, 22.1, 22.4, 22.9, 23.2, 24.6, 25.1, 26.6, and 34.2 in its powder X-ray diffraction spectrum.

[0016] The type III crystal of the compound represented by formula I provided by the present disclosure has an X-ray powder diffraction spectrum as shown in FIG.

[0017] In the Form I crystal of the compound of formula I provided by the present disclosure, the error range of the 2θ angle is ±0.2.

[0018] The present invention further provides a method for preparing crystalline Form I of the compound of formula I, comprising the steps of mixing and stirring the compound of formula I with a suitable amount of isopropyl ether and isolating the solid.

[0019] The present invention further provides a method for preparing crystalline Form II of the compound of formula I, comprising the steps of mixing and stirring the compound of formula I with a suitable amount of methyl tert-butyl ether and isolating the solid.

[0020] The present invention further provides a method for preparing crystalline Form III of the compound of formula I, comprising the steps of mixing and stirring the compound of formula I with a suitable amount of 1,4-dioxane, and isolating the solid.

[0021] In some embodiments, the method for preparing the crystals further comprises adding another solvent to remove residual solvent and slurrying the mixture. The other solvent is preferably ethyl acetate or the like. If necessary, the mixture may be slurried at a low temperature, which can be attempted through the experience of a person skilled in the art.

[0022] The present disclosure further provides a method for purifying a compound of formula I, comprising the steps of mixing and stirring the compound of formula I with methyl tert-butyl ether and separating the solids.

[0023] In some embodiments, the method further comprises mixing and stirring the separated solid with methyl tert-butyl ether and a second solvent to precipitate and separate the solid, the second solvent being one or more selected from N,N-dimethylformamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, dioxane, toluene, ethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, and isopropyl alcohol, preferably ethyl acetate.

[0024] The structure of the crystals obtained in the present disclosure is determined and the crystals are studied by powder X-ray diffraction spectrum (XRPD) and differential scanning calorimetry (DSC).

[0025] The crystallization method of the crystals of the present disclosure is a conventional method such as volatilization crystallization, cooling crystallization, or room temperature crystallization.

[0026] The starting material used in the method for preparing the crystals of the present disclosure may be any form of the compound represented by formula I, and specific forms include, but are not limited to, amorphous, any crystalline, hydrated, solvated, etc.

[0027] The present disclosure further provides pharmaceutical compositions comprising a crystal of a compound of Formula I and one or more pharma- ceutically acceptable carriers or excipients.

[0028] The present disclosure further provides pharmaceutical compositions prepared from a crystal of a compound of formula I and one or more pharma- ceutically acceptable carriers or excipients.

[0029] The present disclosure further provides a method for preparing a pharmaceutical composition comprising mixing a crystal of a compound of formula I with one or more pharma- ceutically acceptable carriers or excipients.

[0030] The disclosure further provides the use of a crystal of a compound of formula I, or a pharmaceutical composition prepared by the process, in the preparation of a medicament for treating a physiological disorder, condition or disease in a patient, wherein the physiological disorder, condition or disease is preferably a respiratory disorder, cough, inflammatory disease, skin disease, ophthalmological disease, depression, anxiety, phobia, bipolar disorder, alcoholism, neuroactive substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDs-related dementia, Town's disease, stress-related disorder, obsessive-compulsive disorder, bulemia, anorexia nervosa, bulimia, mania, premenstrual syndrome, gastrointestinal dysfunction, atherosclerosis, fibrotic disease, obesity, type II diabetes, headache, neuropathic pain, post-exercise pain, chronic pain syndrome, bladder disorder, genitourinary disorder, or vomiting or nausea.

[0031] The crystal of the compound of formula I described in the present disclosure has good physicochemical properties, among which, type II crystal has less solvent residue, and has significant advantages as raw drug.Other crystals have some solvent residue and are easily dissolved in conventional solvents, so that it is difficult to remove the residual solvent.In addition, the raw drug of certain crystals is more useful for the preparation of medicines due to its excellent physicochemical properties.

[0032] In the specification and claims of this application, unless otherwise specified, the scientific and technical terms used herein have the meanings that are generally understood by those skilled in the art.However, in order to better understand this disclosure, the definitions and explanations of some relevant terms are provided below.Furthermore, if the definitions and explanations of terms provided in this application contradict the meanings that are generally understood by those skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

[0033] The "X-ray powder diffraction spectrum or XRPD" described in the present disclosure satisfies the Bragg formula, 2d sinθ=nλ (where λ is the wavelength of the X-ray, the diffraction order n is any positive integer, and generally, the first-order diffraction peak is taken, where n=1), when X-rays are incident on an atomic plane of a crystal or a part of a crystal sample with a lattice spacing of d at an oblique angle θ (which is the supplementary angle of the incident angle and is also called the Bragg angle), and this series of X-ray powder diffraction patterns can be measured.

[0034] As used in this disclosure, "X-ray powder diffraction spectrum or XRPD" is a spectrum obtained by using Cu-Ka radiation in an X-ray powder diffractometer.

[0035] "Differential Scanning Calorimetry or DSC" as described in this disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference during the heating or constant temperature process of the sample to characterize all physical and chemical changes associated with thermal effects and obtain phase change information of the sample.

[0036] "Thermogravimetric analysis or TGA" as described in this disclosure refers to the continuous measurement of the mass of a sample as a function of temperature or time under programmed temperature control.

[0037] "2θ or 2θ angle" as described in this disclosure refers to the diffraction angle, where θ is the Bragg angle, the unit is ° or degree, and the error range of 2θ is ±0.3 or ±0.2 or ±0.1.

[0038] The "crystal interplanar spacing or crystal interplanar distance (d value)" described in this disclosure refers to three non-parallel unit vectors a, b, c selected by the space lattice that connect two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units called interplanar spacings. The space lattice is divided according to the lines of the determined rectangular parallelepiped units, resulting in a series of rectilinear grids called space lattices or crystal lattices. The lattice and crystal lattice reflect the periodicity of the crystal structure using geometric points and lines, respectively, and different crystal planes have different interplanar spacings (i.e., the distance between two adjacent parallel crystal planes); the unit is Å or angstroms.

[0039] "Weight volume percentage" (w / v) as used in this disclosure refers to the mass (in g) of a component contained per 100 mL of a liquid system, i.e., g / 100 mL. [Brief description of the drawings]

[0040] [Figure 1] 1 is an amorphous XRPD spectrum of the compound of formula I. [Diagram 2] 1 is an XRPD spectrum of crystalline form I of the compound represented by formula I. [Diagram 3] 1 is an XRPD spectrum of crystalline form II of the compound of formula I. [Figure 4] 1 is an XRPD spectrum of crystalline form III of the compound represented by formula I. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The present invention will be described in more detail in conjunction with the following examples. However, the examples of the present invention are only used to illustrate the technical solutions of the present invention, and do not limit the essence and scope of the present invention.

[0042] Test conditions for the equipment used in the test:

[0043] 1. Differential Scanning Calorimeter (DSC) Instrument model: METTLER TOLEDO DSC 1 Purge gas: Nitrogen gas Heating rate: 10.0℃ / min Temperature range: 40~250℃

[0044] 2. X-ray Powder Diffraction (XRPD) Equipment model: BRUKER D8 FOCUS X-ray tube: Monochromatic Cu-Kα radiation (Cu-Kα1 wavelength is 1.5406 Å, Cu-Kα2 wavelength is 1.54439 Å, and Cu-Kα wavelength is the weighted average of Kα1 and Kα2 λ=1.5418 Å) Scanning mode: θ / 2θ, Scanning range: 2~40° Voltage: 40KV, Current: 40mA

[0045] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are within the range of 10-6 -6 The units are expressed in ppm. NMR was measured using a Bruker AVANCE-400 nuclear magnetometer, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0046] MS is measured using a FINNIGAN LCQAd (ESI mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX)).

[0047] High performance liquid chromatography (HPLC) analyses are performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0048] Chiral HPLC analysis is performed using an Agilent 1260 DAD high performance liquid chromatograph.

[0049] For high performance liquid phase preparations, Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs are used.

[0050] Chiral preparations use a Shimadzu LC-20AP preparative chromatograph.

[0051] The CombiFlash high-speed fractionation device used is Combiflash Rf200 (TELEDYNE ISCO).

[0052] The silica gel plate for thin layer chromatography uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specifications of the silica gel plate used in thin layer chromatography (TLC) are 0.15mm~0.2mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm~0.5mm.

[0053] In silica gel column chromatography, Yantai Yellow Sea silica gel 200 to 300 mesh silica gel is usually used as a carrier.

[0054] Known starting materials of the present disclosure can be synthesized using or according to methods known in the art or can be purchased commercially from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela (Accela ChemBio Inc), Darui Chemicals, etc.

[0055] Unless otherwise noted in the examples, all reactions can be carried out under an argon or nitrogen gas atmosphere.

[0056] By argon or nitrogen gas atmosphere it is meant that the reaction bottle is connected to a balloon of argon or nitrogen gas with a volume of about 1 L.

[0057] By hydrogen gas atmosphere is meant that a hydrogen gas balloon of approximately 1 L volume is connected to the reaction bottle.

[0058] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenation apparatus and a Clear Blue QL-500 hydrogen generation apparatus or a HC2-SS hydrogenation apparatus.

[0059] The hydrogenation reaction is usually carried out by evacuating and filling with hydrogen three times.

[0060] Microwave reactions use a CEM Discover-S 908860 microwave reactor.

[0061] Unless otherwise explained in the examples, solutions refer to aqueous solutions.

[0062] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0063] The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The developer used in the reaction, the eluent system of column chromatography used in purifying the compound, and the developer system of thin layer chromatography included A: n-hexane / ethyl acetate system and B: dichloromethane / methanol system, and the volume ratio of the solvents was adjusted according to the polarity of the compound, and can also be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine and acetic acid.

[0064] Example 1: Preparation of compounds of formula I [ka]

[0065] [ka]

[0066] Under N2 protection, compound 1 (2.43 g, 4.86 mmol, 1 eq) was weighed into a 100 mL three-necked bottle and dissolved in dichloromethane (36 mL), diisopropylethylamine (5 g, 38.76 mmol, 8 eq) was added, the mixture was cooled to -30°C, trimethylchlorosilane (1.36 g, 12.52 mmol, 2.6 eq) was added, and the mixture was stirred at room temperature for 2 hours. Then, the mixture was cooled to -25°C, chloromethyl chloroformate (0.77g, 6mmol, 1.23eq) was added dropwise to the dichloromethane solution, and the reaction was completed while controlling the temperature at -20°C to -5°C. The reaction solution was poured into ice water, the liquid was separated, and the mixture was extracted with dichloromethane, water and 1N hydrochloric acid solution were added, the liquid was separated, and the mixture was washed successively with brine, saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 3.0g of a yellow gel, with a yield of 104%.

[0067] [ka]

[0068] Under the protection of N2, compound 2 (2.8 g, 4.53 mmol, 1 eq), tetrabutylammonium iodide (1.68 g, 4.55 mmol, 1 eq), di-tert-butyl potassium phosphate (5.63 g, 22.67 mmol, 5 eq) and dioxane (84 mL) were added to a 500 mL three-necked bottle, heated to 55° C. and stirred for 4 hours. The reaction solution was cooled, poured into ethyl acetate and water, the liquid was separated, extracted with ethyl acetate, washed with aqueous sodium sulfite solution, then washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 3.73 g of a yellow solid, 107% yield.

[0069] Step 3: [ka]

[0070] Under the protection of N2, compound 3 (6.65 g, 8.67 mmol, 1 eq) was added to a 500 mL single-mouth bottle and dissolved in dichloromethane (200 mL). Trifluoroacetic acid (9.89 g, 86.7 mmol, 10.0 eq) was slowly added under ice water cooling, stirred until the reaction was completed, and concentrated to obtain 2.29 g of oily matter, which was purified by reverse phase silica gel column (C18) (solution A: 20 mmol of NH4HCO3 aqueous solution, solution B: acetonitrile), then adjusted to pH=1-2 with 1 M phosphoric acid, extracted with dichloromethane, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.7 g of the target product.

[0071] 1 H-NMR(400MHz,CD3OD): δ(ppm) 7.89(s,2H),7.86(s,1H),7.41-7.27(m,5H),5.66(d,J=12Hz,1H),5.50-5.47(m,1H),4.60 (d,J=8Hz,1H),4.20-3.88(m,3H),2.51-2.10(m,5H),1.86-1.66(m,3H),1.44-1.31(m,4H).

[0072] Powder X-ray diffraction detection showed that compound 4 (ie, the compound represented by formula I) was amorphous, and the XRPD spectrum is shown in FIG.

[0073] Example 2: Preparation of Form I Crystals of the Compound of Formula I About 5.0 g of the compound represented by formula I is weighed out, 50 ml of isopropyl ether is added, and stirring is continued to dissolve the solid, stirring is continued until the solid precipitates, and the mixture is filtered and dried under vacuum to obtain the crystal form I of the compound represented by formula I, whose XRPD spectrum is shown in FIG. 2 and the characteristic peak positions are shown in Table 1. The DSC spectrum shows an endothermic peak at 102.48° C.

[0074] [Table 1-1] [Table 1-2]

[0075] Example 3: Preparation of Crystalline Form II of the Compound of Formula I About 1.0g of the compound represented by formula I was weighed, 6ml of methyl tert-butyl ether was added, and the solid was dissolved by stirring. The crystals were precipitated by cooling in an ice-water bath for 2 hours, filtered, and the cake was slurried in 1350μl of ethyl acetate and 1350μl of methyl tert-butyl ether for 2 hours, slurried in an ice-water bath for 1 hour, filtered, and dried in vacuum to obtain the II crystals of the compound represented by formula I, whose XRPD spectrum is shown in FIG. 3, and the characteristic peak positions are shown in Table 2. The DSC spectrum shows an endothermic peak at 126.07℃.

[0076] [Table 2-1] [Table 2-2]

[0077] Example 4: Preparation of Crystalline Form III of the Compound of Formula I About 2.0 g of the compound represented by formula I is weighed out, 30 ml of 1,4-dioxane is added, and the mixture is stirred at room temperature until it is completely dissolved, and the stirring is continued until a solid precipitates, and the mixture is filtered and dried in vacuum to obtain the III-type crystal of the compound represented by formula I, whose XRPD spectrum is shown in FIG. 4 and the characteristic peak positions are shown in Table 3. The DSC spectrum shows an endothermic peak at 112.36° C.

[0078] [Table 3-1] [Table 3-2]

[0079] Example 5: Solvent Residual Amount of Crystals of Compound of Formula I The amount of remaining solvent in the crystals of the compound represented by formula I was measured by gas chromatography, and the results are shown in the table below. Among them, the amount of remaining solvent in the crystals of type II was the smallest.

[0080] [Table 4]

[0081] Example 6: Preparation of a pharmaceutical composition of the compound of formula I Tert-butyl alcohol and water were mixed in a 1:1 volume ratio to obtain a 50% tert-butyl alcohol solution. 90% of the target volume of the solution was taken, and 5% (weight to volume percentage) of mannitol and 4.36% of the compound of formula I raw material were added thereto, and dissolved by stirring at room temperature (dissolved is considered when the solution has no significant lumps or flocculent insoluble matter). The pH was adjusted to 5 with dilute hydrochloric acid or sodium hydroxide, filtered through a 45 μm organic filter to obtain a clear solution, and made to volume with 50% tert-butyl alcohol. The above solution was stored at 4° C. before being dispensed. After dispensing according to the target volume, the stopper was filled halfway and a freeze-drying program was performed. After the program was completed, it was filled with nitrogen and the plug was pressed to remove it from the box.

[0082] When the type II crystals of the compound of formula I were used as the raw material of the compound of formula I, the raw material dissolved more quickly, the raw material did not aggregate, and there were no significant lumps or flocculent insoluble matters in the solution, which did not affect the preparation of the formulation.

[0083] When an amorphous compound of formula I is used as a raw material for the compound of formula I, the raw material aggregates in large amounts in the solution, and as a result, the raw material cannot be completely dissolved, making it difficult to prepare a freeze-dried formulation.

[0084] Example 7 1.0 g of the type I crystals of the compound represented by formula I was added to 1.5 mL of ethyl acetate, stirred at room temperature, filtered, and dried in vacuum, and it was determined that the crystals were converted to type II crystals of the compound represented by formula I.

[0085] Example 8 1.0 g of the type III crystals of the compound represented by formula I was added to 1.5 mL of ethyl acetate, stirred at room temperature, filtered, and dried in vacuum, and it was determined that the type III crystals of the compound represented by formula I were converted.

Claims

1. Form I crystal of the compound represented by formula I. 【Chemistry 1】 (Its powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 4.1, 10.3, 11.6, 12.3, 17.8, 20.6, and 20.8.)

2. The I-type crystal of the compound represented by formula I according to claim 1, wherein the powder X-ray diffraction spectrum has characteristic diffraction peaks at 2θ angles of 4.1, 10.3, 10.6, 11.6, 12.3, 13.1, 14.0, 15.0, 16.0, 16.4, 17.1, 17.8, 18.0, 18.3, 18.6, 19.1, 19.4, 19.6, 20.2, 20.6, 20.8, 21, 21.7, 22.2, 22.5, 23.0, 23.4, 24.0, 24.3, 24.7, 27.4, and 30.

7.

3. 2. The compound of claim 1, wherein the powder X-ray diffraction spectrum is as shown in FIG.

2.

4. A type II crystal of the compound represented by formula I, having characteristic peaks at 2θ angles of 5.4, 8.4, 13.6, 17.2, 17.8, 20.6 and 21.5 in a powder X-ray diffraction spectrum.

5. The type II crystal of the compound represented by formula I according to claim 4, wherein the powder X-ray diffraction spectrum has characteristic peaks at 2θ angles of 5.4, 7.8, 8.4, 9.5, 10.7, 11.4, 11.6, 13.6, 13.8, 14.0, 14.5, 14.8, 15.6, 15.8, 16.2, 16.7, 17.2, 17.8, 18.6, 19.0, 19.6, 20.1, 20.6, 21.0, 21.5, 21.8, 22.3, 22.8, 23.3, 23.5, 23.8, 24.1, 24.7, 25.0, 25.4, and 25.

7.

6. 5. The compound of claim 4, wherein the X-ray powder diffraction spectrum is as shown in FIG.

3.

7. A type III crystal of the compound represented by formula I, having characteristic peaks at 2θ angles of 10.0, 17.6, 18.0, 18.7, 19.5, 20.4, and 20.9 in a powder X-ray diffraction spectrum.

8. 8. The compound of formula I according to claim 7, wherein the powder X-ray diffraction spectrum is as shown in FIG.

9. The crystal of the compound represented by formula I according to any one of claims 1 to 8, wherein the error range of the 2θ angle is ±0.

2.

10. A method for preparing the crystal form II of the compound of formula I according to any one of claims 4 to 6, comprising the steps of mixing and stirring the compound of formula I with a suitable amount of methyl tert-butyl ether, and isolating the solid.

11. A pharmaceutical composition comprising a crystal of a compound of formula I according to any one of claims 1 to 9, and one or more pharma- ceutically acceptable carriers or excipients.

12. A method for preparing a pharmaceutical composition, comprising the step of mixing a crystalline compound of formula I according to any one of claims 1 to 9 with one or more pharma- ceutically acceptable carriers or excipients.

13. Use of a crystal of a compound of formula I as defined in any one of claims 1 to 9, or a pharmaceutical composition as defined in claim 11, in the preparation of a medicament for treating a physiological disorder, condition or disease in a patient, comprising The physiological disorder, condition or disease is preferably a respiratory disorder, cough, inflammatory disease, skin disease, ophthalmological disease, depression, anxiety, phobia, bipolar disorder, alcoholism, neuroactive substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDs-related dementia, Town's disease, stress-related disorder, obsessive-compulsive disorder, bulemia, anorexia nervosa, binge eating disorder, manic states, premenstrual syndrome, gastrointestinal dysfunction, atherosclerosis, fibrotic disease, obesity, type II diabetes, headache, neuropathic pain, post-exercise pain, chronic pain syndrome, bladder disorder, genitourinary disorder, or vomiting or nausea.

14. A method for purifying a compound of formula I, comprising the steps of mixing and stirring the compound of formula I with methyl tert-butyl ether and isolating the solids.

15. 15. The method of claim 14, further comprising mixing and stirring the separated solid with methyl tert-butyl ether and a second solvent to precipitate and separate the solid, wherein the second solvent is one or more selected from N,N-dimethylformamide, 1-methyl-2-pyrrolidone, dimethylsulfoxide, tetrahydrofuran, ethyl acetate, isopropyl acetate, butyl acetate, dioxane, toluene, ethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, and isopropyl alcohol, preferably ethyl acetate.

Images