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

Abstract

The present invention relates to crystals of N-(benzoyl)-phenylalanine compounds, their pharmaceutical compositions, preparation methods and uses. Specifically, the compounds are shown in formula (I) and formula (II). The crystal of the compound of formula (I) has crystal form A, and the crystal of the compound of formula (II) has crystal form B. The two crystal forms have good stability, high repeatability and strong operability in the preparation method, and have important application value in preventing and / or treating diseases related to α4β7 integrin.

Description

Technical Field

[0001] The present invention belongs to the technical field of crystalline drugs, and particularly relates to crystals of N-(benzoyl)-phenylalanine compounds, pharmaceutical compositions containing such crystalline drugs, as well as the preparation methods and uses of such crystalline drugs. More particularly, the present invention relates to two crystal forms of (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)phenyl)propionic acid, corresponding pharmaceutical compositions, and the preparation methods and uses of the two crystal forms. Background Art

[0002] Inflammatory bowel disease (IBD) is a series of chronic, inflammatory diseases mainly involving the digestive tract. IBD includes ulcerative colitis (UC), Crohn's disease (CD), and indeterminate colitis. For example, during the occurrence and development of IBD, immune cells migrate to the intestinal site through the interaction of α4β7 integrin with its ligand mucosal addressin 1 (MAdCAM-1) and abnormally aggregate in the intestinal mucosal layer. α4β7 integrin controls the transfer of lymphocytes to intestinal tissues and their retention in the intestine through its interaction with MAdCAM-1.

[0003] It has been proposed that inhibiting the interaction between integrin and its ligand is an effective method for treating various autoimmune and inflammatory diseases, and blocking the α4β7-MAdCAM-1 interaction has shown therapeutic effects on inflammatory bowel diseases such as Crohn's disease and ulcerative colitis.

[0004] PCT / CN2021 / 132456 reported a series of N-(benzoyl)-phenylalanine compounds with strong α4β7-MAdCAM-1 inhibitory activity, which can be used for the prevention and / or treatment of α4β7 integrin-related diseases (such as autoimmune diseases and inflammatory diseases), including the compound with the chemical name (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoic acid. The preparation method of this compound is as follows: Dissolve methyl (S)-2-(2-chloro-6-fluorobenzamido)-3-(4-(6',7'-difluoro-2'-oxospiro[cyclopropane-1,3'-indoline]-1'-yl)phenyl)propanoate in tetrahydrofuran, and then add 0.5 mol / L aqueous sodium hydroxide solution to the reaction system, and react at room temperature for 2 h. Adjust the pH value 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 respectively, dry over anhydrous sodium sulfate, filter by suction, concentrate under reduced pressure, and purify the concentrate by reverse-phase HPLC (H2O / CH3CN system containing 0.1% formic acid) to obtain the compound shown in formula (I).

[0005]

[0006] The product obtained by the above method is an amorphous substance (as shown in Figure 7 ), and since amorphous is a relatively unstable solid form in thermodynamics and is prone to transformation or degradation, etc., it leads to a decrease in the chemical purity of the compound, thereby affecting the final quality of the drug. Summary of the Invention

[0007] Aiming at the above defects, the present invention unexpectedly finds that the crystal form A of the compound shown in formula (I) and the crystal form B of the compound shown in formula (II) have the properties of high stability, simple preparation process, and suitability for large-scale industrial production.

[0008] In the first aspect, the present invention provides the compound shown in formula (I), which exists in the form of crystals with crystal form A, and the crystallographic parameters of the crystal form A are as follows:

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

[0010] In some embodiments, the XRPD pattern of Form A further has characteristic peaks at least at one place (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 places) where the 2θ value is 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 Form A further has characteristic peaks at least at one place (e.g., 1, 2, or 3 places) where the 2θ value is 31.6±0.2°, 38.3±0.2°, 40.0±0.2°.

[0012] In some embodiments, the XRPD pattern of Form A is substantially as Figure 1 shown.

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

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

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

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

[0017] Using Cu-Kα radiation, the XRPD pattern of Form B has characteristic peaks at 2θ values of 8.5±0.2°, 11.0±0.2°, 17.9±0.2°.

[0018] In some embodiments, the XRPD pattern of Form B further has characteristic peaks at least at one place (e.g., 1, 2, 3, 4, 5, or 6 places) where the 2θ value is 14.3±0.2°, 15.5±0.2°, 19.3±0.2°, 20.1±0.2°, 24.4±0.2°, 25.5±0.2°.

[0019] In some embodiments, the XRPD pattern of Form B further has characteristic peaks at least at one (e.g., 1, 2, 3, 4, 5, or 6) 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 Form B is substantially as Figure 3 shown.

[0021] In some embodiments, the differential scanning calorimetry (DSC) of 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) of Form B shows a weight loss of about 3.6% at 50 °C - 150 °C. Combining with the DSC analysis, Form B is a monohydrate crystal form.

[0023] In some embodiments, the DSC and TGA patterns of Form B are substantially as Figure 4 shown.

[0024] In a third aspect, the present invention provides a method for preparing the compound represented by formula (I) in the form of crystals having Form A, which is selected from the suspension polymorph conversion method.

[0025] In some embodiments, the specific steps of the above suspension polymorph conversion method include: adding the compound represented by formula (I) in the form of an amorphous substance to a binary mixed solvent to prepare a suspension, performing solid-liquid separation (preferably centrifugal separation) after constant temperature stirring, and drying the obtained solid (preferably vacuum drying) to obtain the compound represented by formula (I) in the form of crystals having Form A.

[0026] In some embodiments, the binary mixed solvent includes 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 - 1:9, preferably 1:4 - 1:5, and more preferably 1:5.

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

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

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

[0032] In a fourth aspect, the present invention provides a method for preparing the compound of formula (II) in the form of crystals having crystal form B, which is selected from the solvent evaporation method and the anti-solvent method.

[0033] In some embodiments, the specific steps of the above solvent evaporation method include:

[0034] The compound of formula (I) in amorphous form is added to an alcohol solvent, dissolved and then left to stand and volatilize at room temperature to obtain the compound of formula (II) in the form of crystals having crystal form B.

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

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

[0037] In some embodiments, the specific steps of the above anti-solvent method include:

[0038] The compound of formula (I) in amorphous form is added to a good solvent, dissolved and then added to an anti-solvent, stirred and then subjected to solid-liquid separation (preferably centrifugal separation), and the obtained solid is dried (preferably vacuum dried) to obtain the compound of formula (II) in the form of crystals having crystal 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 dosage ratio (solid-liquid ratio) of the compound of formula (I) in amorphous form to the good solvent is 40 - 70 mg:1 ml, preferably 55 mg:1 ml.

[0042] In some embodiments, the dosage 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 time of the stirring at room temperature 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 of formula (I) having crystal form A and / or the compound of formula (II) having crystal form B as described above, and at least one pharmaceutically acceptable carrier.

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

[0046] In a sixth aspect, the present invention provides the use of the compound of formula (I) having crystal form A and / or the compound of formula (II) having crystal form B as described above in the preparation of a drug for preventing and / or treating a disease related to α4β7 integrin.

[0047] The diseases related to α4β7 integrin include autoimmune diseases and inflammatory diseases; preferably, the inflammatory disease is inflammatory bowel disease (IBD), for example, ulcerative colitis (UC), Crohn's disease (CD).

[0048] The crystal form A of the compound of formula (I) and the crystal form B of the compound of formula (II) provided by the present invention have the following beneficial effects:

[0049] (1) The crystal form A and crystal form B of the present invention have good stability

[0050] The crystalline raw materials provided by the present invention have good physical and chemical stability under different storage conditions. The crystal form A and crystal form B are placed at 60°C (high temperature), 92.5% RH (high humidity), 4500 lux (light), and 40°C / 75% RH (accelerated condition) for 15 days respectively, and there are no obvious changes in the chemical purity and crystal form of the crystal form A and crystal form B. This indicates that during storage, the crystal form A and crystal form B of the present invention and the pharmaceutical preparations containing crystal form A and crystal form B basically remain unchanged, thus ensuring the quality of the raw materials and preparations.

[0051] (2) The crystal form A and crystal form B of the present invention have low hygroscopicity

[0052] The weight gain of polymorph A of the present invention under 80% relative humidity is 0.09%, belonging to non - hygroscopic or almost non - hygroscopic; the weight gain of polymorph B under 80% relative humidity is 0.71%, belonging to slightly hygroscopic. This indicates that polymorph A and polymorph B of the present invention are not easily affected by high humidity and deliquesce, thereby improving the stability, fluidity and uniformity during processing of the drug, etc., and improving the quality of the pharmaceutical preparation.

[0053] (3) Polymorph A and polymorph B of the present invention have good solubility

[0054] Polymorph A and polymorph B of the present invention both have good solubility in FeSSIF (fed - state simulated intestinal fluid) and FaSSIF (fasted - state simulated intestinal fluid). Good intestinal solubility is beneficial to the good absorption of the drug in the body, thereby improving the bioavailability and efficacy of the drug.

[0055] (4) The preparation processes of polymorph A and polymorph B of the present invention have good reproducibility, simple operations, and are suitable for industrial production.

[0056] In summary, polymorph A and polymorph B of the present invention have important application values in the preparation of drugs for preventing and / or treating diseases related to α4β7 integrin (for example, autoimmune diseases, inflammatory diseases). Brief Description of the Drawings

[0057] Figure 1 XPRD pattern of polymorph A of the compound of formula (I) prepared in Example 1.

[0058] Figure 2 DSC / TGA pattern of polymorph A of the compound of formula (I) prepared in Example 1.

[0059] Figure 3 XPRD pattern of polymorph B of the compound of formula (II) prepared in Example 3.

[0060] Figure 4 DSC / TGA pattern of polymorph B of the compound of formula (II) prepared in Example 3.

[0061] Figure 5 XPRD pattern of the amorphous powder of the compound of formula (I) prepared in Example 15 of PCT / CN2021 / 132456.

[0062] Figure 6 DVS pattern of polymorph A of the compound of formula (I) in Example 6.

[0063] Figure 7 XPRD pattern of polymorph A of the compound of formula (I) in Example 7 after being placed for 15 days under high temperature, high humidity, light and accelerated experiments.

[0064] Figure 8 DVS pattern of crystalline form B of the compound of formula (II) for Example 9.

[0065] Figure 9 XPRD pattern of crystalline form B of the compound of formula (II) after being placed for 15 days under high temperature, high humidity, light and accelerated tests for Example 10. Detailed implementation manners

[0066] The X-ray powder diffraction (XRPD) method used in the present invention is as follows: Analysis is carried out using a Bruker D8 Advance diffractometer. Using Cu-Kα radiation, under the operating conditions of 40 KV and 40 Ma, an X-ray powder diffraction pattern is obtained. The sample is tested at room temperature, and the sample to be detected is placed on a silicon phosphide wafer. The detailed detection conditions are as follows: Scanning is carried out at a step size of 0.02° in the range of 3 - 45°, and the exposure time is 0.08 seconds. Data is collected using Diffrac.Measurement Center software and processed using Diffrac.Eva software.

[0067] The differential scanning calorimetry (DSC) method used in the present invention is as follows: Differential scanning calorimetry is carried out using a TA Discovery 2500 instrument with a thermal analysis controller. Data is collected and analyzed using trios software. Approximately 1 - 2 mg is accurately weighed and placed in a punctured DSC Tzero sample pan. Using a linear heating device at 10 °C / min, the sample is analyzed from 25 °C to 290 °C. During use, the DSC furnace chamber is purged with dry nitrogen at a purge rate of 50 ml / min.

[0068] The thermogravimetric analysis (TGA) method used in the present invention is as follows: Thermogravimetric analysis is carried out using a TA Discovery 55 instrument with a thermal analysis controller. Data is collected and analyzed using trios software. Approximately 2 - 5 mg of the sample is placed in a balanced aluminum sample pan and automatically weighed in the TGA heating furnace. Using a linear heating device at 10 °C / min, the sample is analyzed from 25 °C to 290 °C. During use, the DSC chamber is purged with dry nitrogen. The nitrogen purge rate at the sample is 60 mL / min, and the nitrogen purge rate at the balance is 40 mL / min.

[0069] The solubility results in the present invention are determined using a SHIMADZU LC 2030C 3D Plus high performance liquid chromatograph. The chromatographic column model is YMC Pack ODS-AQ C18, 4.6×250 mm, 5 μm. The detection wavelength is 220 nm, the flow rate is 1.2 ml / min, the column temperature is 30 °C, and the mobile phase is: 0.1% phosphoric acid water - acetonitrile gradient elution.

[0070] In the present invention, the hygroscopicity results were determined using a DVS Intrinsic type dynamic moisture and gas sorption instrument from Surface Measurement Systems, UK. The humidity was changed as 50% - 95% - 0% - 50%, the humidity change amount for each gradient within the range of 0% to 90% was 10%, the gas flow: 200 ml / min, the temperature: 25 °C, and the test points: one test point was taken for every 10% humidity per liter.

[0071] The technical solution of the present invention will be described below in conjunction with specific embodiments. Those of ordinary skill in the art can understand that the following embodiments are only for further elaborating the present invention and do not limit the scope of the present invention. Unless otherwise specified, the drugs, reagents, materials, instruments, etc. used in the following embodiments can be obtained through conventional commercial means.

[0072] Example 1 Preparation of Crystal Form A

[0073] Weigh 40 mg of the sample (the compound of formula (I) in amorphous form), add 0.1 ml of ethylene glycol monomethyl ether and 0.4 ml of methyl tert-butyl ether, prepare a suspension, stir the suspension at 50 °C for 1 day, centrifuge the suspension, and vacuum-dry the solid at room temperature to obtain crystal form A. Its XRPD pattern is as Figure 1 shown, and the DSC and TGA patterns are as Figure 2 shown.

[0074] Table 1

[0075] Number Diffraction Angle 2θ d Value Intensity % 1 5.152° 17.13880 18.6 2 10.447° 8.46068 75.4 3 12.311° 7.18391 28.3 4 13.082° 6.76188 74.2 5 13.597° 6.50719 69.1 6 14.719° 6.01349 18.4 7 15.693° 5.64239 36.6 8 18.808° 4.71426 64.6 9 18.843° 4.70576 62.5 10 19.574° 4.53153 100.0 11 20.190° 4.39473 88.4 12 21.858° 4.06293 76.9 13 22.092° 4.02047 86.4 14 22.109° 4.01731 82.9 15 24.743° 3.59529 21.7 16 26.537° 3.35628 19.4 17 28.451° 3.13468 18.6 18 31.641° 2.82551 7.9 19 33.108° 2.70355 11.9 20 38.296° 2.34842 7.4 21 40.004° 2.25201 6.7

[0076] Example 2 Preparation of Crystal Form A

[0077] Weigh 504 mg of the sample (the compound of formula (I) in amorphous form), in a mixed solvent of 12.6 ml of acetone / water (V / V = 1:5), stir the suspension at 50 °C for 8 hours, centrifuge the obtained white suspension, and vacuum-dry the solid at 50 °C to obtain crystal form A. After testing, its XRPD pattern is Figure 1 substantially the same.

[0078] Example 3 Preparation of Crystal Form B

[0079] Add 20 mg of the sample (the compound of formula (I) in amorphous form) to 0.4 ml of ethanol, dissolve it and let it stand at room temperature to volatilize for 5 days to obtain crystal form B. Its XRPD pattern is as Figure 3 shown, and the DSC and TGA patterns are as Figure 4 shown.

[0080] It was confirmed by experimental determination that crystal form B can be converted to crystal form A at temperatures above 150 °C. Table 2

[0081] Number Diffraction Angle 2θ d Value Intensity % 1 4.084 21.61671 1.3 2 8.142 10.85096 2.0 3 8.530 10.35778 52.0 4 11.029 8.01590 100.0 5 12.155 7.27595 0.8 6 14.269 6.20208 18.0 7 14.957 5.91853 2.2 8 15.493 5.71464 17.8 9 16.208 5.46414 0.5 10 17.023 5.20444 2.9 11 17.852 4.96469 30.3 12 18.647 4.75470 2.9 13 19.279 4.60019 19.7 14 19.669 4.50997 0.8 15 20.108 4.41232 11.3 16 20.822 4.26266 5.7 17 21.051 4.21681 0.9 18 21.628 4.10559 4.5 19 22.084 4.02189 2.5 20 22.268 3.98905 1.8 21 22.676 3.91821 5.4 22 22.841 3.89022 1.9 23 23.153 3.83845 1.9 24 23.937 3.71461 7.6 25 24.386 3.64715 22.9 26 24.845 3.58076 9.7 27 25.516 3.48812 14.1 28 26.426 3.37010 3.3 29 26.895 3.31230 1.7 30 27.809 3.20551 1.5 31 28.510 3.12830 5.0 32 29.411 3.03447 0.7 33 29.845 2.99134 1.5 34 30.083 2.96815 3.4 35 30.398 2.93817 4.8 36 31.196 2.86479 2.4 37 32.317 2.76796 2.6 38 32.533 2.75006 8.4 39 33.429 2.67838 0.5 40 33.674 2.65941 0.8 41 34.340 2.60935 4.6 42 35.598 2.51995 0.5

[0082] 43 36.176 2.48100 0.7 44 36.550 2.45650 1.5 45 36.915 2.43302 0.4 46 37.669 2.38604 0.7 47 38.760 2.32134 0.6 48 39.047 2.30496 2.3 49 40.013 2.25150 0.9 50 41.122 2.19332 1.9 51 41.504 2.17402 0.4 52 41.872 2.15575 2.1 53 42.946 2.10428 0.5 54 43.621 2.07326 1.8

[0083] Preparation of Crystal Form B in Example 4

[0084] Add 20 mg of the sample (the compound of formula (I) in amorphous form) to 0.35 ml of ethanol. After dissolution, add the sample solution to 3 ml of cyclohexane. Stir at room temperature for 1 h and then stir in an ice bath. Centrifuge and vacuum dry the solid at room temperature to obtain Crystal Form B. After testing, its XRPD pattern is the same as that of Figure 4 substantially the same.

[0085] Solubility of Crystal Form A in Example 5

[0086] Add 20 mg of the sample (the compound of formula (I) in the form of crystals of Crystal Form A) to a 10-ml conical tube. 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. Sampling is carried out at 0.5 h, 2 h, and 24 h respectively. Filter the sample through a water-based microporous membrane and discard the initial filtrate to obtain the test solution.

[0087] Take the test solution (20 μL) and perform HPLC detection. Calculate the sample concentration by the standard curve method. The specific results are shown in the following table.

[0088] Table 3. Solubility test results of Crystal Form A in different media

[0089]

[0090] Conclusion: As can be seen from Table 3, the solubility of Crystal Form A in FeSSIF and FaSIF is relatively good.

[0091] Hygroscopicity of Crystal Form A in Example 6

[0092] Take an appropriate amount of the test sample (the compound of formula (I) in the form of crystals of Crystal Form A) and test its hygroscopicity using a dynamic moisture sorption instrument. The experimental results are shown in Table 4, and the DVS pattern of the hygroscopicity experiment of Crystal Form A is as shown in Figure 6 shown.

[0093] Table 4. Hygroscopicity test results of Crystal Form A of the present invention

[0094] Test Sample Weight Gain at 80% RH / % Crystal Form A 0.09％

[0095] Experimental conclusion: From Table 4 and Figure 6It is known that the weight gain of polymorph A at 80% RH is 0.09%. According to the definition standard of weight gain due to hygroscopicity, it belongs to non-hygroscopic or almost non-hygroscopic, indicating that polymorph A of the present invention is not easily affected by high humidity and deliquesces.

[0096] Stability of Polymorph A in Example 7

[0097] Take an appropriate amount of a batch of test samples (the compound of formula (I) in the form of crystals of polymorph A), place them in a petri dish, spread them into a thin layer with a thickness of ≤5 mm, and place them at high temperature of 60 °C, high humidity of 92.5% RH, light of 4500 lux, and accelerated conditions of 40 °C / 75% RH for 15 days respectively. Sampling is carried out on the 7th day and 15th day, observe the color change of the samples, detect the purity of the samples by HPLC, and detect the crystal form of the samples by XPRD. The test results are shown in Table 5, and the XRPD pattern is shown in Figure 7 .

[0098] Table 5. Stability test results of polymorph A and amorphous form

[0099]

[0100] It can be seen from Table 5 and Figure 7 It is known that after being placed for 15 days under the conditions of high temperature of 60 °C, high humidity of 92.5% RH, light of 4500 lux, and accelerated conditions of 40 °C / 75% RH, the purity and crystal form of polymorph A have no obvious changes, and compared with the amorphous form, polymorph A of the present invention has better stability and is suitable for medicinal use.

[0101] Solubility of Polymorph B in Example 8

[0102] Add 20 mg of the sample (the compound of formula (II) in the form of crystals of polymorph B) into a 10 ml conical tube, add 4 ml of water or biological medium (FeSSIF (pH 5.0) or FaSSIF (pH 6.5)) respectively, shake in a constant temperature bath at 37 °C for 24 h, and the shaking speed is 1000 rpm. Sampling is carried out at 0.5 h, 2 h, and 24 h respectively. The samples are filtered through a hydrophilic microporous membrane, and the initial filtrate is discarded to obtain the test solution.

[0103] Take the test solution (20 μL), detect it by HPLC, and calculate the sample concentration by the standard curve method. The specific results are shown in the following table.

[0104] Table 6. Solubility test results of polymorph B in different media

[0105]

[0106] Conclusion: It can be seen from Table 6 that the solubility of polymorph B in FeSSIF and FaSIF is also relatively good.

[0107] Hygroscopicity of Polymorph B in Example 9

[0108] Take an appropriate amount of the test substance (the compound of formula (II) in the form of crystals of polymorph B), and use a dynamic vapor sorption instrument to test its hygroscopicity. The experimental results are shown in Table 7, and the DVS diagram of the hygroscopicity experiment of polymorph B is basically as Figure 8 shown.

[0109] Table 7. Hygroscopicity test results of polymorph B of the present invention

[0110] Test Sample Weight Gain at 80% RH / % Crystal Form B 0.71％

[0111] Experimental conclusion: From Table 7 and Figure 8 it can be seen that the weight gain of polymorph B at 80% humidity is 0.71%. According to the definition standard of hygroscopic weight gain, it belongs to slightly hygroscopic, indicating that polymorph B of the present invention is not easily affected by high humidity and deliquesces.

[0112] Stability of polymorph B in Example 10

[0113] Take an appropriate amount of a batch of test substances (the compound of formula (II) in the form of crystals of polymorph B), put them in a petri dish, spread them into a thin layer with a thickness of ≤5 mm, and place them at high temperature of 60 °C, high humidity of 92.5% RH, light of 4500 lux and accelerated conditions of 40 °C / 75% RH for 15 days respectively. Sampling is carried out on the 15th day, the color change of the sample is observed, the purity of the sample is detected by HPLC, and the crystal form of the sample is detected by XPRD. The test results are shown in Table 8, and the XRPD pattern is shown in Figure 9 .

[0114] Table 8. Stability test results of polymorph B

[0115]

[0116] From Table 8 and Figure 9 it can be seen that when placed for 15 days under the conditions of high temperature of 60 °C, high humidity of 92.5% RH, light of 4500 lux and accelerated conditions of 40 °C / 75% RH, the purity and crystal form of polymorph B have no obvious changes, and compared with the amorphous form, polymorph B of the present invention also has better stability and is suitable for medicinal use.

Claims

1. A compound of formula (I), which exists in the form of crystals having polymorph A and, using Cu-Kα radiation, has characteristic peaks in its X-ray powder diffraction pattern 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°.

2. The compound of formula (I) according to claim 1, wherein its X-ray powder diffraction pattern has characteristic peaks at least at 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°.

3. The compound of formula (I) according to claim 2, wherein its X-ray powder diffraction pattern has characteristic peaks at least at one of the 2θ values of 31.6 ± 0.2°, 38.3 ± 0.2°, 40.0 ± 0.2°.

4. The compound of formula (I) according to claim 3, wherein its X-ray powder diffraction pattern is substantially as shown in Figure 1.

5. The compound of formula (I) according to any one of claims 1-4, wherein its differential scanning calorimetry pattern has an endothermic peak at 236 ± 3 °C; and / or, its thermogravimetric analysis pattern shows a weight loss of about 0.2% at 25 °C - 120 °C.

6. The compound of formula (I) according to claim 5, wherein its differential scanning calorimetry pattern is substantially as shown in Figure 2.

7. The compound of formula (I) according to claim 5, wherein its thermogravimetric analysis pattern is substantially as shown in Figure 2.

8. The compound of formula (I) according to claim 5, wherein its differential scanning calorimetry pattern is substantially as shown in Figure 2; and / or, its thermogravimetric analysis pattern is substantially as shown in Figure 2.

9. A compound of formula (II), which exists in the form of crystals having polymorph B and, using Cu-Kα radiation, has characteristic peaks in its X-ray powder diffraction pattern at 2θ values of 8.5 ± 0.2°, 11.0 ± 0.2°, 17.9 ± 0.2°.

10. The compound of formula (II) according to claim 9, wherein its X-ray powder diffraction pattern has characteristic peaks at least at 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°.

11. The compound of formula (II) according to claim 10, wherein its X-ray powder diffraction pattern has characteristic peaks at least at 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°.

12. The compound represented by formula (II) according to claim 11, wherein its X-ray powder diffraction pattern is substantially as shown in Figure 3.

13. The compound represented by formula (II) according to any one of claims 9-12, wherein its differential scanning calorimetry pattern has endothermic peaks at 121 ± 3 °C and 234 ± 3 °C, and an exothermic peak at 133 ± 3 °C; and / or, its thermogravimetric analysis pattern shows a weight loss of approximately 3.6% at 50 °C - 150 °C.

14. The compound represented by formula (II) according to claim 13, wherein its differential scanning calorimetry pattern is substantially as shown in Figure 4.

15. The compound represented by formula (II) according to claim 13, wherein its thermogravimetric analysis pattern is substantially as shown in Figure 4.

16. The compound represented by formula (II) according to claim 13, wherein its differential scanning calorimetry pattern is substantially as shown in Figure 4; and / or, its thermogravimetric analysis pattern is substantially as shown in Figure 4.

17. A method for preparing the compound represented by formula (I) according to any one of claims 1-8, which is selected from the suspension polymorph conversion method.

18. A method for preparing the compound represented by formula (II) according to any one of claims 9-16, which is selected from the solvent evaporation method and the anti-solvent method.

19. A pharmaceutical composition comprising a prophylactically and / or therapeutically effective amount of the compound represented by formula (I) according to any one of claims 1-8 and / or the compound represented by formula (II) according to any one of claims 9-16, and at least one pharmaceutically acceptable carrier.

20. Use of the compound represented by formula (I) according to any one of claims 1-8 and / or the compound represented by formula (II) according to any one of claims 9-16 in the preparation of a drug for preventing and / or treating a disease associated with α4β7 integrin.

21. The use according to claim 20, wherein the diseases associated with α4β7 integrin include autoimmune diseases and inflammatory diseases.

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