Crystals of N-(benzoyl)-phenylalanine compounds, pharmaceutical compositions thereof, 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 between 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 the 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 types of 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-based compounds with strong α4β7-MAdCAM-1 inhibitory activity and useful for the prevention and / or treatment of diseases related to α4β7 integrin (such as autoimmune diseases and inflammatory diseases). Among them, the chemical name is (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6’,7’-difluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)propionic acid, and the compound is included. The preparation method of this compound is as follows: Dissolve methyl (S)-2-(2-chloro-6-fluorobenzamide)-3-(4-(6’,7’-difluoro-2’-oxospiro[cyclopropane-1,3’-indoline]-1’-yl)phenyl)propionate in tetrahydrofuran, and further add 0.5 mol / L aqueous sodium hydroxide solution to the reaction system, and carry out the reaction at room temperature for 2 h. Adjust the pH of the reaction system to 1-2 with 2 mol / L dilute hydrochloric acid, extract with dichloromethane three times (2 mL each time), combine the organic layers, wash the organic layer with water and saturated brine once each, dry over anhydrous sodium sulfate, extract and filter, concentrate under reduced pressure, and purify the concentrate by reverse-phase HPLC (H 2 O / CH 3 CN system) to obtain the compound represented by formula (I).

[0005]

Chemical formula

[0006] The product obtained by the above method is an amorphous substance (as shown in Figure 7). Amorphous substances are relatively unstable solid forms in thermodynamics and are prone to occurences such as transitions and decompositions. Therefore, the chemical purity of the compound decreases, which in turn affects the final quality of the pharmaceutical product.

Summary of the Invention

Means for Solving the Problems

[0007] In view of the above-mentioned defects, the present invention unexpectedly discovers that the crystalline form A of the compound represented by formula (I) and the crystalline form B of the compound represented by formula (II) have high stability, a simple preparation process, and properties suitable for large-scale industrial production.

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

[0009] Using Cu-Kα radiation, the X-ray powder diffraction (XRPD) pattern of the crystalline form A 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°, 22.1 ± 0.2°. Further, the XRPD pattern of the crystalline form A has at least three characteristic peaks with good peak separation at 2θ values of 10.4 ± 0.2°, 13.1 ± 0.2°, 13.6 ± 0.2°.

[0010] In some embodiments, the XRPD pattern of the crystalline form A also has characteristic peaks at at least one position (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 positions) of 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°, 33.1 ± 0.2°.

[0011] In some embodiments, the XRPD pattern of the crystalline form A also has characteristic peaks at at least one position (e.g., 1, 2, or 3 positions) among 2θ values of 31.6 ± 0.2°, 38.3 ± 0.2°, 40.2 ± 0.2°.

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

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

[0014] In some embodiments, the thermogravimetric analysis (TGA) pattern of the crystalline form A shows a weight loss of about 0.2% at 25°C to 120°C.

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

[0016] In a second aspect, the present invention provides a compound represented by formula (II), which exists in a crystalline form having crystalline form B, and the crystallographic parameters of the crystalline form B are as follows.

[0017] Using Cu-Kα radiation, the XRPD pattern of the crystalline form B has 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 the crystalline form B also has characteristic peaks at at least one (e.g., one, two, three, four, five, or six) 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°.

[0019] In some embodiments, the XRPD pattern of the crystalline form B also has characteristic peaks at at least one (e.g., one, two, three, four, five, or six) of the 2θ values of 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°.

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

[0021] In some embodiments, the differential scanning calorimetry pattern (DSC) of the crystalline form B has endothermic peaks at 121 ± 3°C and 234 ± 3°C, and an exothermic 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) existing 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) existing 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, and more preferably 1:5.

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

[0030] In some embodiments, the constant-temperature 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 the fourth aspect, the present invention provides a method for preparing a compound represented by formula (II) existing in a crystal form having the crystal form B, which is selected from the solvent evaporation method and the antisolvent method.

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

[0034] Add the compound represented by formula (I) existing in the form of an amorphous substance to an alcohol-based solvent, allow it to dissolve and then stand at room temperature for volatilization to obtain a compound represented by formula (II) existing in a crystal form having the crystal form B.

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

[0036] In some embodiments, the usage ratio (solid-liquid ratio) of the compound represented by formula (I) existing in the form of an amorphous substance to the alcohol-based solvent 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] The compound represented by formula (I) present in the form of an amorphous substance is added to a good solvent, dissolved, then added to an anti-solvent, and after stirring, solid-liquid separation (preferably centrifugation) is carried out, and the obtained solid is dried (preferably vacuum drying) to obtain the compound represented by formula (II) present in a crystalline form having crystalline form B.

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

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

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

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

[0043] In some embodiments, the stirring includes stirring at room temperature and optionally stirring in an ice bath. Preferably, the room temperature stirring time is 0.5 - 3 hours, preferably 1 hour.

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

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

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

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

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

[0049] (1) The crystalline form A and crystalline form B of the present invention have good stability. The crystalline raw drugs provided by the present invention have good physical and chemical stability under different storage conditions. When the crystalline form A and crystalline form B are left for 15 days under the conditions of high temperature of 60°C, high humidity of 92.5% RH, light irradiation of 4500 lux, and acceleration of 40°C / 75% RH, respectively, neither the chemical purity nor the crystalline form of the crystalline form A and crystalline form B changed significantly. This indicates that during the storage process of the crystalline form A and crystalline form B of the present invention and drug formulations containing the crystalline form A and crystalline form B, the crystalline form A and crystalline form B basically remain unchanged, guaranteeing the quality of the raw drug and the formulation.

[0050] (2) The crystalline form A and crystalline form B of the present invention have low hygroscopicity. The weight increase of the crystalline form A of the present invention under 80% relative humidity conditions is 0.09%, indicating no or almost no hygroscopicity. The weight increase of the crystalline form B under 80% relative humidity conditions is 0.71%, indicating slightly hygroscopic. This shows that the crystalline form A and crystalline form B of the present invention are less likely to deliquesce even in a high humidity environment, improving the stability, fluidity, and uniformity during processing of the drug, and enhancing the quality of the drug formulation.

[0051] (3) The solubility of the crystalline form A and crystalline form B of the present invention is good. The solubility of the crystalline forms A and B of the present invention in FeSSIF (fed-state simulated intestinal fluid) and FaSSIF (fasted-state simulated intestinal fluid) is good. Good intestinal solubility is beneficial for good absorption of the drug in the body and can enhance the bioavailability and therapeutic effect of the drug.

[0052] (4) The preparation processes of the crystalline forms A and B of the present invention have good reproducibility, are simple to operate, and are suitable for industrial production.

[0053] As described above, the crystalline forms A and B of the present invention have important application value in the preparation of pharmaceuticals for preventing and / or treating diseases related to α4β7 integrin (for example, autoimmune diseases, inflammatory diseases).

Brief Description of the Drawings

[0054]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Modes for Carrying Out the Invention

[0055] The X-ray powder diffraction (XRPD) method used in the present invention is as follows: Analyze using a Bruker D8 Advance diffractometer, use Cu-Kα radiation, and obtain an X-ray powder diffraction pattern under operating conditions of 40 KV and 40 Ma. The sample is tested at room temperature, and the sample to be measured is placed on a silicon phosphide sheet. The test conditions are specifically as follows: Scan every 0.02° within the range of 3 to 45°, and the exposure time is 0.08 seconds. Collect data using Diffrac.Measurement Center software and process data using Diffrac.Eva software.

[0056] The differential scanning calorimetry (DSC) method used in the present invention is as follows: Perform a differential scanning calorimetry test using a TA Discovery 2500 instrument equipped with a thermal analysis controller, collect data, and analyze using trios software. After accurately weighing about 1 to 2 mg, place it in a perforated DSC Tzero sample dish, and use a linear heating device at 10 °C / min to perform sample analysis at 25 °C to 290 °C. During use, purge the DSC furnace with dry nitrogen, and the purge rate is 50 ml / min.

[0057] The thermogravimetric analysis (TGA) method used in the present invention is as follows: Perform a thermogravimetric test using a TA Discovery 55 instrument equipped with a thermal analysis controller. Collect data and analyze using trios software. Put about 2 to 5 mg of the sample into an equilibrated aluminum sample dish, and automatically measure the weight in a TGA heating furnace. Use a linear heating device at 10 °C / min to perform sample analysis at 25 °C to 290 °C. During use, purge the DSC chamber with dry nitrogen, the purge rate of the sample part is 60 ml / min, and the purge rate of the balance part is 40 ml / min.

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

[0059] The hygroscopicity of the present invention was measured using a DVS Intrinsic type dynamic moisture and gas sorption analyzer from Surface Measurement Systems, UK. The humidity change was 50% - 95% - 0% - 50%, the humidity change amount for each gradient within the range of 0% to 90% was 10%, the gas flow rate was 200 ml / min, the temperature was 25 °C, and the measurement points were to take one measurement point per liter at 10% humidity.

[0060] Hereinafter, the technical solution of the present invention will be described together with specific examples. Those skilled in the art can understand that the following examples are for further elaborating the present invention and do not limit the scope of the present invention. Unless otherwise specifically limited, 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 Weighed 40 mg of the sample (the compound of formula (I) existing in the form of an amorphous substance), added 0.1 ml of ethylene glycol monomethyl ether and 0.4 ml of methyl tert-butyl ether to prepare a suspension, suspended and stirred at 50 °C for 1 day, centrifuged the suspension, and dried the solid in vacuo at room temperature to obtain crystal form A. Its 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 Weigh 504 mg of the sample (the compound of formula (I) existing in the form of an amorphous substance), suspend and stir it in 12.6 ml of an acetone / water (V / V = 1:5) mixed solvent at 50 °C for 8 hours. Centrifuge the obtained white suspension, and dry the solid under vacuum at 50 °C to obtain crystalline form A. Its XRPD pattern was tested to be basically the same as that in Figure 1.

[0064] Example 3 Preparation of Crystalline Form B Add 20 mg of the sample (the compound of formula (I) existing in the form of an amorphous substance) to 0.4 ml of ethanol. After dissolution, let it stand at room temperature for 5 days to volatilize and obtain crystalline form B. Its XRPD pattern is shown in Figure 3, and the DSC and TGA patterns are shown in Figure 4.

[0065] It was confirmed by tests that crystalline form B can be converted into crystalline form A at 150 °C or higher.

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

[0067] Example 4 Preparation of Crystalline Form B Add 20 mg of the sample (the compound of formula (I) existing in the form of an amorphous substance) to 0.35 ml of ethanol. After dissolution, add the sample solution to 3 ml of cyclohexane, stir at room temperature for 1 h, then stir in an ice bath, centrifuge, and dry the solid under vacuum at room temperature to obtain crystalline form B. Its XRPD pattern was tested to be basically the same as that in Figure 4.

[0068] Example 5 Solubility of Crystalline Form A Add 20 mg of the sample (the compound of formula (I) existing in the crystalline form having crystalline form A) to a 10 ml tapered tube, add 4 ml of water or a biological medium (FeSSIF (pH 5.0) or FaSSIF (pH 6.5)) respectively, shake in a 37 °C constant temperature bath for 24 h at a shaking speed of 1000 rpm. Take samples at 0.5 h, 2 h, and 24 h respectively, filter the samples through a water-based microporous filtration membrane, discard the first filtrate, and obtain the test solution.

[0069] Take 20 μL of the test solution and test it by HPLC. Calculate the concentration of the sample by the standard calibration curve method, and show the results in the following table.

[0070]

Table 3

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

[0072] Example 6 Hygroscopicity of Crystalline Form A Take an appropriate amount of the test sample (the compound of formula (I) present in the crystalline form having crystalline form A), and measure its hygroscopicity using a dynamic moisture sorption meter. The test results are shown in Table 4, and the DVS pattern of the hygroscopicity test of crystalline 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 is determined that there is no or almost no hygroscopicity, indicating that crystalline form A of the present invention is not easily deliquescent even in a high humidity environment.

[0075] Example 7 Stability of Crystalline Form A Take an appropriate amount of the test sample (the compound of formula (I) present in the crystalline form having crystalline form A), put it in a watch glass, spread it into a thin layer with a thickness ≤ 5 mm, and leave it standing for 15 days respectively under the conditions of high temperature of 60 °C, high humidity of 92.5% RH, light irradiation of 4500 lux, and acceleration of 40 °C / 75% RH. Take the samples on the 7th day and the 15th day, observe the color change of the samples, measure the purity of the samples by HPLC, and measure the crystalline form of the samples by XPRD. The test results are shown in Table 5, and the XRPD pattern is shown in Figure 7.

[0076]

Table 5

[0077] As can be seen from Table 5 and Figure 7, when left for 15 days under the conditions of high temperature of 60 °C, high humidity of 92.5% RH, light irradiation of 4500 lux, and acceleration of 40 °C / 75% RH, neither the purity nor the crystal form of crystalline form A shows any obvious change. Compared with the amorphous form, the stability of crystalline form A of the present invention is better and it is suitable for use in pharmaceuticals.

[0078] Example 8 Solubility of Crystalline Form B Add 20 mg of the sample (the compound of formula (II) present in the crystalline form having crystalline form B) to a 10 ml tapered tube, and add 4 ml of water or biological medium (FeSSIF (pH 5.0) or FaSSIF (pH 6.5)) respectively. Shake in a 37 °C constant temperature bath for 24 h at a shaking speed of 1000 rpm. Take samples at 0.5 h, 2 h, and 24 h respectively, filter the samples through a water-based microporous filtration membrane, discard the first filtrate, and obtain the test solution.

[0079] Collect the test solution (20 μL) and perform a test by HPLC. Calculate the concentration of the sample by the standard calibration curve method, and show the results in the following table.

[0080]

Table 6

[0081] Conclusion: As can be seen from Table 6, the solubility of crystalline form B in FeSSIF and FaSSIF is relatively good.

[0082] Example 9 Hygroscopicity of Crystalline Form B Take an appropriate amount of the test sample (the compound of formula (II) present in the crystalline form having crystalline form B) and measure its hygroscopicity using a dynamic moisture sorption meter. The test results are shown in Table 7, and the DVS pattern of the hygroscopicity test of crystalline 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 had a weight increase of 0.71% at 80% humidity. Based on the definition criteria for weight increase due to hygroscopicity, it was determined to be slightly hygroscopic, indicating that Crystal Form B of the present invention is less likely to deliquesce even in a high humidity environment.

[0085] Example 10 Stability of Crystal Form B An appropriate amount of the test article (the compound of formula (II) present in a crystal form having Crystal Form B) was taken and placed in a watch glass, spread into a thin layer with a thickness ≤ 5 mm, and left standing for 15 days respectively under the conditions of high temperature 60°C, high humidity 92.5% RH, light irradiation 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 standing for 15 days under the conditions of high temperature 60°C, high humidity 92.5% RH, light irradiation 4500 lux, and accelerated conditions of 40°C / 75% RH, there were no obvious changes in either the purity or the crystal form of Crystal Form B. Compared with the amorphous form, the stability of Crystal Form B of the present invention is better and it is suitable for use in pharmaceuticals.

Claims

1. A compound represented by formula (I), 【Chemical 1】 which exists in a crystalline form having Crystal Form A, and when using Cu-Kα radiation, its X-ray powder diffraction pattern 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°, 22.1 ± 0.2°; the compound represented by the above formula (I).

2. Its X-ray powder diffraction pattern has characteristic peaks at at least one of the 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°, 33.1 ± 0.2°, preferably, its X-ray powder diffraction pattern has characteristic peaks at at least one of the 2θ values of 31.6 ± 0.2°, 38.3 ± 0.2°, 40.2 ± 0.2°, more preferably, its X-ray powder diffraction pattern is basically as shown in Figure 1; the compound represented by formula (I) according to Claim 1, characterized in that.

3. Its differential scanning calorimetry pattern has an endothermic peak at 236 ± 3 °C, preferably, its differential scanning calorimetry pattern is basically as shown in Figure 2, and / or, its thermogravimetric analysis pattern shows a weight loss of about 0.2% at 25 °C to 120 °C, preferably, its thermogravimetric analysis pattern is basically as shown in Figure 2; the compound represented by formula (I) according to Claim 1 or 2, characterized in that.

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

5. Its X-ray powder diffraction pattern has characteristic peaks 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°, 25.5 ± 0.2°, preferably, its X-ray powder diffraction pattern has characteristic peaks at at least one of the 2θ values of 20.8 ± 0.2°, 22.7 ± 0.2°, 23.9 ± 0.2°, 24.8 ± 0.2°, 28.5 ± 0.2°, 32.5 ± 0.2°, More preferably, the X-ray powder diffraction pattern of the compound represented by the formula (II) according to claim 4 is basically as shown in FIG.

3.

6. The differential scanning calorimetry pattern has endothermic peaks at 121 ± 3 °C and 234 ± 3 °C, and an exothermic peak at 133 ± 3 °C. Preferably, the differential scanning calorimetry pattern is basically as shown in FIG. 4, and / or The thermogravimetric analysis pattern shows a weight loss of about 3.6% at 50 °C to 150 °C. Preferably, the thermogravimetric analysis pattern is basically as shown in FIG. 4, the compound represented by the formula (II) according to claim 4 or 5.

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

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

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

10. Use in the preparation of a medicament for the prevention and / or treatment of a disease related to α4β7 integrin of the compound represented by the formula (I) according to claim 1 or 2 and / or the compound represented by the formula (II) according to claim 4 or 5, Preferably, the diseases related to α4β7 integrin include autoimmune diseases and inflammatory diseases.

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