Crystalline forms of 4-phenylthiazole derivatives and their preparation methods

Abstract

The present invention relates to crystalline forms of 4-phenylthiazole derivatives, pharmaceutical compositions containing same, methods of preparation, and the use of the crystalline forms for manufacturing medicaments for treating thrombocytopenia. [Selected figure] Figure 1

Description

Detailed Description of the Invention

[0001] This application claims priority to Chinese Patent Application No. 201810585583.7, filed on June 8, 2018, entitled "CRYSTAL FORM OF 4-PHENYLTHIAZOLE DERIVATIVE AND PREPARATION METHOD THEREOF," the entire contents of which are incorporated herein by reference.

[0002] [Technical field] The present disclosure relates to crystalline forms of 4-phenylthiazole derivatives and methods for their preparation.

[0003] [background] 4-Phenylthiazole derivatives (also known as compounds of Formula I) having the following structure are useful for treating thrombocytopenia. [ka]

[0004] Thrombopoietin is a polypeptide cytokine consisting of 332 amino acids that promotes platelet production through receptor-stimulated differentiation and proliferation of megakaryocytes. Therefore, 4-phenylthiazole derivatives can be used as drugs to treat symptoms of thrombocytopenia, a blood disorder associated with abnormal platelet counts.

[0005] The solid crystalline form of a compound can substantially affect the physical properties of the compound, including, but not limited to, (1) packing properties such as molar volume, density, and hygroscopicity; (2) thermodynamic properties such as melting temperature, vapor pressure, and solubility; (3) mechanical properties such as decomposition rate and stability (including stability under environmental conditions, particularly humidity and storage conditions); (4) surface properties such as surface area, wettability, interfacial tension, and appearance; (5) mechanical properties such as hardness, tensile strength, compressibility, handleability, flowability, and miscibility; or (6) filtration properties. The selection and control of the solid crystalline form is important for pharmaceutical formulations of compounds. Careful selection and control of the solid crystalline form can reduce synthesis, processing, formulation, or administration problems associated with the compound.

[0006] Chinese Patent No. 1419547 and US Patent No. 2015 / 0148385 disclose methods for synthesizing the compound. Chinese Patent No. 101809008 discloses a crystalline form of the compound of Formula I (referred to herein as crystalline form Y) having major peaks at 2θ diffraction angles of 17.8, 21.1, 22.5, 23.3, 24.1, and 24.4°.

[0007] [Summary of the Invention] The present invention provides a compound of formula I, crystalline form D of the 4-phenylthiazole derivative (also referred to as crystalline form according to the invention or crystalline form D according to the invention or crystalline form D). [ka]

[0008] In one aspect, the present invention provides crystalline form D of the compound of formula I, wherein form D has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles (2θ) of about 4.9±0.2°, about 6.0±0.2°, about 12.5±0.2°, about 18.3±0.2°, about 18.9±0.2°, about 21.0±0.2°, and about 23.8±0.2°.

[0009] In some preferred embodiments, crystalline form D has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles (2θ) of about 4.9±0.2°, about 6.0±0.2°, about 7.3±0.2°, about 12.5±0.2°, about 18.3±0.2°, about 18.9±0.2°, about 19.7±0.2°, about 21.0±0.2°, about 22.2±0.2°, and about 23.8±0.2°.

[0010] In some preferred embodiments, crystalline form D has an XRPD pattern comprising peaks at diffraction angles (2θ) of about 4.9±0.2°, about 6.0±0.2°, about 12.5±0.2°, about 14.7±0.2°, about 15.6±0.2°, about 17.1±0.2°, about 18.3±0.2°, about 18.9±0.2°, about 21.0±0.2°, about 23.8±0.2°, and about 24.9±0.2°.

[0011] In some preferred embodiments, crystalline form D has an XRPD pattern comprising peaks at diffraction angles (2θ) of about 4.9±0.2°, about 6.0±0.2°, about 7.3±0.2°, about 12.5±0.2°, about 14.7±0.2°, about 15.6±0.2°, about 17.1±0.2°, about 18.3±0.2°, about 18.9±0.2°, about 19.7±0.2°, about 21.0±0.2°, about 22.2±0.2°, about 23.8±0.2°, and about 24.9±0.2°.

[0012] In other preferred embodiments, the crystalline form D has an angle of about 4.1±0.2°, about 4.9±0.2°, about 6.0±0.2°, about 6.2±0.2°, about 8.7±0.2°, about 9.8±0.2°, about 10.1±0.2°, about 12.5±0.2°, about 13.4±0.2°, about 14.0±0.2°, about 14.7±0.2°, about 15.6±0.2°, about 17.1±0.2°, about It has an XRPD pattern containing peaks at diffraction angles (2θ) of 17.9±0.2°, about 18.3±0.2°, about 18.5±0.2°, about 18.9±0.2°, about 19.9±0.2°, about 21.0±0.2°, about 21.3±0.2°, about 21.8±0.2°, about 22.7±0.2°, about 23.4±0.2°, about 23.8±0.2°, and about 24.9±0.2°.

[0013] In other preferred embodiments, crystalline form D has an average molecular weight of about 4.1±0.2°, about 4.9±0.2°, about 6.0±0.2°, about 6.2±0.2°, about 7.3±0.2°, about 8.7±0.2°, about 9.8±0.2°, about 10.1±0.2°, about 12.5±0.2°, about 13.4±0.2°, about 14.0±0.2°, about 14.7±0.2°, about 15.6±0.2°, about 17.1±0.2°, about 17.9±0.2°, about 18. 0.2°, about 18.3±0.2°, about 18.5±0.2°, about 18.9±0.2°, about 19.7±0.2°, about 19.9±0.2°, about 21.0±0.2°, about 21.3±0.2°, about 21.8±0.2°, about 22.2±0.2°, about 22.7±0.2°, about 23.4±0.2°, about 23.8±0.2°, and about 24.9±0.2° diffraction angles (2θ).

[0014] In a more preferred embodiment, crystalline form D has an XRPD pattern comprising peaks at diffraction angles (2θ) substantially identical to those shown in FIG.

[0015] In a more preferred embodiment, crystalline form D has an XRPD pattern with peaks substantially identical to those shown in FIG.

[0016] In a more preferred embodiment, crystalline form D has an XRPD pattern as shown in FIG.

[0017] In another aspect, the present invention provides a process for preparing crystalline form D, comprising: 1) dissolving the compound of formula I as a solid in a good solvent for crystallization; 2) adding the solution obtained in step 1) to a poor solvent for crystallization to crystallize; 3) isolating the obtained product and optionally drying the obtained product to obtain crystalline form D; The good solvent for crystallization is selected from ether solvents, ester solvents and mixtures thereof; The present invention provides a process wherein the anti-solvent for crystallization is selected from alkane solvents, arene solvents and mixtures thereof.

[0018] In some embodiments, the volume ratio of the good solvent for crystallization to the poor solvent for crystallization is about 1:20 to about 20:1, preferably about 1:1 to about 1:10, more preferably 1:3 to 1:8, and even more preferably 1:4 to 1:7.

[0019] In some preferred embodiments, the good solvent for crystallization is an ether solvent or an ester solvent, preferably an ether solvent.

[0020] In some other preferred embodiments, the anti-solvent for crystallization is an alkane solvent.

[0021] In some embodiments of the preparation process according to the present invention, the ester solvent is selected from ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, amyl acetate, and combinations thereof, preferably selected from ethyl acetate, isopropyl acetate, and combinations thereof.

[0022] In some other embodiments of the preparation process according to the present invention, the ether solvent is selected from diethyl ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane and combinations thereof, preferably selected from tetrahydrofuran, 1,4-dioxane and combinations thereof.

[0023] In still other embodiments of the preparation process according to the present invention, the alkane solvent is selected from n-pentane, n-hexane, cyclohexane, n-heptane, octane and combinations thereof, preferably n-pentane, n-hexane, n-heptane and combinations thereof, more preferably n-pentane, n-hexane and combinations thereof.

[0024] In some other embodiments of the preparation process according to the present invention, the arene solvent is selected from benzene, toluene, xylene, and combinations thereof.

[0025] In another aspect, the present invention provides a pharmaceutical composition comprising crystalline form D according to the present invention and one or more pharmaceutically acceptable carriers.

[0026] In yet another aspect, the present invention provides the use of crystalline form D according to the present invention or the pharmaceutical composition according to the present invention for the manufacture of a medicament for treating or preventing thrombocytopenia.

[0027] In yet another aspect, the present invention provides crystalline form D according to the present invention or a pharmaceutical composition according to the present invention for use in the treatment or prevention of thrombocytopenia.

[0028] In yet another aspect, the present invention provides a method for treating or preventing thrombocytopenia, comprising the step of administering to a subject in need thereof an effective amount of crystalline form D according to the present invention or the pharmaceutical composition according to the present invention. [Brief explanation of the drawings]

[0029] [Figure 1] 1 shows the XRPD pattern of crystalline form D according to the present invention (the x-axis represents the position of the diffraction angle 2θ (°), and the y-axis represents the diffraction intensity). [Figure 2] 1 shows the DSC curve of crystalline form D according to the present invention (x-axis represents temperature (° C.) and y-axis represents heat flow (W / g)). [Figure 3] 1 shows the thermogravimetric analysis curve of crystalline form D according to the present invention (x-axis represents temperature (° C.) and y-axis represents weight percent (%)). [Figure 4] 1 shows the XRPD patterns of crystalline form D according to the present invention before and after a high temperature stability test (the x-axis represents the position of the diffraction angle 2θ (°), and the y-axis represents the diffraction intensity). [Figure 5] 1 shows the XRPD patterns of crystalline form D according to the present invention before and after high humidity stability testing (the x-axis represents the position of the diffraction angle 2θ (°), and the y-axis represents the diffraction intensity). [Figure 6] 1 shows the XRPD patterns of crystalline form D according to the present invention before and after long-term and accelerated stability tests (x-axis represents the position of the diffraction angle 2θ (°), y-axis represents the diffraction intensity).

[0030] [Detailed explanation] While the present invention will be described in detail, it should be understood that this description is given by way of example only and not by way of limitation.

[0031] General Definitions and Terminology Unless otherwise specified, the technical and scientific terms used herein have the same meaning as those understood by those skilled in the art. In the event of any discrepancy, the definitions provided herein shall prevail. When a specific amount, concentration, or other value or parameter is described in the form of a range, a preferred range, or a preferred upper or lower limit, it should be understood that this is equivalent to specifically revealing any range formed by combining any upper or preferred value with any lower or preferred value, regardless of whether the range is explicitly stated. Unless otherwise specified, the numerical ranges described herein are intended to include the end points of the range, as well as all integers and fractions (decimals) within the range.

[0032] When used with a numerical variable, the term "approximate" or "about" typically refers to the value of the variable within experimental error (e.g., within a 95% confidence interval of the mean) or within ±10% of a specified value, or within a broader range, and all values ​​of the variable.

[0033] The phrase "comprise" or its synonyms "contain," "include," "have," etc., is open-ended and does not exclude other unrecited elements, steps, or ingredients. The phrase "consisting of" excludes unrecited elements, steps, or ingredients. The phrase "consisting essentially of" refers to the specified elements, steps, or ingredients within a specified range, along with any elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. The phrase "comprise" should be understood to encompass the phrases "consisting essentially of" and "consisting of."

[0034] The term "optionally" or "optionally" means that the subsequently described event may or may not occur. The term encompasses cases where the event may occur or cases where the event may not occur.

[0035] As used herein, ranges of values ​​(e.g., "1 to 10") and subranges thereof (e.g., "2 to 6," "6 to 10," "3 to 10," etc.) include any value within the range (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).

[0036] As used herein, the term "compound of Formula I" refers to a compound 4-phenylthiazole derivative represented by the following structural formula: [ka]

[0037] As used herein, the term "solid form" refers to a solid form of a compound of Formula I, for example, a crystalline or amorphous form.

[0038] As used herein, the term "amorphous" refers to any solid material that lacks three-dimensional order. In some cases, amorphous solids can be characterized by known techniques, including XRPD crystallography, differential scanning calorimetry (DSC), solid-state nuclear magnetic resonance (ssNMR) spectroscopy, or a combination thereof. As described below, amorphous solids have XRPD patterns that lack distinct diffraction peaks.

[0039] As used herein, the term "crystalline form" or "crystal" refers to any solid material that has three-dimensional order, which, unlike amorphous materials, has a characteristic XRPD pattern with clearly defined peaks.

[0040] As used herein, the term "substantially pure" means that the crystalline content of the compound is about 95% by weight or more, preferably about 98% by weight or more, and more preferably about 99% by weight or more, based on the total amount of the compound of formula I.

[0041] As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters, data, or values ​​derived therefrom. XRPD patterns are generally characterized by diffraction angle position (x-axis) and / or intensity (y-axis).

[0042] As used herein, the term "2θ" refers to the diffraction angle, given as degrees (°), set in an X-ray diffraction experiment, which is generally the x-axis unit of the diffraction pattern. If the incident beam diffracts at an angle theta (θ) with a particular lattice plane, the experimental setup should report the reflected beam at an angle 2θ (2θ). It should be understood that references herein to specific 2θ values ​​for a particular crystalline form are intended to mean the 2θ values ​​(in degrees) measured using the X-ray diffraction experimental conditions described herein, e.g., using a Cu-Kα radiation source as described herein. As used herein, XRPD patterns are preferably measured using X'Pert in transmission mode at room temperature. 3 The samples were collected using an X-ray powder diffraction analyzer using Cu-Kα radiation with a scan range of 2θ from 3.5° to 40°.

[0043] As used herein, the term "substantially identical" with respect to X-ray diffraction peaks means that typical peak position and / or intensity variations are taken into account. For example, those skilled in the art will understand that diffraction angles (2θ) typically exhibit some variation, typically on the order of 0.1 to 0.2 degrees, and that the instrument used to measure diffraction may also introduce some variation. Furthermore, those skilled in the art will understand that relative peak intensities will vary due to differences between instruments, as well as crystallinity, preferred orientation, sample surface preparation, and other factors known to those skilled in the art, and should be considered only as a qualitative measure.

[0044] As used herein, "the highest peak temperature of the endothermic peak" in the DSC curve of a crystalline form refers to the peak value that represents the endothermic peak profile of the DSC curve.The highest peak temperature of the endothermic peak measured by DSC may vary depending on the purity, weight, particle size of the test substance, and the test heating rate and system error of the device.The values ​​shown cannot be interpreted as absolute values ​​(see: Guo Yonghui, Yang Ning, Lu Yang.Application of Differential Scanning Calorimetry in the Research of Crystal Form Drugs [C] / / China Crystal Form Drug R&D Technology Seminar.2010).

[0045] It should be understood that DSC curves may vary slightly depending on the type of instrument used or the test conditions. For example, a Mettler Toledo DSC1 differential scanning calorimeter can be used to determine DSC curves. As used herein, the term "substantially identical" with respect to DSC curves takes into account the representative characteristic peak positions. For example, those skilled in the art will understand that the characteristic peak positions may exhibit some degree of variation, usually up to 5°C. For solid samples containing polymorphs, the heating rate of a DSC test significantly affects the DSC curve. At relatively fast heating rates, the thermal hysteresis effect of the instrument is evident, and solid crystalline forms with high melting points do not have sufficient time to recrystallize. Therefore, DSC curves often only show the melting endothermic peak of the crystalline form with a low melting point. At moderate heating rates, the DSC curve shows two peaks: one for the crystalline form with a low melting point and the other for the solid crystalline form with a high melting point. Only at relatively low heating rates does the thermal hysteresis effect of the instrument become weak, showing three peaks: a melting peak for the crystalline form with a low melting point, an exothermic peak for recrystallization, and an endothermic peak for the melting peak for the crystalline form with a high melting point. Those skilled in the art will understand that determining the range of heating rates corresponding to the above different DSC curves may vary depending on the weight, morphology, particle size, and distribution of the test substance (see Giron D. Thermal analysis and calorimetric methods in the characterization of polymorphs and solvates [J]. Thermochimica Acta, 1995, 248:1-59).

[0046] Thermogravimetric analysis (TGA) is a common method for determining the thermal stability of compounds. TGA curves can be measured, for example, using a Mettler Toledo TGA1 instrument. The TGA error can be within approximately ±0.5% by weight. The term "substantially identical" means that such error variations are taken into account. Exemplary test conditions are a temperature range of 35 to 500°C, a heating rate of 10 K / min, and nitrogen (99.99%) purge gas.

[0047] Particle size detection is a common method for determining particle size. Particle size can be measured, for example, using a Malvern Mastersizer 3000 laser particle size analyzer with a Hydro LV injector. Particle size distributions, also known as median particle sizes, such as Dv(10) (also called D10), Dv(50) (also called D50), and Dv(90) (also called D90), refer to the particle size corresponding to the cumulative particle size distribution of a sample when it reaches 50%. D50 indicates that 50% of the particles in the sample have a particle size larger than this value and 50% of the particles have a particle size smaller than this value. Similarly, a particle size value corresponding to D90 indicates that 90% of the particles in the sample have a particle size smaller than this value. A particle size value corresponding to D10 indicates that 10% of the particles in the sample have a particle size smaller than this value. The particle size of crystalline form D may affect the position of the DSC endothermic peak. Such changes are within ±5°C. The particle size distribution of crystalline form D is the original particle size distribution of crystalline form D.

[0048] As used herein, the term "ester" refers to an ester having 3 to 10 carbon atoms. Examples include, but are not limited to, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, amyl acetate, or a combination thereof, preferably ethyl acetate, isopropyl acetate, or a combination thereof.

[0049] As used herein, the term "ether" refers to an ether having 2 to 6 carbon atoms. Examples include, but are not limited to, diethyl ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane, or a combination thereof, preferably tetrahydrofuran, 1,4-dioxane, or a combination thereof.

[0050] As used herein, the term "alkane" refers to an alkane having 1 to 10 carbon atoms. Examples include, but are not limited to, n-pentane, n-hexane, cyclohexane, n-heptane, octane, or a combination thereof, preferably n-pentane, n-hexane, n-heptane, or a combination thereof, more preferably n-pentane, n-hexane, or a combination thereof.

[0051] As used herein, the term "arene" refers to an arene having 6 to 10 carbon atoms. Examples include, but are not limited to, benzene, toluene, xylene, or combinations thereof.

[0052] As used herein, the term "good solvent" refers to a solvent that provides a relatively high solubility for a substance, the crystalline form of which is desired. The term "poor solvent" refers to a solvent used to precipitate a desired crystalline substance. For example, if a solid substance is dissolved in a "good solvent" to form a solution, adding a "poor solvent" thereto, or adding the resulting solution to a "poor solvent," will precipitate the substance and give the corresponding crystalline form.

[0053] As used herein, the term "room temperature" refers to about 20 to about 30°C, preferably about 25°C.

[0054] Crystalline Form D of the compound of formula I In one aspect, the present invention provides crystalline form D of the compound of formula I, wherein form D has an XRPD pattern comprising peaks at diffraction angles (2θ) of about 4.9±0.2°, about 6.0±0.2°, about 12.5±0.2°, about 18.3±0.2°, about 18.9±0.2°, about 21.0±0.2°, and about 23.8±0.2°.

[0055] In some embodiments, crystalline form D has an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles (2θ) of about 4.9±0.2°, about 6.0±0.2°, about 7.3±0.2°, about 12.5±0.2°, about 18.3±0.2°, about 18.9±0.2°, about 19.7±0.2°, about 21.0±0.2°, about 22.2±0.2°, and about 23.8±0.2°.

[0056] In some embodiments, crystalline form D has an XRPD pattern comprising peaks at diffraction angles (2θ) of about 4.9±0.2°, about 6.0±0.2°, about 12.5±0.2°, about 14.7±0.2°, about 15.6±0.2°, about 17.1±0.2°, about 18.3±0.2°, about 18.9±0.2°, about 21.0±0.2°, about 23.8±0.2°, and about 24.9±0.2°.

[0057] In some embodiments, crystalline form D has an XRPD pattern comprising peaks at diffraction angles (2θ) of about 4.9±0.2°, about 6.0±0.2°, about 7.3±0.2°, about 12.5±0.2°, about 14.7±0.2°, about 15.6±0.2°, about 17.1±0.2°, about 18.3±0.2°, about 18.9±0.2°, about 19.7±0.2°, about 21.0±0.2°, about 22.2±0.2°, about 23.8±0.2°, and about 24.9±0.2°.

[0058] In some embodiments, crystalline form D has an angle of about 4.1±0.2°, about 4.9±0.2°, about 6.0±0.2°, about 6.2±0.2°, about 8.7±0.2°, about 9.8±0.2°, about 10.1±0.2°, about 12.5±0.2°, about 13.4±0.2°, about 14.0±0.2°, about 14.7±0.2°, about 15.6±0.2°, about 17.1±0.2°, about 18. It has an XRPD pattern containing peaks at diffraction angles (2θ) of 7.9±0.2°, about 18.3±0.2°, about 18.5±0.2°, about 18.9±0.2°, about 19.9±0.2°, about 21.0±0.2°, about 21.3±0.2°, about 21.8±0.2°, about 22.7±0.2°, about 23.4±0.2°, about 23.8±0.2°, and about 24.9±0.2°.

[0059] In some embodiments, crystalline form D has an α-aspartate bond with an α-aspartate bond at about 4.1±0.2°, about 4.9±0.2°, about 6.0±0.2°, about 6.2±0.2°, about 7.3±0.2°, about 8.7±0.2°, about 9.8±0.2°, about 10.1±0.2°, about 12.5±0.2°, about 13.4±0.2°, about 14.0±0.2°, about 14.7±0.2°, about 15.6±0.2°, about 17.1±0.2, or about 17.9±0.2°. 2°, about 18.3±0.2°, about 18.5±0.2°, about 18.9±0.2°, about 19.7±0.2°, about 19.9±0.2°, about 21.0±0.2°, about 21.3±0.2°, about 21.8±0.2°, about 22.2±0.2°, about 22.7±0.2°, about 23.4±0.2°, about 23.8±0.2°, and about 24.9±0.2°.

[0060] In a further embodiment, crystalline form D has an XRPD pattern comprising peaks at the following diffraction angles (2θ) (Table 1): [Table 1] TIFF0007813100000005.tif152149

[0061] In a further embodiment, crystalline form D has an XRPD pattern comprising peaks at diffraction angles (2θ) substantially identical to those shown in Figure 1. In yet another embodiment, crystalline form D has an XRPD pattern with peaks substantially identical to those shown in Figure 1. In yet another embodiment, crystalline form D has an XRPD pattern as shown in Figure 1.

[0062] In a preferred embodiment, crystalline form D has a differential scanning calorimetry (DSC) curve comprising characteristic peaks at temperatures substantially identical to those shown in Figure 2. In a more preferred embodiment, crystalline form D has a DSC curve comprising characteristic peaks substantially identical to those shown in Figure 2. In an even more preferred embodiment, crystalline form D has a DSC curve comprising characteristic peaks identical to those shown in Figure 2.

[0063] In some embodiments, crystalline form D has a DSC comprising an endothermic peak with a maximum peak temperature of about 138 to about 145° C. In particular embodiments, crystalline form D has a DSC comprising an endothermic peak with a maximum peak temperature of about 141° C.

[0064] In some embodiments, crystalline form D has a TGA curve comprising a weight loss profile substantially identical to that shown in Figure 3. In preferred embodiments, crystalline form D has a TGA curve substantially as shown in Figure 3. In even more preferred embodiments, crystalline form D has a TGA curve as shown in Figure 3.

[0065] In some embodiments, crystalline form D has a TGA curve that indicates that crystalline form D begins to decompose at about 225 to about 235° C. In certain embodiments, crystalline form D has a TGA curve that indicates that crystalline form D begins to decompose at about 230° C. crystalline form D exhibits substantially no weight loss before decomposition.

[0066] In some embodiments, crystalline form D has the following particle size distribution: Dv(10): about 2 to about 3.5 μm, Dv(50): about 10 to about 20 μm, Dv(90): about 40 to about 60 μm. In particular embodiments, crystalline form D has the following particle size distribution: Dv(10): about 2.925 μm, Dv(50): about 15.360 μm, Dv(90): about 47.631 μm.

[0067] Crystalline form D according to the present invention is substantially pure.

[0068] Preparation of Crystalline Form D In another aspect, the present invention also provides a process for preparing crystalline form D of the compound of formula I.

[0069] In an embodiment of the process for preparing crystalline form D according to the present invention, the process comprises: 1) dissolving the compound of formula I as a solid in a good solvent for crystallization; 2) adding the solution obtained in step 1) to a poor solvent for crystallization to crystallize; 3) separating the obtained product and optionally drying the obtained product to obtain crystalline form D.

[0070] In some embodiments, the good solvent for crystallization in step 1) is selected from an ether solvent, an ester solvent, and a mixture thereof. In some preferred embodiments, the good solvent for crystallization is an ether solvent or an ester solvent, more preferably an ether solvent.

[0071] In another embodiment, the anti-solvent for crystallization in step 2) is selected from alkane solvents, arene solvents and mixtures thereof, preferably alkane solvents.

[0072] The ester solvent may be ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, amyl acetate or a combination thereof, preferably ethyl acetate, isopropyl acetate or a combination thereof.

[0073] The ether solvent may be diethyl ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane or a combination thereof, preferably tetrahydrofuran, 1,4-dioxane or a combination thereof.

[0074] The alkane solvent may be n-pentane, n-hexane, cyclohexane, n-heptane, octane or a combination thereof, preferably n-pentane, n-hexane, n-heptane or a combination thereof, more preferably n-pentane, n-hexane or a combination thereof.

[0075] The arene solvent may be benzene, toluene, xylene, or a combination thereof.

[0076] In some further preferred embodiments, the good solvent for crystallization is an ether solvent, preferably tetrahydrofuran, 1,4-dioxane, or a combination thereof, and the poor solvent for crystallization is an alkane solvent, preferably n-pentane, n-hexane, n-heptane, or a combination thereof, more preferably n-pentane, n-hexane, or a combination thereof.

[0077] In step 1), heating may be performed to promote dissolution of the compound of formula I. Unless otherwise specified, there is no particular limitation on the temperature for "heating" in the preparation process, as long as it is lower than the boiling point of the solvent. The preferred heating temperature is 30 to 90°C, more preferably 35 to 85°C, for example, 40°C, 60°C, or 80°C. This step can be performed at room temperature.

[0078] In some embodiments, in step 1), the ratio (w / v) of the weight of the compound of Formula I added as a solid to the volume of the good solvent for crystallization is about 1:1 to about 1:10, preferably about 1:3 to about 1:5, for example, 1:3.3, 1:3, or 1:5.

[0079] In some embodiments, the volume ratio of the good solvent for crystallization to the poor solvent for crystallization is about 1:20 to about 20:1, preferably about 1:1 to about 1:10, more preferably about 1:3 to about 1:8, even more preferably about 1:4 to about 1:7, for example, 1:4, 1:6, or 1:6.7.

[0080] In some embodiments, the "adding" of step 2) is done dropwise.

[0081] In other embodiments, the "addition" of step 2) is done all at once.

[0082] In the preparation process according to the present invention, seed crystals may be optionally added. Adding seed crystals may shorten the crystallization time to some extent. The type and amount of seed crystals added are those that can promote the crystallization of the compound of formula I to form the desired crystalline form.

[0083] In some embodiments, in step 2), seed crystals of crystalline form D are optionally added to the antisolvent for crystallization. The amount added can be about 0.01 to about 5 (w / w)%, preferably 0.03 to 2 (w / w)%, for example, about 1 (w / w)% or 0.33 (w / w)%. w / w refers to the weight percentage of crystalline form D and the compound of formula I.

[0084] After step 2), stirring may be optionally carried out for crystallization. Unless otherwise specified, there is no particular limitation on the speed and time of "stirring" as long as the drug can be mixed uniformly.

[0085] Unless otherwise specified, crystallization can occur at any step of the preparation process, for example, simultaneously with stirring.

[0086] The prepared crystalline form can be separated and recovered by processes including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for solid separation under pressure or vacuum, preferably by filtration separation.

[0087] There are no particular limitations on the "drying" conditions for the process for preparing a new crystalline form of the compound of Formula I. "Drying" herein is preferably carried out under reduced pressure, more preferably in vacuum, at any temperature, preferably room temperature, until the residual solvent level is reduced to within the limits set forth in the International Conference on Harmonisation (ICH) guidelines. The residual solvent level may vary depending on the type of solvent, but should not exceed about 5000 ppm, or preferably about 4000 ppm, or more preferably about 3000 ppm. Drying can be carried out using a fluidized bed dryer, rotary vacuum dryer, spin flash dryer, tray dryer, vacuum oven, air oven, flash dryer, or the like. Drying can be carried out at about 100°C or less, about 80°C or less, about 60°C or less, about 50°C or less, about 30°C or less, or any other suitable temperature, under atmospheric pressure or reduced pressure (preferably vacuum), for any time sufficient to achieve the desired results (e.g., about 1, about 2, about 3, about 5, about 10, about 15, about 20, about 24 hours, or overnight). Drying can be carried out for any desired period of time to obtain a product having the desired attributes.

[0088] In some preferred embodiments, the process for preparing crystalline form D according to the present invention comprises: 1) dissolving a compound of formula I as a solid in an ether or ester solvent; 2) adding the solution obtained in step 1) dropwise to an alkane solvent to crystallize; 3) separating the obtained product and optionally drying the obtained product to obtain crystalline form D.

[0089] In some further preferred embodiments, the process for preparing crystalline form D according to the present invention comprises: 1) dissolving the compound of formula I as a solid in an ether solvent; 2) adding the solution obtained in step 1) dropwise to an alkane solvent to crystallize; 3) separating the obtained product and optionally drying the obtained product to obtain crystalline form D.

[0090] In some embodiments, the volume ratio of the ether solvent to the alkane solvent is about 1:20 to about 20:1, preferably about 1:1 to about 1:10, more preferably about 1:3 to about 1:8, and even more preferably about 1:4 to about 1:7.

[0091] In another embodiment, step 2) further comprises adding seed crystals of crystalline form D. The amount of seed crystals of crystalline form D added can be about 0.01 to about 5 (w / w)%, preferably 0.03 to 2 (w / w)%, for example, about 1 (w / w)%, 0.33 (w / w)%.

[0092] In the above process, the ether solvent may be diethyl ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane or a combination thereof, preferably tetrahydrofuran, 1,4-dioxane or a combination thereof.

[0093] In the above process, the alkane solvent may be n-pentane, n-hexane, cyclohexane, n-heptane, octane or a combination thereof, preferably n-pentane, n-hexane, n-heptane or a combination thereof, more preferably n-pentane, n-hexane or a combination thereof.

[0094] The crystalline form D obtained by the process according to the invention is substantially pure.

[0095] Pharmaceutical Compositions and Uses In some embodiments, the present invention provides pharmaceutical compositions comprising crystalline form D according to the present invention and one or more pharmaceutically acceptable carriers.

[0096] In one aspect, the present invention provides the use of crystalline form D according to the present invention or the pharmaceutical composition according to the present invention for the manufacture of a medicament for the prevention or treatment of thrombocytopenia.

[0097] In another aspect, the present invention provides crystalline form D according to the present invention or a pharmaceutical composition according to the present invention for use in the prevention or treatment of thrombocytopenia.

[0098] In yet another aspect, the present invention provides a method for preventing or treating thrombocytopenia, comprising administering to a subject in need thereof an effective amount of crystalline form D according to the present invention or the pharmaceutical composition according to the present invention.

[0099] The thrombocytopenia herein includes blood diseases accompanied by abnormalities in platelet count, such as thrombocytopenia after hematopoietic stem cell transplantation (such as bone marrow transplantation), thrombocytopenia after chemotherapy, aplastic anemia, myelodysplastic syndrome, acquired thrombocytopenia (such as idiopathic thrombocytopenic purpura), congenital thrombocytopenia (such as thrombopoietin deficiency), viral pneumonia (such as hepatitis C), and other liver diseases (such as cirrhosis). For example, prophylaxis and treatment can be performed for thrombocytopenia caused by the administration of anticancer drugs for hematopoietic tumors, solid tumors, etc. They can be used as therapeutic agents for thrombocytopenia caused by the administration of anticancer drugs, and as prophylactic agents when the anticancer drug is expected to cause thrombocytopenia. They can also be used as therapeutic and / or prophylactic agents when platelet counts are expected to decrease during surgery on the cardiovascular system (such as the heart and blood vessels).

[0100] As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, vehicle, excipient, or medium that is co-administered with a therapeutic agent and that, within the scope of sound medical judgment, is suitable for contact with human and / or animal tissue without undue toxicity, irritation, allergic response, or other problem or complication, and has an acceptable benefit / risk ratio.

[0101] Pharmaceutically acceptable carriers that can be used in pharmaceutical compositions according to the present invention include, but are not limited to, sterile liquids, such as water and oils, including those derived from petroleum, animal, vegetable, or synthetic sources, such as soybean oil, peanut oil, mineral oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Normal saline and aqueous glucose and glycerin solutions can be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include glucose, starch, lactose, gelatin, maltose, sucrose, chalk, silica gel, glyceryl monostearate, sodium stearate, talc, sodium chloride, glycerin, propanediol, water, ethanol, and the like. The compositions may, if desired, contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, cellulose, sodium saccharin, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers can be found, for example, in Remington's Pharmaceutical Sciences (1990).

[0102] The compositions according to the invention can act systemically and / or locally, and for this purpose can be administered via a suitable route, for example by injection, intraarterial, subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal administration, orally, nasally, bucally, transmucosally, topically, in ophthalmic formulations or via inhalation.

[0103] For these routes of administration, the pharmaceutical compositions can be administered in a suitable dosage form, including but not limited to, tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, aqueous suspensions, injections, elixirs, and syrups.

[0104] Pharmaceutical compositions according to the present invention can be prepared by any process well known in the art, for example, by mixing, dissolving, granulating, sugar-coating, pulverizing, emulsifying, lyophilizing, etc. The term "therapeutically effective amount" refers to those of the compound after administration that will relieve to some extent one or more of the symptoms of the disease being treated.

[0105] Dosage regimen can be adjusted to obtain the optimal response desired.For example, can be administered a single bolus, or can be administered in several divided doses over time, or can be proportionally reduced or increased as indicated by the exigencies of the treatment situation.It should be noted that dosage value can vary according to the type and severity of the condition to be alleviated, and can include single or multiple doses.It should further be understood that for any specific subject, specific dosage regimen should be adjusted over time according to individual need and the professional judgment of the person who manages or supervises the administration of composition.

[0106] The dosage of the compounds according to the present invention will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the compound formulation, and the discretion of the prescribing physician. Generally, an effective dosage is about 0.0001 to about 100 mg / kg body weight / day, e.g., about 0.01 to about 10 mg / kg / day, in single or divided doses. For a 70 kg human, the total amount would be about 0.007 mg / day to about 7000 mg / day, e.g., about 0.7 mg / day to about 700 mg / day. In some cases, dosage levels at or below the lower end of the above range may be sufficient. In other cases, higher doses can be used without causing adverse side effects if the higher dose is initially divided into several lower doses administered throughout the day.

[0107] The content or amount of the compound according to the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg, suitably 0.1 to 500 mg, preferably 0.5 to 300 mg, more preferably 1 to 150 mg, particularly preferably 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0108] Unless otherwise specified, as used herein, the term "treating" refers to reversing, alleviating, inhibiting the onset of the disorder or condition to which the term relates, or one or more symptoms of such disorder or condition, or preventing the disorder or condition, or one or more symptoms of such disorder or condition.

[0109] As used herein, the term "individual" includes a human or non-human animal. Exemplary human subjects include a human (referred to as a patient) subject having a disease (such as those described herein) or a normal subject. The term "non-human animal" includes all vertebrates, e.g., non-mammals (e.g., amphibians, reptiles, birds) and mammals, e.g., non-human primates, livestock and / or domestic animals (e.g., dogs, cats, sheep, cows, pigs, etc.).

[0110] Beneficial effects The advantages of crystalline form D according to the present invention include, but are not limited to, high solubility, good stability, and good pharmacokinetic properties, and its applicability for preparation into pharmaceutical formulations. The process for preparing the crystalline form is simple and effective, and suitable for scale production.

[0111] Specifically, crystalline form D according to the present invention has good physical properties including, but not limited to, solubility, dissolution, light resistance, low moisture absorption, high heat resistance, high humidity resistance, stability, flowability, and significantly improved adhesion.

[0112] For example, crystalline form D according to the present invention can significantly shorten filtration time, shorten manufacturing time, and save costs during formulation preparation. Crystalline form D according to the present invention has good photostability, ensuring reliability during storage and transportation, thereby ensuring the safety of the formulation. The crystalline form does not require special packaging treatment to protect against the effects of light, thereby reducing costs. The crystalline form is not decomposed by light, improving the safety and efficacy of the formulation after long-term storage. Patients using the crystalline form do not experience photosensitization reactions of the formulation due to exposure to sunlight.

[0113] Crystalline form D according to the present invention shows little or no decomposition during storage or transportation at ambient temperature. DSC analysis of the crystalline form shows that melting or desolvation occurs above 50° C. The crystalline form exhibits good thermal and long-term stability, suggesting its applicability in standard formulation processes.

[0114] Crystalline form D according to the present invention exhibits good chemical and physical stability, ease of preparation, and improved suitability for pharmaceutical preparation. For example, crystalline form D according to the present invention can be ground into a fine powder and sieved through 100 μm and 50 μm filtration screens. The ground crystalline form D has the same XRPD pattern as before grinding.

[0115] The crystalline form D according to the present invention exhibits excellent effects in preventing or treating blood disorders associated with abnormal platelet counts, such as thrombocytopenia, and maintains sufficient biological activity and can provide an effective therapeutic dose of the compound of formula I in vivo.

[0116] The crystalline form D of the present invention is suitable and convenient for scale production, and the formulations obtained therefrom have reduced irritation and enhanced absorption, thereby addressing the problem of metabolic rate, significantly reducing toxicity, improving safety, and effectively ensuring the quality and performance of the formulations. [Example]

[0117] The present invention is further illustrated by the following examples, the purpose of which is to understand the invention.

[0118] Preparation and Characterization of Crystalline Form D of the Compound of Formula I Apparatus and method X-ray powder diffraction (XRPD) X'Pert in transmission mode at room temperature 3XRPD patterns were collected using an X-ray powder diffraction analyzer using Cu-Kα radiation at a scan voltage of 40 kV, a current of 40 mA, an increment of 0.013°, a counting time of 50 seconds for each increment, and a scan range of 2θ from 3.5° to 40°.

[0119] Differential scanning calorimetry (DSC) DSC was collected using a Mettler Toledo DSC1 differential scanning calorimeter, the heating rate of the DSC instrument is 10 K / min.

[0120] Thermogravimetric analysis (TGA) TGA was collected using a Mettler Toledo TGA1 thermogravimetric analyzer, with the purge gas being N2 (99.99%) at 100 ml / min, the heating rate being 10 K / min, and the temperature range being 35–500 °C.

[0121] Particle size analysis Particle size analysis is performed using a Malvern Mastersizer 3000 laser particle sizer equipped with a Hydro LV injector.

[0122] Example 1 3 g of the compound of formula I was weighed into a container, and 10 ml of tetrahydrofuran was added thereto. The mixture was stirred until dissolved. At room temperature, 1% (w / w) of seed crystals of crystalline form D and 60 ml of n-pentane were added to a separate container with stirring. The tetrahydrofuran solution of the compound of formula I was added dropwise to the n-pentane container with stirring for crystallization. After filtration and drying, crystalline form D was obtained.

[0123] The obtained crystalline form D was subjected to XRPD analysis, and the XRPD pattern is shown in FIG. 1, and the related data are shown in Table 1.

[0124] Particle size determination was performed on crystalline form D. Form D has the following particle size distribution: Dv(10): 2.925 μm, Dv(50): 15.360 μm, Dv(90): 47.631 μm.

[0125] DSC determination was performed on crystalline form D, and the resulting DSC curve is shown in Figure 2. In the curve, the onset temperature of the endothermic peak (Onset) and the maximum peak temperature (Peak) of the sample were approximately 134°C and 141°C, respectively, and the final melting temperature (Endset) was approximately 145°C.

[0126] TGA determination was carried out on crystalline form D and the resulting TGA curve is shown in Figure 3. The curve shows that the sample started to decompose at about 230°C and no weight loss was observed before decomposition.

[0127] Example 2 1 g of the compound of formula I was weighed into a container, and 3 ml of tetrahydrofuran was added thereto. The mixture was stirred until dissolved. At room temperature, 20 ml of n-hexane and 1% (w / w) of seed crystals of crystalline form D of the compound of formula I were added to a separate container with stirring. The tetrahydrofuran solution of the compound of formula I was added dropwise to the n-hexane container with stirring for crystallization. The mixture was filtered and dried. The resulting crystalline form had substantially the same XRPD pattern and DSC curve as those in Example 1, indicating that crystalline form D was obtained.

[0128] Example 3 1 g of the compound of formula I was weighed into a container, and 3 ml of tetrahydrofuran was added thereto. The mixture was stirred until dissolved. At room temperature, 20 ml of n-heptane and 1% (w / w) of seed crystals of crystalline form D of the compound of formula I were added to a separate container with stirring. The tetrahydrofuran solution of the compound of formula I was added dropwise to the n-heptane container with stirring for crystallization. The mixture was filtered and dried. The resulting crystalline form had substantially the same XRPD pattern and DSC curve as those in Example 1, indicating that crystalline form D was obtained.

[0129] Example 4 1 g of the compound of formula I was weighed into a container, and 5 ml of 1,4-dioxane was added thereto. The mixture was stirred until dissolved. At room temperature, 20 ml of n-pentane and 1% (w / w) of seed crystals of crystalline form D of the compound of formula I were added to a separate container with stirring. The 1,4-dioxane solution of the compound of formula I was added dropwise to the n-pentane container with stirring for crystallization. The mixture was filtered and dried. The resulting crystalline form had substantially the same XRPD pattern and DSC curve as those in Example 1, indicating that crystalline form D was obtained.

[0130] Example 5 1 g of the compound of formula I was weighed into a container, and 5 ml of 1,4-dioxane was added thereto. The mixture was stirred until dissolved. At room temperature, 20 ml of n-hexane and 1% (w / w) of seed crystals of crystalline form D of the compound of formula I were added to a separate container with stirring. The 1,4-dioxane solution of the compound of formula I was added dropwise to the n-hexane container with stirring for crystallization. The mixture was filtered and dried. The resulting crystalline form had substantially the same XRPD pattern and DSC curve as those in Example 1, indicating that crystalline form D was obtained.

[0131] Experimental Example 1: Solubility test In this example, the solubility of the crystalline forms was investigated by testing the solubility of two crystalline forms in simulated human gastric fluid at different pH levels.

[0132] Solubility test: HPLC external standard method Chromatography columns: octadecylsilane-bonded silica gel as filler Mobile phase: phosphate buffer (pH 3.5):methanol:acetonitrile = 2:9:9 (volume ratio) Detection wavelength: 215 nm

[0133] Excess amounts of crystalline form D and crystalline form Y were placed in a plugged tube, to which 10 ml of water (purified water), HCl solution of pH 1.2, HCl solution of pH 2.0, acetate buffer of pH 4.0, and phosphate buffers of pH 4.5, 5.0, 6.8, and 8.0 were added, followed by shaking in a water bath at 37°C and then filtering. The filtrate was then subjected to HPLC assay.

[0134] For the preparation of various pH buffer solutions, the dissolution media can be referred to the "Guideline for Dissolution Test of Normal Oral Solid Formulation" issued by the Center for Drug Evaluation of China Food and Drug Administration, which is detailed as follows:

[0135] A pH 1.2 hydrochloric acid solution is prepared by diluting 7.65 ml of hydrochloric acid to 1000 ml with water and mixing well.

[0136] A pH 2.0 hydrochloric acid solution is prepared by diluting 1.17 ml of hydrochloric acid to 1000 ml with water and mixing well.

[0137] A pH 4.0 acetate buffer solution is prepared by diluting a mixture of 1.22 g of sodium acetate and 20.5 mL of 2 mol / L acetic acid solution to 1000 mL with water and mixing well. A 2 mol / L acetic acid solution is prepared by diluting 114 mL of glacial acetic acid to 1000 mL with water.

[0138] Phosphate buffer solutions of pH 4.5, 5.0, 6.8, and 8.0 are prepared by adjusting the pH of 0.2 mol / L monopotassium phosphate solution to pH 4.5, 5.0, 6.8, and 8.0 with 0.2 mol / L sodium hydroxide solution. 0.2 mol / L monopotassium phosphate solution is prepared by dissolving 27.22 g of monopotassium phosphate in water and diluting to 1000 mL. 0.2 mol / L sodium hydroxide solution is prepared by dissolving 8.00 g of sodium hydroxide in water and diluting to 1000 mL. [Table 2]

[0139] As shown in Table 2, the solubility of the two crystalline forms in simulated human gastric fluid at various pH values ​​was tested, and crystalline form D according to the present invention showed significantly better solubility than crystalline form Y.

[0140] Experimental Example 2: Stability test In this example, a high temperature and humidity test was used to investigate the chemical stability of the crystalline form according to the present invention.

[0141] Purity test: HPLC method (Chinese Pharmacopoeia 2015, Vol. IV, General Principles 0512) Chromatography columns: octadecylsilane-bonded silica gel as filler Mobile phase A: 0.02 mol / L phosphate buffer (pH 3.0) - methanol - acetonitrile Mobile phase B: methanol-acetonitrile-water Detection wavelength: 215 nm Elution conditions: gradient elution

[0142] Weight loss in drying assay: Chinese Pharmacopoeia 2015, Volume IV, General Principles 0831 Experimental Example 2-1: High temperature stability test Form D of the compound of formula I was placed in a sealed clean glass bottle and placed in a constant temperature bath at 60°C. Samples were taken at 10 days and 30 days, respectively, to determine the impurity content. The purity evolution is shown in Table 3, and the XRPD is shown in Figure 4. [Table 3]

[0143] As can be seen from Table 3 and Figure 4, crystalline form D does not show any obvious change in purity or change in crystalline form under high temperature conditions, demonstrating high temperature stability.

[0144] Experimental Example 2-2: High humidity stability test Crystalline Form D of the compound of Formula I was spread in an open Petri dish with a thickness of ≦5 mm in a constant temperature incubator at room temperature and 92.5% relative humidity (RH). Samples were taken at 10 days / 30 days to determine the impurity content. The change in purity and weight loss during drying are shown in Table 4, and the XRPD is shown in Figure 5. [Table 4]

[0145] As can be seen from Table 4 and Figure 5, crystalline form D exhibits no obvious change in purity under high humidity conditions, little change in weight loss during drying, and no change in crystalline form, indicating high humidity stability.

[0146] Experimental Example 2-3: Long-term and accelerated stability tests An inner bag (pharmaceutical low-density polyethylene bag) and an outer bag (pharmaceutical polyester / aluminum / polyethylene composite film bag) were used to package crystalline form D of the compound of formula I and placed under the following stability test conditions for stability testing. The chemical purity data are shown in Table 5, and the change in crystalline form was investigated using XRPD and is shown in Figure 6. [Table 5]

[0147] As can be seen from Table 5 and Figure 6, crystalline form D shows no change in purity or crystalline form after more than 6 months under long-term and accelerated conditions, indicating good stability.

[0148] Experimental Example 3: Pharmacokinetics study The crystalline form D of the compound of formula I was administered to dogs, mice and monkeys to investigate the pharmacokinetic properties of the crystalline form D. The results showed that the crystalline form D of the compound of formula I has good pharmacokinetic properties.

[0149] Those skilled in the art will recognize that many modifications and variations can be made to the present invention without departing from the spirit and scope of the invention. The embodiments described herein are provided by way of example only and should not be construed as limiting. The true scope and spirit is defined by the following claims, with the specification and examples being exemplary only.

Claims

1. A crystal of crystalline form D of the compound of formula I, The crystal of crystalline form D is characterized in that the crystal has an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) of 4.9±0.2°, 6.0±0.2°, 12.5±0.2°, 18.3±0.2°, 18.9±0.2°, 21.0±0.2°, and 23.8±0.2°. 【Chemistry 1】

2. 2. A crystal of crystalline form D according to claim 1, The crystal of crystalline form D is characterized in that the crystal has an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) of 4.9±0.2°, 6.0±0.2°, 7.3±0.2°, 12.5±0.2°, 18.3±0.2°, 18.9±0.2°, 19.7±0.2°, 21.0±0.2°, 22.2±0.2°, and 23.8±0.2°.

3. 2. A crystal of crystalline form D according to claim 1, The crystal of crystalline form D is characterized in that the crystal has an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) of 4.9±0.2°, 6.0±0.2°, 12.5±0.2°, 14.7±0.2°, 15.6±0.2°, 17.1±0.2°, 18.3±0.2°, 18.9±0.2°, 21.0±0.2°, 23.8±0.2°, and 24.9±0.2°.

4. A crystal of crystalline form D according to any one of claims 1 to 3, The crystal of crystalline form D is characterized in that the crystal has an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) of 4.9±0.2°, 6.0±0.2°, 7.3±0.2°, 12.5±0.2°, 14.7±0.2°, 15.6±0.2°, 17.1±0.2°, 18.3±0.2°, 18.9±0.2°, 19.7±0.2°, 21.0±0.2°, 22.2±0.2°, 23.8±0.2°, and 24.9±0.2°.

5. 2. A crystal of crystalline form D according to claim 1, The crystals were at 4.1±0.2°, 4.9±0.2°, 6.0±0.2°, 6.2±0.2°, 8.7±0.2°, 9.8±0.2°, 10.1±0.2°, 12.5±0.2°, 13.4±0.2°, 14.0±0.2°, 14.7±0.2°, 15.6±0.2°, 17.1±0.2°, 17.9±0.2°, 18.3±0. A crystal of crystalline form D, characterized by having an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) of 18.2°, 18.5±0.2°, 18.9±0.2°, 19.9±0.2°, 21.0±0.2°, 21.3±0.2°, 21.8±0.2°, 22.7±0.2°, 23.4±0.2°, 23.8±0.2°, and 24.9±0.2°.

6. A crystal of crystalline form D according to any one of claims 1 to 5, The crystals were oriented at 4.1±0.2°, 4.9±0.2°, 6.0±0.2°, 6.2±0.2°, 7.3±0.2°, 8.7±0.2°, 9.8±0.2°, 10.1±0.2°, 12.5±0.2°, 13.4±0.2°, 14.0±0.2°, 14.7±0.2°, 15.6±0.2°, 17.1±0.2°, 17.9±0.2°, 18.3±0.2°, 18. A crystal of crystalline form D, characterized by having an X-ray powder diffraction pattern containing peaks at diffraction angles (2θ) of 15.5±0.2°, 18.9±0.2°, 19.7±0.2°, 19.9±0.2°, 21.0±0.2°, 21.3±0.2°, 21.8±0.2°, 22.2±0.2°, 22.7±0.2°, 23.4±0.2°, 23.8±0.2°, and 24.9±0.2°.

7. A process for preparing crystals of crystalline form D according to any one of claims 1 to 6, comprising: 1) dissolving the compound of formula I as a solid in a good solvent for crystallization; 2) adding the solution obtained in step 1) to a poor solvent for crystallization to crystallize; 3) separating the obtained product and optionally drying the obtained product to obtain crystals of said crystalline form D; the good solvent for crystallization is selected from tetrahydrofuran, 1,4-dioxane, and combinations thereof; The process wherein said anti-solvent for crystallization is selected from n-pentane, n-hexane, n-heptane and combinations thereof.

8. 8. The process of claim 7, 10. The process according to claim 9, wherein the volume ratio of said good solvent for crystallization to said poor solvent for crystallization is from 1:20 to 20:

1.

9. A pharmaceutical composition comprising a crystal of crystalline form D according to any one of claims 1 to 6 and one or more pharmaceutically acceptable carriers.

10. Use of the crystal of crystalline form D according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 9 for the manufacture of a medicament for preventing or treating thrombocytopenia.

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