Crystals of N-(benzoyl)-phenylalanine compounds, their pharmaceutical compositions, preparation methods, and uses.

Abstract

The present invention relates to crystals of N-(benzoyl)-phenylalanine-based compounds, pharmaceutical compositions thereof, preparation methods and uses. Specifically, as shown in Formula (I) and Formula (II), the crystals of the compound of Formula (I) have crystal form A, and the crystals of the compound of Formula (II) have crystal form B. The two crystal forms have good stability, high reproducibility of the preparation method, high operability, and important application value in the prevention and / or treatment of diseases related to α4β7 integrin. [Chemical formula 1] TIFF2025518346000014.tif44156

Description

Technical Field

[0001] The present invention belongs to the field of crystalline pharmaceutical technology, and specifically relates to crystals of N-(benzoyl)-phenylalanine-based compounds, pharmaceutical compositions containing the crystalline pharmaceuticals, and preparation methods and uses of the crystalline pharmaceuticals. In particular, it relates to two types of crystals of (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6’,7’-difluoro-2’-oxospiro[cyclopropane-1,3’-indolin]-1’-yl)phenyl)propionic acid, corresponding pharmaceutical compositions, and preparation methods and uses of the two crystal forms.

Background Art

[0002] Inflammatory bowel disease (IBD) is a disease that mainly causes chronic inflammation in the digestive tract. IBD includes ulcerative colitis (UC), Crohn's disease (CD), and indeterminate colitis. For example, in the occurrence and exacerbation process of IBD, immune cells migrate to the intestinal tract site and abnormally aggregate in the intestinal mucosal layer through the interaction of α4β7 integrin and its ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1). α4β7 integrin controls the migration of lymphocytes to the intestinal tissue and their retention in the intestine through interaction with MAdCAM-1.

[0003] It has been pointed out that inhibiting the interaction between integrin and its ligand is an effective method for treating multiple autoimmune and inflammatory diseases, and inhibiting the α4β7-MAdCAM-1 interaction has already shown a therapeutic effect on inflammatory bowel diseases (such as Crohn's disease and ulcerative colitis).

[0004] PCT / CN2021 / 132456 reports N-(benzoyl)-phenylalanine compounds that exhibit strong α4β7-MAdCAM-1 inhibitory activity and are useful for the prevention and / or treatment of diseases related to α4β7 integrins (such as autoimmune diseases and inflammatory diseases). Among these is a compound with the chemical name (S)-2-(2-chloro-6-fluorobenzoamide)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionic acid. The preparation method for this compound is as follows: Methyl (S)-2-(2-chloro-6-fluorobenzoamide)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propionate is dissolved in tetrahydrofuran, and 0.5 mol / L aqueous sodium hydroxide solution is added to the reaction system, and the reaction is carried out at room temperature for 2 hours. The pH of the reaction system is adjusted to 1-2 with 2 mol / L dilute hydrochloric acid, dichloromethane is extracted three times (2 mL each time), the organic layers are combined, each organic layer is washed once with water and saturated brine, dried over anhydrous sodium sulfate, extracted and filtered, concentrated under reduced pressure, and the concentrate is purified by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the compound represented by formula (I).

[0005] [ka]

[0006] The product obtained by the above method is an amorphous substance (as shown in Figure 7), and amorphous substances are relatively unstable solid forms in thermodynamics, prone to transitions and decomposition, which reduces the chemical purity of the compound and ultimately affects the final quality of the pharmaceutical product. [Overview of the project] [Means for solving the problem]

[0007] In response to the above-mentioned defects, the present invention unexpectedly discovered that crystalline form A of the compound represented by formula (I) and crystalline form B of the compound represented by formula (II) are highly stable, have a simple preparation process, and possess properties suitable for large-scale industrial production.

[0008] In a first embodiment, the present invention provides a compound represented by formula (I) that exists in a crystalline form having crystal form A, the crystallographic parameters of crystal form A are as follows.

[0009] Using Cu-Kα emission, the X-ray powder diffraction (XRPD) pattern of crystal form A shows characteristic peaks at 2θ values ​​of 10.4±0.2°, 13.1±0.2°, 13.6±0.2°, 18.8±0.2°, 19.6±0.2°, 20.2±0.2°, 21.9±0.2°, and 22.1±0.2°. Furthermore, the XRPD pattern of crystal form A has at least three characteristic peaks with good peak and resolution at 2θ values ​​of 10.4±0.2°, 13.1±0.2°, and 13.6±0.2°.

[0010] In some embodiments, the XRPD pattern of crystal form A also has characteristic peaks at at least one location (e.g., one, two, three, four, five, six, seven, or eight locations) at 2θ values ​​of 5.2±0.2°, 12.3±0.2°, 14.7±0.2°, 15.7±0.2°, 24.7±0.2°, 26.5±0.2°, 28.5±0.2°, and 33.1±0.2°.

[0011] In some embodiments, the XRPD pattern of crystal form A also has characteristic peaks at at least one of the 2θ values ​​31.6±0.2°, 38.3±0.2°, and 40.2±0.2° (e.g., one, two, or three peaks).

[0012] In some embodiments, the XRPD pattern of crystal form A is as shown in Figure 1.

[0013] In some embodiments, the differential scanning calorimetry (DSC) pattern of crystal form A shows an endothermic peak at 236±3°C.

[0014] In some embodiments, the thermogravimetric analysis (TGA) pattern of crystal form A shows a weight loss of approximately 0.2% between 25°C and 120°C.

[0015] In some embodiments, the DSC and TGA patterns of crystal form A are basically as shown in Figure 2.

[0016] In a second embodiment, the present invention provides a compound represented by formula (II) that exists in a crystalline form having crystal form B, the crystallographic parameters of crystal form B being as follows.

[0017] Using Cu-Kα emission, the XRPD pattern of crystal form B exhibits characteristic peaks at 2θ values ​​of 8.5±0.2°, 11.2±0.2°, and 17.9±0.2°.

[0018] In some embodiments, the XRPD pattern of crystal form B also has characteristic peaks at at least one location (e.g., one, two, three, four, five, or six locations) at 2θ values ​​of 14.3±0.2°, 15.5±0.2°, 19.3±0.2°, 20.1±0.2°, 24.4±0.2°, and 25.5±0.2°.

[0019] In some embodiments, the XRPD pattern of crystal form B also has characteristic peaks at at least one of the following 2θ values: 20.8±0.2°, 22.7±0.2°, 23.9±0.2°, 24.8±0.2°, 28.5±0.2°, and 32.5±0.2° (e.g., one, two, three, four, five, or six peaks).

[0020] In some embodiments, the XRPD pattern of crystal form B is basically as shown in Figure 3.

[0021] In some embodiments, the differential scanning calorimetry (DSC) pattern of crystal form B shows endothermic peaks at 121±3°C and 234±3°C, and a heat dissipation peak at 133±3°C.

[0022] In some embodiments, the thermogravimetric analysis (TGA) pattern of the crystalline form B shows a weight loss of about 3.6% at 50°C to 150°C. In combination with the DSC analysis, the crystalline form B is a hydrate crystalline form.

[0023] In some embodiments, the DSC and TGA patterns of the crystalline form B are basically as shown in FIG. 4.

[0024] In a third aspect, the present invention provides a method for preparing a compound represented by formula (I) that exists in a crystalline form having crystalline form A, which is selected from the suspension crystallization transformation method.

[0025] In some embodiments, the suspension crystallization transformation method specifically includes the following steps: adding a compound represented by formula (I) existing in the form of an amorphous substance to a binary mixed solvent to prepare a suspension, performing solid-liquid separation (preferably centrifugation) after constant temperature stirring, and drying the obtained solid (preferably vacuum drying) to obtain a compound represented by formula (I) that exists in a crystalline form having crystalline form A.

[0026] In some embodiments, examples of the binary mixed solvent include ethylene glycol monomethyl ether / methyl tert-butyl ether, ethylene glycol dimethyl ether / methyl tert-butyl ether, 4-methyl-2-pentanone / water, and acetone / water.

[0027] In some embodiments, the binary mixed solvent is ethylene glycol monomethyl ether / methyl tert-butyl ether or acetone / water, preferably acetone / water.

[0028] In some embodiments, the volume ratio of the two solvents in the binary mixed solvent is 1:3 to 1:9, preferably 1:4 to 1:5, more preferably 1:5.

[0029] In some embodiments, the ratio of the compound represented by formula (I), which exists in a amorphous form, to the binary mixed solvent (solid-liquid ratio) is 30-80 mg:1 ml, preferably 40-80 mg:1 ml, and more preferably 40 mg:1 ml.

[0030] In some embodiments, the constant stirring temperature is room temperature to 60°C, preferably 50 to 60°C, and more preferably 50°C.

[0031] In some embodiments, the constant temperature stirring time is 4 to 120 hours, preferably 8 to 24 hours, and more preferably 8 hours.

[0032] In a fourth embodiment, the present invention provides a method for preparing a compound represented by formula (II) that exists in a crystalline form having the crystalline form B, selected from a solvent volatilization method and an antisolvent method.

[0033] In some embodiments, the solvent volatilization method specifically includes the following steps.

[0034] A compound represented by formula (I), which exists in an amorphous form, is added to an alcohol-based solvent, dissolved, and then allowed to stand and volatilize at room temperature to obtain a compound represented by formula (II), which exists in a crystalline form having crystalline form B.

[0035] In some embodiments, the alcoholic solvent is at least one of methanol and ethanol, and is preferably ethanol.

[0036] In some embodiments, the ratio of the compound represented by formula (I), which exists in a amorphous form, to the alcoholic solvent (solid-liquid ratio) is 20 to 80 mg:1 ml, preferably 50 mg:1 ml.

[0037] In some embodiments, the antisolvent method specifically includes the following steps.

[0038] A compound represented by formula (I), existing in amorphous form, is added to a good solvent, dissolved, then added to the antisolvent, stirred, and then subjected to solid-liquid separation (preferably by centrifugation). The resulting solid is dried (preferably by vacuum drying) to obtain a compound represented by formula (II), existing in crystalline form having crystal form B.

[0039] In some embodiments, the good solvent is at least one of methanol and ethanol, and is preferably ethanol.

[0040] In some embodiments, the antisolvent is at least one of cyclohexane and n-heptane, preferably cyclohexane.

[0041] In some embodiments, the ratio of the compound represented by formula (I), which exists in a amorphous form, to the good solvent (solid-liquid ratio) is 40-70 mg:1 ml, preferably 55 mg:1 ml.

[0042] In some embodiments, the ratio (volume ratio) of the antisolvent to the good solvent is 5 to 15:1, preferably 10:1.

[0043] In some embodiments, the stirring includes stirring at room temperature and stirring in an ice bath of an optional nature, and the stirring time at room temperature is preferably 0.5 to 3 hours, preferably 1 hour.

[0044] In a fifth embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) having crystalline form A and / or a compound represented by formula (II) having crystalline form B in a preventive and / or therapeutically effective amount, and at least one pharmaceutically acceptable carrier.

[0045] Preferably, the pharmaceutically acceptable carrier is an inert and non-toxic carrier, which may include pharmaceutically used diluents, binders, disintegrants, flow promoters, lubricants, and inclusion agents such as starch, lactose, powdered cellulose, microcrystalline cellulose, and gum arabic.

[0046] In a sixth embodiment, the present invention provides applications for the compound represented by formula (I) having crystal form A and / or the compound represented by formula (II) having crystal form B in the preparation of pharmaceuticals for the prevention and / or treatment of diseases related to α4β7 integrin.

[0047] Diseases related to the aforementioned α4β7 integrin include autoimmune diseases and inflammatory diseases, and preferably, the inflammatory disease is inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD).

[0048] The crystalline forms A of the compound represented by formula (I) and B of the compound represented by formula (II) provided by the present invention have the following advantageous effects.

[0049] (1) Crystal forms A and B of the present invention have good stability. The crystalline raw materials provided by the present invention all exhibit good physical and chemical stability under different storage conditions. When crystalline form A and crystalline form B were left for 15 days under high temperature of 60°C, high humidity of 92.5% RH, light irradiation of 4500 lux, and accelerated temperature of 40°C / 75% RH, respectively, the chemical purity and crystalline form of crystalline form A and crystalline form B did not change significantly. This indicates that crystalline form A and crystalline form B, and drug formulations containing crystalline form A and crystalline form B, remain essentially unchanged during storage, guaranteeing the quality of the raw materials and formulations.

[0050] (2) Crystal forms A and B of the present invention have low hygroscopicity. The weight increase of crystalline form A of the present invention under 80% relative humidity conditions is 0.09%, indicating little to no hygroscopicity. The weight increase of crystalline form B under 80% relative humidity conditions is 0.71%, indicating slight hygroscopicity. This indicates that crystalline forms A and B of the present invention are less prone to deliquescention even in high-humidity environments, thereby improving drug stability, fluidity and uniformity during processing, and enhancing the quality of drug formulations.

[0051] (3) The solubility of crystalline forms A and B of the present invention is good. Both crystalline forms A and B of the present invention exhibit good solubility in FeSSIF (feeding-simulated intestinal fluid) and FaSSIF (fasting-simulated intestinal fluid). Good intestinal solubility is advantageous for good absorption of drugs in the body, and can enhance the bioavailability and therapeutic effect of drugs.

[0052] (4) The preparation process for crystal forms A and B of the present invention is highly reproducible, easy to operate, and suitable for industrial production.

[0053] As described above, the crystalline forms A and B of the present invention have significant application value in the preparation of pharmaceuticals for preventing and / or treating diseases related to α4β7 integrins (e.g., autoimmune diseases, inflammatory diseases). [Brief explanation of the drawing]

[0054] [Figure 1] This is the XPRD pattern of crystalline form A of the compound of formula (I) prepared in Example 1. [Figure 2] This is the DSC / TTGA pattern of crystalline form A of the compound of formula (I) prepared in Example 1. [Figure 3] This is the XPRD pattern of crystalline form B of the compound of formula (II) prepared in Example 3. [Figure 4] This is the DSC / TTGA pattern of crystalline form B of the compound of formula (II) prepared in Example 3. [Figure 5] This is the XPRD pattern of the atypical powder of the compound of formula (I) prepared in Example 15 of PCT / CN2021 / 132456. [Figure 6] This is the DVS pattern of crystalline form A of the compound of formula (I) in Example 6. [Figure 7] This is the XPRD pattern of crystalline form A of compound (I) from Example 7 when left for 15 days in a high-temperature, high-humidity, light-irradiated, and accelerated testing environment. [Figure 8] This is the DVS pattern for crystalline form B of the compound of formula (II) in Example 9. [Figure 9]This is the XPRD pattern of crystalline form B of compound (II) from Example 10 when left for 15 days in a high-temperature, high-humidity, light-irradiated, and accelerated testing environment. [Modes for carrying out the invention]

[0055] The X-ray powder diffraction (XRPD) method used in this invention is as follows: Analysis is performed using a Bruker D8 Advance diffractometer, and an X-ray powder diffraction pattern is obtained using Cu-Kα emission under operating conditions of 40KV and 40Ma. The sample is tested under room temperature conditions and placed on a silicon phosphide sheet. The specific test conditions are as follows: scanning is performed in 0.02° increments within the range of 3 to 45°, with an exposure time of 0.08 seconds. Data is collected using Diffrac.Measurement Center software and processed using Diffrac.Eva software.

[0056] The differential scanning calorimetry (DSC) method used in this invention is as follows: Differential scanning calorimetry is performed using a TA Discovery 2500 instrument equipped with a thermal analysis controller, data is collected, and analysis is performed using trios software. After accurately weighing approximately 1-2 mg, the sample is placed in a perforated DSC Tzero sample dish, and the sample is analyzed at 25°C to 290°C using a linear heating device at 10°C / min. During use, the DSC furnace is purged with dry nitrogen at a purging rate of 50 ml / min.

[0057] The thermogravimetric analysis (TGA) method used in this invention is as follows: Thermogravimetric analysis is performed using a TA Discovery 55 instrument with a thermal analysis controller. Data is collected and analyzed using trios software. Approximately 2-5 mg of sample is placed in an equilibrated aluminum sample dish and automatically weighed in a TGA heating furnace. Sample analysis is performed at 25°C-290°C using a linear heating device at 10°C / min. During use, the DSC chamber is purged with dry nitrogen, with a purging rate of 60 ml / min for the sample section and 40 ml / min for the balance section.

[0058] The solubility of the present invention was measured using SHIMADZU LC 2030C 3D Plus high-efficiency liquid chromatography. The chromatography column model was YMC Pack ODS-AQC18, 4.6 × 250 mm, 5 μm, with a detection wavelength of 220 nm, a flow rate of 1.2 ml / min, a column temperature of 30°C, and gradient elution with 0.1% aqueous phosphate-acetonitrile mobile phase.

[0059] The hygroscopic properties of the present invention were measured using a DVS Intrinsic type dynamic moisture and gas adsorption meter from Surface Measurement Systems, UK. The humidity changes were 50%-95%-0%-50%, with a humidity change of 10% in each gradient within the 0%-90% range. The airflow was 200 ml / min, the temperature was 25°C, and one measurement point was taken for every 10% humidity.

[0060] The technical solutions of the present invention will be described below with specific examples. Those skilled in the art will understand that the following examples are for the purpose of further detailing the present invention and do not limit its scope. Unless otherwise specified, the pharmaceuticals, reagents, materials, equipment, etc. used in the following examples are available by general commercial means.

[0061] Example 1: Preparation of crystal form A 40 mg of the sample (compound of formula (I) existing in an amorphous form) was weighed, and 0.1 ml of ethylene glycol monomethyl ether and 0.4 ml of methyl tert-butyl ether were added to prepare a suspension. The suspension was stirred at 50°C for 1 day, the suspension was centrifuged, and the solid was vacuum-dried at room temperature to obtain crystal form A. The XRPD pattern is shown in Figure 1, and the DSC and TGA patterns are shown in Figure 2.

[0062] [Table 1]

[0063] Example 2 Preparation of crystal form A 504 mg of the sample (compound of formula (I) existing in amorphous form) was weighed and suspended and stirred in 12.6 ml of acetone / water (V / V=1:5) mixed solvent at 50°C for 8 hours. The resulting white suspension was centrifuged, and the solid was vacuum-dried at 50°C to obtain crystalline form A. Its XRPD pattern was tested to be essentially the same as that shown in Figure 1.

[0064] Example 3 Preparation of crystal form B 20 mg of the sample (compound of formula (I) existing in an amorphous form) was added to 0.4 ml of ethanol, dissolved, and allowed to stand and volatilize at room temperature for 5 days to obtain crystalline form B. The XRPD pattern is shown in Figure 3, and the DSC and TGA patterns are shown in Figure 4.

[0065] Tests confirmed that crystal form B can be converted to crystal form A at temperatures above 150°C.

[0066] [Table 2-1] [Table 2-2]

[0067] Example 4 Preparation of crystal form B 20 mg of the sample (compound of formula (I) existing in amorphous form) was added to 0.35 ml of ethanol, dissolved, and then the sample solution was added to 3 ml of cyclohexane. After stirring at room temperature for 1 hour, the mixture was stirred in an ice bath, centrifuged, and the solid was vacuum-dried at room temperature to obtain crystal form B. Its XRPD pattern was tested to be essentially the same as that shown in Figure 4.

[0068] Example 5 Solubility of crystal form A 20 mg of the sample (compound of formula (I) existing in crystalline form having crystal form A) was added to a 10 ml tapered tube, and 4 ml of water or biological medium (FeSSIF (pH 5.0) or FaSSIF (pH 6.5)) was added to each tube. The mixture was shaken in a 37°C constant temperature bath for 24 hours at a shaking speed of 1000 rpm, and samples were taken at 0.5 hours, 2 hours, and 24 hours, respectively. The samples were filtered through an aqueous micropore filtration membrane, and the first filtrate was discarded to obtain the test solution.

[0069] A 20 μL sample of the test solution was taken and tested by HPLC. The concentration of the sample was calculated using the standard calibration curve method, and the results are shown in the table below.

[0070] [Table 3]

[0071] Conclusion: As can be seen from Table 3, the solubility of crystal form A in FeSSIF and FaSSIF is relatively good.

[0072] Example 6: Hygroscopicity of crystal form A An appropriate amount of the test sample (a compound of formula (I) existing in a crystalline form having crystal form A) was taken, and its hygroscopicity was measured using a dynamic moisture adsorption meter. The test results are shown in Table 4, and the DVS pattern of the hygroscopicity test for crystal form A is shown in Figure 6.

[0073] [Table 4]

[0074] Conclusion: As can be seen from Table 4 and Figure 6, crystalline form A increased in weight by 0.09% at 80% RH. Based on the definition criteria for weight increase due to hygroscopicity, it was determined that it has little to no hygroscopicity, and therefore, crystalline form A of the present invention is less prone to deliquescent even in high-humidity environments.

[0075] Example 7: Stability of Crystal Form A An appropriate amount of the test sample (compound of formula (I) existing in a crystalline form having crystal form A) was placed in a watch glass and spread into a thin layer with a thickness of ≤5 mm. The sample was left for 15 days under high temperature of 60°C, high humidity of 92.5% RH, light irradiation of 4500 lux, and accelerated conditions of 40°C / 75% RH. Samples were taken on the 7th and 15th days, the color change of the sample was observed, the purity of the sample was measured by HPLC, and the crystal form of the sample was measured by XPRD. The test results are shown in Table 5, and the XRPD patterns are shown in Figure 7.

[0076] [Table 5]

[0077] As can be seen from Table 5 and Figure 7, when left for 15 days under high temperature of 60°C, high humidity of 92.5%RH, light irradiation of 4500 lux, and accelerated temperature of 40°C / 75%RH, there was no significant change in either the purity or crystalline form of crystal form A. Compared to the amorphous form, crystal form A of the present invention has better stability and is suitable for use in pharmaceuticals.

[0078] Example 8 Solubility of crystal form B 20 mg of the sample (formula (II) compound, existing in crystalline form with crystal form B) was added to a 10 ml tapered tube, and 4 ml of water or biological medium (FeSSIF (pH 5.0) or FaSSIF (pH 6.5)) was added to each tube. The mixture was shaken in a 37°C constant temperature bath for 24 hours at a shaking speed of 1000 rpm, and samples were taken at 0.5 hours, 2 hours, and 24 hours, respectively. The samples were filtered through an aqueous micropore filtration membrane, and the first filtrate was discarded to obtain the test solution.

[0079] A 20 μL sample of the test solution was taken and tested by HPLC. The concentration of the sample was calculated using the standard calibration curve method, and the results are shown in the table below.

[0080] [Table 6]

[0081] Conclusion: As can be seen from Table 6, crystal form B also exhibits relatively good solubility in FeSSIF and FaSSIF.

[0082] Example 9: Hygroscopicity of crystalline form B An appropriate amount of the test sample (a compound of formula (II) existing in a crystalline form having crystal form B) was taken, and its hygroscopicity was measured using a dynamic moisture adsorption meter. The test results are shown in Table 7, and the DVS pattern of the hygroscopicity test for crystal form B is shown in Figure 8.

[0083] [Table 7]

[0084] Conclusion: As can be seen from Table 7 and Figure 8, crystal form B increased in weight by 0.71% at 80% humidity. Based on the definition criteria for weight increase due to hygroscopicity, it was determined to be slightly hygroscopic, and thus, crystal form B of the present invention is less prone to deliquescent even in high-humidity environments.

[0085] Example 10 Stability of Crystal Form B An appropriate amount of the test sample (a compound of formula (II) existing in a crystalline form having crystal form B) was placed in a watch glass and spread into a thin layer with a thickness of ≤5 mm. The sample was left for 15 days under high temperature of 60°C, high humidity of 92.5% RH, light irradiation of 4500 lux, and accelerated conditions of 40°C / 75% RH. On the 15th day, a sample was taken, the color change of the sample was observed, the purity of the sample was measured by HPLC, and the crystal form of the sample was measured by XPRD. The test results are shown in Table 8, and the XRPD pattern is shown in Figure 9.

[0086] [Table 8]

[0087] As can be seen from Table 8 and Figure 9, when left for 15 days under high temperature of 60°C, high humidity of 92.5%RH, light irradiation of 4500 lux, and accelerated temperature of 40°C / 75%RH, there was no significant change in either the purity or crystalline morphology of crystal form B. Compared to the amorphous form, crystal form B of the present invention has better stability and is suitable for use in pharmaceuticals.

Claims

1. A crystal of the compound represented by formula (I), 【Chemistry 1】 A crystal of the compound represented by formula (I), which exists in a crystalline form having crystal form A, and whose X-ray powder diffraction pattern, when measured using Cu-Kα emission, has characteristic peaks at 2θ values ​​of 10.4±0.2°, 13.1±0.2°, 13.6±0.2°, 18.8±0.2°, 19.6±0.2°, 20.2±0.2°, 21.9±0.2°, and 22.1±0.2°.

2. The X-ray powder diffraction pattern further includes a characteristic peak at at least one of the following 2θ values: 5.2±0.2°, 12.3±0.2°, 14.7±0.2°, 15.7±0.2°, 24.7±0.2°, 26.5±0.2°, 28.5±0.2°, and 33.1±0.2°. A crystal of the compound represented by formula (I) as described in claim 1.

3. The differential scanning calorimetry pattern of the crystal has an endothermic peak at 236 ± 3°C. and / or, The thermogravimetric analysis pattern of the aforementioned crystal shows a weight loss of 0.2% between 25°C and 120°C. A crystal of the compound represented by formula (I) according to claim 1 or 2, characterized in that it is a crystal of the compound represented by formula (I) according to claim 1 or 2.

4. A crystal of the compound represented by formula (II), 【Chemistry 2】 A crystal of the compound represented by formula (II), characterized in that it exists in a crystalline form having crystal form B, and its X-ray powder diffraction pattern, when using Cu-Kα emission, has characteristic peaks at 2θ values ​​of 8.5±0.2°, 11.2±0.2°, and 17.9±0.2°.

5. The X-ray powder diffraction pattern further includes a characteristic peak at at least one of the 2θ values ​​of 14.3±0.2°, 15.5±0.2°, 19.3±0.2°, 20.1±0.2°, 24.4±0.2°, and 25.5±0.2°. A crystal of the compound represented by formula (II) as described in feature 4.

6. The differential scanning calorimetry pattern of the crystal has endothermic peaks at 121±3°C and 234±3°C, and a heat dissipation peak at 133±3°C. and / or, The thermogravimetric analysis pattern of the aforementioned crystal shows a weight loss of 3.6% between 50°C and 150°C. A crystal of the compound represented by formula (II) according to claim 4 or 5, characterized in that it is a crystal of the compound represented by formula (II) according to claim 4 or 5.

7. A method for preparing crystals of a compound represented by formula (I) according to claim 1 or 2, the preparation method being selected from the suspension crystallization method.

8. A method for preparing crystals of a compound represented by formula (II) according to claim 4 or 5, the method being selected from a solvent evaporation method and an antisolvent method.

9. A pharmaceutical composition comprising a preventive and / or therapeutically effective amount of crystals of a compound represented by formula (I) according to claim 1 or 2 and / or crystals of a compound represented by formula (II) according to claim 4 or 5, and at least one pharmaceutically acceptable carrier.

10. Use of crystals of the compound represented by formula (I) according to claim 1 or 2 and / or crystals of the compound represented by formula (II) according to claim 4 or 5 in the preparation of pharmaceuticals for the prevention and / or treatment of diseases related to α4β7 integrin.

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