Pterostilbene compound, pharmaceutical composition and application of pterostilbene compound in preparation of anti-inflammatory drugs

Abstract

The invention relates to a pterostilbene compound, a pharmaceutical composition and application of the pterostilbene compound in preparation of anti-inflammatory drugs. The compound shown in the formula (I) or the pharmaceutically acceptable salt thereof provided by the invention has relatively high stability and high bioavailability, can effectively improve symptoms such as colon shortening, diarrhea, hematochezia and weight loss caused by DSS-induced mouse colitis, has a remarkable inhibition effect on intestinal inflammation, and can be used for preparing anti-inflammatory drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a pterostilbene compound, a pharmaceutical composition and their use in the preparation of anti-inflammatory drugs. Background Art

[0002] Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the gastrointestinal tract. The cause of IBD is very complex and its pathogenesis is still unclear. Current studies have shown that IBD may be affected by a combination of multiple factors, such as host genetic susceptibility, intestinal microbiota, environmental factors and immune abnormalities. So far, the clinical drugs used for the treatment of IBD mainly include classical anti-inflammatory drugs, immunosuppressive drugs and some antibody drugs. There is still no effective drug that can completely cure IBD. The clinical treatment goal is to relieve symptoms, maintain an asymptomatic state and prevent recurrence. Therefore, the development of new therapeutic drugs with small side effects and definite curative effects has far-reaching clinical application prospects and important social significance. Summary of the Invention

[0003] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0004]

[0005] According to an embodiment of the present invention, the pharmaceutically acceptable salt may be an acid addition salt, such as an acid addition salt formed by the compound of formula (I) and the following inorganic acids: such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfate, or an acid addition salt formed by the following organic acids: such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, amidosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfate or thiocyanic acid; preferably fumaric acid.

[0006] According to an embodiment of the present invention, the structure of the pharmaceutically acceptable salt is as follows:

[0007]

[0008] The present invention also provides a method for preparing the compound shown in formula (I), which comprises the following steps: reacting compound 1 with compound 2 to obtain the compound shown in formula (I);

[0009]

[0010] Wherein, X is selected from halogen, such as Cl, Br, I.

[0011] The present invention also provides a method for preparing a pharmaceutically acceptable salt of the compound shown in formula (I), which comprises the following steps: mixing the compound shown in formula (I) with an acid in a solvent to obtain a pharmaceutically acceptable salt of the compound shown in formula (I); the acid has the definition described above.

[0012] According to an embodiment of the present invention, the preparation method comprises dissolving the compound shown in formula (I) in a solvent, and then adding an acid to continue the reaction to obtain a pharmaceutically acceptable salt of the compound shown in formula (I).

[0013] According to an embodiment of the present invention, the preparation method comprises dissolving the compound shown in formula (I) in ethyl acetate, and adding fumaric acid to react to obtain the fumarate of the compound shown in formula (I).

[0014] A pharmaceutical composition comprising the compound shown in formula (I) or a pharmaceutically acceptable salt thereof.

[0015] The present invention also provides the use of the compound shown in formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of an anti-inflammatory drug, for example, in the preparation of a drug for treating inflammatory bowel disease.

[0016] A method for treating an inflammatory disease, which comprises administering to a patient a therapeutically effective amount of the compound shown in formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition.

[0017] According to an embodiment of the present invention, the inflammatory disease is inflammatory bowel disease.

[0018] The present invention also provides a compound shown in formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition for treating an inflammatory disease. Description of the Drawings

[0019] Figure 1 Effect of PTE-2 on DAI score in a murine colitis model induced by DSS (DAI score = (body weight loss score + fecal score + fecal blood score) / 3; "***" indicates P < 0.001 compared with the blank control group; "##" indicates P < 0.01 compared with the model control group).

[0020] Figure 2Effect of PTE-2 on the colorectal length in a DSS-induced mouse colitis model ("***" indicates P < 0.001 compared with the blank control group; "##" indicates P < 0.01 compared with the model control group).

[0021] Figure 3 Effect of PTE-2 on the HE staining score in a DSS-induced mouse colitis model ("***" indicates P < 0.001 compared with the blank control group; "#" indicates P < 0.05 compared with the model control group).

[0022] Figure 4 Effect of PTE-2 on the body weight in a DSS-induced mouse colitis model ("***" indicates P < 0.001 compared with the blank control group; "#" indicates P < 0.05 compared with the model control group).

[0023] Beneficial effects

[0024] The compound of formula (I) provided by the present invention or its pharmaceutically acceptable salt has high stability and high bioavailability, and can effectively improve the symptoms such as colon shortening, diarrhea, bloody stools, and weight loss caused by DSS-induced mouse colitis, and has a significant inhibitory effect on intestinal inflammation, and can be used for preparing anti-inflammatory drugs (such as drugs for treating inflammatory bowel disease). Detailed implementation manners

[0025] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are only used to illustrate and explain the present disclosure exemplarily, and should not be construed as limiting the protection scope of the present disclosure. All technologies implemented based on the above content of the present disclosure are covered within the scope of protection intended by the present disclosure.

[0026] Unless otherwise specified, the raw materials and reagents used in the following embodiments are all commercially available products, or can be prepared by known methods.

[0027] Example 1

[0028]

[0029] Weigh pterostilbene (Compound 1, 23.43 g, 1.0 eq) and 2-(dimethylamino)ethyl bromide hydrobromide (31.17 g, 1.5 eq) and add them to a round-bottom flask. Add DMF (560 mL) to dissolve. Under nitrogen protection, cool the system to 0 °C. Weigh sodium hydride (12.06 g, 3.0 eq) and add it to the reaction solution. After completion, gradually warm the system to room temperature and continue stirring overnight. After TLC detection shows that most of the raw materials have disappeared, quench the reaction with water, adjust the pH of the system to 2 - 3 with 1N HCl solution, add ethyl acetate for extraction and layering, and discard the organic phase. Adjust the pH of the aqueous phase to 8 - 9 with saturated potassium carbonate solution, extract with ethyl acetate, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Filter by suction and concentrate under reduced pressure to obtain 17.52 g of the compound shown in formula (I), which is a light brown oily substance, with a yield of 58.52%, and it is directly used for the next step. 1 H NMR (600 MHz, DMSO) δ 7.51 (d, J = 9.0 Hz, 2H), 7.20 (d, J = 16.2 Hz, 1H), 7.02 (d, J = 16.2 Hz, 1H), 6.95 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 2.4 Hz, 2H), 6.39 (t, J = 2.4 Hz, 1H), 4.06 (t, J = 6.0 Hz, 2H), 3.77 (s, 6H), 2.62 (t, J = 6.0 Hz, 2H), 2.21 (s, 6H).

[0030] Dissolve the compound shown in formula (I) (17.52 g, 1.0 eq) in ethyl acetate (100 mL), add fumaric acid (3.22 g, 0.9 eq), heat the system to 50 °C, and continue stirring for 5 hours. Then cool to room temperature and filter to obtain 16.27 g of white powder (PTE-2), with a yield of 76.20%. 1 H NMR (600 MHz, DMSO) δ 7.53 (d, J = 9.0 Hz, 2H), 7.21 (d, J = 16.2 Hz, 1H), 7.03 (d, J = 16.2 Hz, 1H), 6.96 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 2.4 Hz, 2H), 6.58 (s, 2H), 6.39 (t, J = 2.4 Hz, 1H), 4.16 (t, J = 5.4 Hz, 2H), 3.77 (s, 6H), 2.91 (t, J = 5.4 Hz, 2H), 2.42 (s, 6H).

[0031] Example 2 Stability Experiment

[0032] Place the test sample in a weighing bottle, disperse it, and the thickness should not exceed 3 mm. Conduct tests under high temperature, high humidity, and light conditions respectively.

[0033] (1) High-temperature test: The test sample was placed with the opening facing upwards in a suitable constant-temperature device. The temperature was set at 60 °C, and the sampling time points were set as 0 day, 5 days, and 10 days to examine the changes in related substances.

[0034] (2) High-humidity test: The test sample was placed with the opening facing upwards in a constant-humidity airtight container. At 25 °C, it was placed for 10 days under the condition of relative humidity 90% ± 5% (KNO₃ saturated solution (relative humidity 92.5%, 25 °C)), and samples were taken on the 5th day and the 10th day to examine the changes in related substances.

[0035] (3) High-intensity light irradiation test: The test sample was placed with the opening facing upwards in a light box and simultaneously exposed to cold white fluorescent lamps and near-ultraviolet lamps. Under the condition of illuminance of 4500 lx ± 500 lx, and the total illuminance of the light source should not be less than 1.2×10 6 lux·hr, and the energy of the near-ultraviolet lamp should not be less than 200 W·hr / m 2 , and samples were taken on the 5th day and the 10th day to examine the changes in related substances.

[0036] Detection method for related substances (HPLC):

[0037] Mobile phase A: H₂O: ACN: H₃PO₄ = 90:10:0.1

[0038] Mobile phase B: H₂O: ACN: H₃PO₄ = 10:90:0.1

[0039] Chromatographic column: Octadecylsilane chemically bonded silica gel as the filler, 4.6*250 mm, 5 μm

[0040] Gradient:

[0041]

[0042] Test sample solution: Take an appropriate amount of this product, dissolve and dilute it with 10% methanol to prepare a solution containing about 5 mg per 1 ml, and inject 10 μl.

[0043] The test results are shown as follows:

[0044]

[0045]

[0046] The results show that the compound described in the present invention is relatively stable under high-temperature and high-humidity conditions, but sensitive to light.

[0047] Example 3

[0048] 1. Experimental method

[0049] (1) Randomly divide the mice into groups according to body weight, with 10 mice in each group and a total of 4 groups. Randomly select 1 group of mice as the blank control group, which drinks normal water. The remaining mice are used to establish a DSS-induced mouse colitis model: Dissolve DSS powder in ultrapure water at a concentration of 3% (add 3 g of DSS to 100 mL of ultrapure water), and let the mice drink it freely, changing the water every other day. The day when the model is established is the first day of the experiment. The remaining 8 groups of mice are randomly divided, and feces are collected every 2 days and stored frozen at -80 °C in a refrigerator. Weigh the mice every day, administer drugs by gavage according to body weight, and observe the status and feces. End the experiment after continuous drug administration for 9 days, dissect the mice to observe the intestinal conditions and conduct sampling.

[0050] (2) Take the colon and rectum, measure the length, take pictures, and fix the samples at 2 cm from the distal end of the colon with paraformaldehyde and send them blindly to a testing company for HE staining and scoring.

[0051] 2. Experimental grouping:

[0052] (1) Blank control group: Drink normal water;

[0053] (2) Model control group: Drink DSS water for 9 days;

[0054] (3) Pterostilbene - 100 mg / kg group, drink DSS water for 9 days;

[0055] (4) PTE - 2 - 100 mg / kg group, drink DSS water for 9 days;

[0056] There are 10 mice in each group and a total of 40 mice.

[0057] 3. Drug preparation and administration method

[0058] Pterostilbene is dissolved in corn oil, sonicated for about 15 minutes, and administered by gavage once a day;

[0059] Compound PTE - 2 is dissolved in normal saline, sonicated for about 15 minutes, and administered by gavage once a day;

[0060] The blank control group and the model control group are given an equal volume of normal saline.

[0061] 4. Experimental results and analysis

[0062] The experimental results are shown in Figures 1 to 4 :

[0063] According to Figure 1It can be seen that from the fourth day of administering the drug, the animals generally showed varying degrees of weight loss and diarrhea. The DAI score was determined based on the percentage of weight loss, the state of feces, and the intestinal bleeding condition. By the end of the experiment, the DAI score of the model control group was significantly higher than that of the blank control group (P < 0.001); the DAI score of the model control group was (2.5 ± 0.4), the DAI score of the pterostilbene-100mg / kg group was (2.2 ± 0.6); the DAI score of the PTE-2-100mg / kg group was (1.8 ± 0.6) (P < 0.01). This indicates that PTE-2 can significantly improve the diarrhea, bloody stools, and other phenomena in mice caused by DSS-induced colitis in mice.

[0064] According to Figure 2 It can be seen that acute colitis induced by DSS will cause the colon of the model animals to shorten. Compared with the blank control group, the colorectal length of the model control group was significantly shortened (P < 0.001). The colorectal length of the model control group was (5.3 ± 0.9 cm), the colorectal length of the pterostilbene-100mg / kg group was (6.0 ± 0.7 cm), and the colorectal length of the PTE-2-100mg / kg group was (6.4 ± 0.7 cm) (P < 0.01). This indicates that PTE-2 can significantly inhibit the shortening of the colon in mice with acute colitis induced by DSS.

[0065] According to Figure 3 It can be seen that compared with the blank control group, the HE staining score of the model control group was significantly increased (P < 0.001). The HE staining score of the model control group was (9.2 ± 3.4), the HE staining score of the pterostilbene-100mg / kg group was (9.6 ± 3.4), and the HE staining score of the PTE-2-100mg / kg group was (4.9 ± 4.5) (P < 0.05). This indicates that PTE-2 can effectively prevent intestinal inflammation in mice with acute colitis induced by DSS.

[0066] According to Figure 4 It can be seen that compared with the blank control group, the body weight of the model control group decreased significantly (P < 0.001). The body weight of the model control group was (19.0 ± 1.8), and the body weight of the PTE-2-100mg / kg group was (20.9 ± 1.8) (P < 0.05). This indicates that PTE-2 can effectively relieve the weight loss in mice with acute colitis induced by DSS.

[0067] The experimental result information is summarized in Table 1 below:

[0068]

[0069] Result analysis:

[0070] Compared with the blank control group, the colorectal length of the model control group was significantly shortened (P < 0.001). The colorectal length of the model control group was (5.3 ± 0.9 cm), and that of the PTE-2-100 mg / kg group was (6.4 ± 0.7 cm) (P < 0.01). There was no statistical difference in the PTE-100 mg / kg group.

[0071] The DAI score of the model control group was (2.5 ± 0.4), and that of the PTE-2-100 mg / kg group was (1.8 ± 0.6), which was significantly lower than that of the model control group (P < 0.01).

[0072] The results of HE staining showed that the score of the model control group was (9.2 ± 3.4), which was significantly different from that of the blank control group (0.3 ± 0.9) (P < 0.001); compared with the model control group, the score of the PTE-2-100 mg / kg group (4.9 ± 4.5) was statistically different (P < 0.05).

[0073] Through the above analysis, it was found that PTE-2 could effectively improve the symptoms of colon shortening, diarrhea, bloody stools, weight loss, etc. caused by DSS-induced colitis in mice, and had a significant inhibitory effect on intestinal inflammation.

[0074] Example 4 Distribution experiment of PTE-2 and pterostilbene in tissues such as the brain

[0075] (1) Take 102 healthy Bar b / c mice weighing about 20 g and divide them into 5 groups, with 12 mice in the blank group.

[0076] A. PTE-2 intragastric administration group (administration dose: 100 mg / kg): 21 mice;

[0077] B. PTE-2 tail vein injection administration group (administration dose: 20 mg / kg), 24 mice.

[0078] C. Pterostilbene intragastric administration group (administration dose: 100 mg / kg): 21 mice;

[0079] D. Pterostilbene tail vein injection administration group (administration dose: 20 mg / kg), 24 mice.

[0080] E. Take blank plasma as the blank matrix, 12 mice.

[0081] (2) Blood samples were collected from the gavage group at 5 min, 15 min, 30 min, 1 h, 3 h, 8 h, and 24 h after administration. Blood samples were collected from the intravenous injection group at 2 min, 5 min, 15 min, 30 min, 1 h, 3 h, 8 h, and 24 h after administration. Blood was collected from the mice by eye enucleation and placed in an anticoagulation tube containing sodium heparin. It was quickly centrifuged at 5000 rpm at low temperature (4 °C) for 10 min to obtain plasma samples. The samples were stored in a -80 °C refrigerator awaiting detection. Three mice were used at each time point.

[0082] (3) The mice were fixed on a foam board. After lifting the chest skin with forceps, the skin and ribs of the chest cavity were cut open with scissors to expose the heart and liver, and the auricle was cut open. The syringe needle was inserted into the left ventricle of the mouse, and normal saline was perfused for 1 min (10 - 20 ml of normal saline) until the limbs, liver, and tongue of the mouse turned white. The mouse's brain was removed: the head skin was cut open to expose the white skull, the cartilage was cut open, the skull cap was carefully removed, the white brain was exposed, and the whole brain was dissected out. At the same time, tissues such as the pancreas, liver, and lung were taken (only the brain tissue was taken from the pterostilbene administration group). The samples were stored in a -80 °C refrigerator awaiting detection.

[0083] (4) The contents of PTE-2 and pterostilbene in the tissues were detected by LC / MS.

[0084] Main instruments

[0085] ExionLC high performance liquid chromatograph, SCIEX;

[0086] Triple Quad TM 4500 triple quadrupole mass spectrometer, SCIEX;

[0087] MS105DU microbalance (one in a hundred thousand), Mettler Toledo Instruments Company;

[0088] S1-0256 orbital shaker, IKA Company;

[0089] JXFSTPRP-CL frozen tissue grinder, Shanghai Jingxin;

[0090] Eppendorf Centrifuge 5425R small bench-top high-speed refrigerated centrifuge, Eppendorf;

[0091] Detection conditions

[0092] Liquid phase conditions:

[0093]

[0094] PTE-2 gradient: Pterostilbene gradient: Mass spectrometry conditions:

[0095]

[0096] MS / MS information

[0097]

[0098] Note: Tolbutamide is the internal standard for calculating the peak area ratio.

[0099] Test results

[0100] The comparison of the exposure levels in plasma and tissues after single intragastric administration and intravenous injection of PTE-2 and pterostilbene is shown in the following table.

[0101]

[0102] Pharmacokinetic study of PTE-2 and pterostilbene in Example 5

[0103] (1) Take 102 healthy Bar b / c mice weighing about 20 g and divide them into 5 groups, with 12 mice in the blank group.

[0104] A. PTE-2 intragastric administration group (dosage: 100 mg / kg): 21 mice;

[0105] B. PTE-2 tail vein injection group (dosage: 20 mg / kg), 24 mice.

[0106] C. Pterostilbene intragastric administration group (dosage: 100 mg / kg): 21 mice;

[0107] D. Pterostilbene tail vein injection group (dosage: 20 mg / kg), 24 mice.

[0108] E. Take blank plasma as the blank matrix, 12 mice.

[0109] (2) Blood samples were collected from the intragastric administration group at 5 min, 15 min, 30 min, 1 h, 3 h, 8 h, and 24 h after administration. Blood samples were collected from the intravenous injection group at 2 min, 5 min, 15 min, 30 min, 1 h, 3 h, 8 h, and 24 h after administration. The mice were bled by removing the eyeballs and the blood was placed in an anticoagulant tube containing sodium heparin. It was quickly centrifuged at 5000 rpm at low temperature (4 °C) for 10 min to obtain plasma samples. They were stored in a -80 °C refrigerator waiting for detection. 3 mice were used at each time point.

[0110] (3) The contents of PTE-2 and pterostilbene in peripheral blood were detected by LC / MS.

[0111] Main instruments

[0112] ExionLC high performance liquid chromatograph, SCIEX;

[0113] Triple Quad TM 4500 triple quadrupole mass spectrometer, SCIEX;

[0114] MS105DU microbalance (one in a hundred thousand), Mettler-Toledo Instruments Company;

[0115] S1-0256 circular shaking mixer, IKA Company;

[0116] JXFSTPRP-CL frozen tissue grinder, Shanghai Jingxin;

[0117] Eppendorf Centrifuge 5425R small bench-top high-speed refrigerated centrifuge, Eppendorf.

[0118] Detection conditions

[0119] Liquid phase conditions:

[0120]

[0121]

[0122] PTE-2 gradient: Pterostilbene gradient: Mass spectrometry conditions:

[0123]

[0124] MS / MS information

[0125]

[0126] Note: Tolbutamide is the internal standard for peak area ratio calculation.

[0127] The main pharmacokinetic parameters after single intragastric and intravenous injection of pterostilbene are shown in the following table.

[0128]

[0129]

[0130] Thus, it can be seen that the compound of the present invention has significantly higher bioavailability.

[0131] The above has given an exemplary description of the implementation manners of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above implementation manners. Any modifications, equivalent replacements, improvements, etc. made by those skilled in the art within the spirit and principle of the present disclosure shall be included in the protection scope of the claims of this application.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The pharmaceutically acceptable salt is an acid addition salt formed by the compound of formula (I) and the following inorganic acids or organic acids: The inorganic acids are selected from hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid, or bisulfate; The organic acids are selected from formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, amidosulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfate or thiocyanic acid; Preferably fumaric acid.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The structure of the pharmaceutically acceptable salt is shown as follows:

4. A method for preparing the compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, comprising the following steps: Compound 1 reacts with Compound 2 to obtain the compound of formula (I); Wherein, X is selected from halogen, such as Cl, Br, I.

5. A method for preparing the compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, comprising the following steps: The pharmaceutically acceptable salt is obtained by mixing the compound of formula (I) with an acid in a solvent; The acid has the definition described in claim 2.

6. The preparation method according to claim 5, characterized in that The preparation method includes dissolving the compound of formula (I) in a solvent and then adding an acid to continue the reaction to obtain the pharmaceutically acceptable salt described in claim 1.

7. The preparation method according to claim 5, characterized in that, The preparation method includes dissolving the compound of formula (I) in ethyl acetate and adding fumaric acid to react to obtain its fumarate.

8. A pharmaceutical composition comprising the compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof.

9. Use of the compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 8 in the preparation of an anti-inflammatory drug.

10. The application according to claim 9, wherein The use is for the preparation of a drug for treating inflammatory bowel disease.

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