Pterostilbene compound, pharmaceutical composition and use thereof in preparation of Anti-inflammatory drugs

Abstract

The compound of formula (I), or a pharmaceutically acceptable salt thereof, provided by the present invention has relatively high stability and high bioavailability, can effectively improve the symptoms of DSS-induced colitis in mice, such as colon shortening, diarrhea, hematochezia and weight loss, has a significant inhibitory effect on intestinal inflammation, and can be used for preparing anti-inflammatory drugs.

Description

Pterostilbene compounds, pharmaceutical compositions and their use in preparing anti-inflammatory drugs

[0001] This application claims the priority benefit of the prior application filed by the applicant with the State Intellectual Property Office of China on January 12, 2024, with patent application number 202410049666.X and entitled “Pterostilbene compounds, pharmaceutical compositions and their use in the preparation of anti-inflammatory drugs”; the full text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present invention belongs to the field of medicine, and in particular relates to a pterostilbene compound, a pharmaceutical composition and use thereof in preparing anti-inflammatory drugs. Background Art

[0003] Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the gastrointestinal tract. The causes of IBD are very complex and its pathogenesis is still unclear. Current studies have shown that IBD may be affected by a combination of factors, such as host genetic susceptibility, intestinal microbiota, environmental factors, and immune abnormalities. To date, clinical drugs used to treat IBD mainly include classic anti-inflammatory drugs, immunosuppressive drugs, and some antibody drugs. There is still no effective drug that can completely cure IBD. The goal of clinical treatment is to relieve symptoms, maintain an asymptomatic state, and prevent recurrence. Therefore, the development of new therapeutic drugs with minimal side effects and definite efficacy has far-reaching clinical application prospects and important social significance. Summary of the Invention

[0004] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[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 represented by formula (I) with the following inorganic acid: for example, 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 with the following organic acid: for example, 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-hydroxybenzoic acid. Preferably, the present invention comprises the following: 1, 2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic 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, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid 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] The present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps: reacting compound 1 with compound 2 to obtain the compound represented by formula (I);

[0008] Wherein, X is selected from halogen, such as Cl, Br, I.

[0009] The present invention also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by formula (I), comprising the following steps: mixing the compound represented by formula (I) with an acid in a solvent to obtain a pharmaceutically acceptable salt of the compound represented by formula (I); the acid has the definition described above.

[0010] According to an embodiment of the present invention, the preparation method comprises dissolving the compound represented by formula (I) in a solvent, adding an acid and continuing the reaction to obtain a pharmaceutically acceptable salt of the compound represented by formula (I).

[0011] According to an embodiment of the present invention, the preparation method comprises dissolving the compound represented by formula (I) in ethyl acetate, and adding fumaric acid to react to obtain a fumarate of the compound represented by formula (I).

[0012] A pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0013] The present invention also provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in the preparation of anti-inflammatory drugs, for example, in the preparation of anti-inflammatory bowel disease drugs.

[0014] A method for treating inflammatory diseases, comprising administering to a patient a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition.

[0015] According to an embodiment of the present invention, the inflammatory disease is inflammatory bowel disease.

[0016] The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for treating inflammatory diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Effect of PTE-2 on the DAI score of the DSS-induced enteritis model in mice (DAI score is (weight loss score + feces score + blood in stool score) / 3; *** " Compared with the blank control group, P < 0.001; " ## ” indicates P < 0.01 compared with the model control group).

[0018] Figure 2 Effects of PTE-2 on colorectal length in a DSS-induced mouse enteritis model (“ *** " Compared with the blank control group, P < 0.001; " ## ” indicates P < 0.01 compared with the model control group).

[0019] Figure 3 Effects of PTE-2 on HE staining scores in the DSS-induced mouse enteritis model (“ *** " Compared with the blank control group, P < 0.001; " # ” indicates P < 0.05 compared with the model control group).

[0020] Figure 4 Effects of PTE-2 on body weight in a DSS-induced enteritis model in mice (“ *** " Compared with the blank control group, P < 0.001; " # ” indicates P < 0.05 compared with the model control group). Beneficial effects

[0021] The compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention has high stability and high bioavailability, can effectively improve the symptoms of DSS-induced colitis in mice, such as colon shortening, diarrhea, bloody stools, and weight loss, and has a significant inhibitory effect on intestinal inflammation. It can be used to prepare anti-inflammatory drugs (e.g., drugs for treating inflammatory bowel disease). DETAILED DESCRIPTION

[0022] 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 merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0023] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0024] Example 1

[0025] Pterostilbene (Compound 1, 23.43 g, 1.0 eq) and 2-(Dimethylamino)bromoethane hydrobromide (31.17 g, 1.5 eq) were weighed into a round-bottom flask and dissolved in DMF (560 mL). Under nitrogen, the reaction mixture was cooled to 0°C. Sodium hydride (12.06 g, 3.0 eq) was added to the reaction mixture. After completion, the mixture was gradually warmed to room temperature and stirred overnight. After TLC analysis indicated that most of the starting material had disappeared, the reaction was quenched with water. The pH of the reaction mixture was adjusted to 2-3 with 1N HCl solution, and the mixture was extracted with ethyl acetate. The organic phase was discarded. The aqueous phase was adjusted to pH 8-9 with saturated potassium carbonate solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to yield 17.52 g of compound (I) as a light brown oil in a yield of 58.52%, which was used directly in the next step. 1 H NMR (600MHz, DMSO) δ7.51(d,J=9.0Hz,2H),7.20(d,J=16.2Hz,1H),7.02(d,J=16.2Hz,1H),6.95(d,J=9.0Hz,2H),6 .74(d,J=2.4Hz,2H),6.39(t,J=2.4Hz,1H),4.06(t,J=6.0Hz,2H),3.77(s,6H),2.62(t,J=6.0Hz,2H),2.21(s,6H).

[0026] The compound represented by formula (I) (17.52 g, 1.0 eq) was dissolved in ethyl acetate (100 mL), and fumaric acid (3.22 g, 0.9 eq) was added. The system was heated to 50°C and stirred for 5 hours. The mixture was then cooled to room temperature and filtered to obtain 16.27 g of a white powder (PTE-2) with a yield of 76.20%. 1H NMR (600MHz, DMSO) δ7.53(d,J=9.0Hz,2H),7.21(d,J=16.2Hz,1H),7.03(d,J=16.2Hz,1H),6.96(d,J=9.0Hz,2H),6.74(d, J=2.4Hz,2H),6.58(s,2H),6.39(t,J=2.4Hz,1H),4.16(t,J=5.4Hz,2H),3.77(s,6H),2.91(t,J=5.4Hz,2H),2.42(s,6H).

[0027] Example 2 Stability Experiment

[0028] Place the test sample in a weighing bottle and spread it out to a thickness of no more than 3mm. Test under high temperature, high humidity and light conditions.

[0029] (1) High temperature test: The test sample is placed in a suitable constant temperature device with the temperature set at 60°C. The inspection time points are set to 0 days, 5 days, and 10 days for sampling to examine the changes in relevant substances.

[0030] (2) High humidity test: The test sample is opened and placed in a constant humidity sealed container. It is placed at 25°C under relative humidity of 90% ± 5% (KNO3 saturated solution (relative humidity 92.5%, 25°C)) for 10 days. Samples are taken on the 5th and 10th days to examine the changes in related substances.

[0031] (3) Strong light irradiation test: The test sample is placed in a light box with its opening exposed to a cool white fluorescent lamp and a near-ultraviolet lamp at the same time. The illumination is 4500 lx ± 500 lx, and the total illumination of the light source should not be less than 1.2 × 10 6 lux·hr, near-ultraviolet lamp energy not less than 200W·hr / m 2 , samples were taken on 5 days and 10 days to examine the changes in related substances.

[0032] Related substance detection method (HPLC):

[0033] Mobile phase A: H2O:ACN:H3PO4=90:10:0.1

[0034] Mobile phase B: H2O:ACN:H3PO4=10:90:0.1

[0035] Chromatographic column: octadecylsilane bonded silica gel as filler, 4.6*250mm, 5μm

[0036] gradient:

[0037] Test solution: Take an appropriate amount of the product, dissolve it in 10% methanol and dilute it to make a solution containing about 5 mg per 1 mL, and inject 10 μL.

[0038] The test results are as follows:

[0039] The results show that the compounds described in the present invention are relatively stable under high temperature and high humidity conditions, but are sensitive to light.

[0040] Example 3

[0041] 1. Experimental Methods

[0042] (1) Mice were randomly divided into 4 groups according to body weight, with 10 mice in each group. One group of mice was randomly selected as the blank control group and was given normal drinking water. The remaining mice were used to establish a DSS-induced mouse enteritis model: DSS powder was dissolved in ultrapure water at a concentration of 3% (3g DSS was added to 100mL ultrapure water). The mice were allowed to drink freely and the water was changed every other day. The day the model was established was the first day of the experiment. The remaining 8 groups of mice were randomly divided into groups, and feces were collected every 2 days and stored in a -80℃ refrigerator. The mice were weighed daily, and the drugs were administered orally according to body weight, and their status and feces were observed. The experiment was terminated after 9 consecutive days of drug administration. The mice were dissected to observe the intestinal conditions and take samples.

[0043] (2) The colon and rectum were collected, their lengths were measured, and photographs were taken. Samples from the distal 2 cm of the colon were fixed with paraformaldehyde and blindly sent to a testing company for HE staining and scoring.

[0044] 2. Experimental groups:

[0045] (1) Blank control group: normal drinking water;

[0046] (2) Model control group: 9 days of DSS drinking water;

[0047] (3) Pterostilbene-100 mg / kg group, DSS drinking water for 9 days;

[0048] (4) PTE-2-100 mg / kg group, DSS drinking water for 9 days;

[0049] There were 10 rats in each group, for a total of 40 rats.

[0050] 3. Drug preparation and administration method

[0051] Pterostilbene was dissolved in corn oil, sonicated for about 15 minutes, and administered orally once daily;

[0052] Compound PTE-2 was dissolved in normal saline, sonicated for approximately 15 minutes, and administered orally once daily;

[0053] The blank control group and the model control group were given an equal volume of normal saline.

[0054] 4. Experimental Results and Analysis

[0055] The experimental results are shown in Figures 1 to 4:

[0056] As shown in Figure 1, starting on the fourth day of administration, animals began to experience varying degrees of weight loss and diarrhea. The DAI score was calculated based on the proportion of weight loss, stool status, and intestinal bleeding. 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-100 mg / kg group was (2.2 ± 0.6), and the DAI score of the PTE-2-100 mg / kg group was (1.8 ± 0.6) (compared with the model control group, P < 0.01). This indicates that PTE-2 can significantly improve the diarrhea and bloody stools caused by DSS-induced colitis in mice.

[0057] As shown in Figure 2, DSS-induced acute colitis causes colon shortening in model animals. 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-100 mg / kg group was (6.0 ± 0.7 cm), and the colorectal length of the PTE-2-100 mg / kg group was (6.4 ± 0.7 cm) (compared with the model control group, P < 0.01). This indicates that PTE-2 can significantly inhibit the shortening of the colon in mice with DSS-induced acute colitis.

[0058] As shown in Figure 3, the HE staining score of the model control group was significantly increased compared with the blank control group (P < 0.001). The HE staining score of the model control group was (9.2 ± 3.4), the HE staining score of the pterostilbene-100 mg / kg group was (9.6 ± 3.4), and the HE staining score of the PTE-2-100 mg / kg group was (4.9 ± 4.5) (compared with the model control group, P < 0.05). This indicates that PTE-2 can effectively improve intestinal inflammation and pathological changes in mice with DSS-induced acute colitis.

[0059] As shown in Figure 4, compared with the blank control group, the model control group had a significant decrease in body weight (P < 0.001). The model control group had a body weight of 19.0 ± 1.8 g, while the PTE-2-100 mg / kg group had a body weight of 20.9 ± 1.8 g (P < 0.05 compared with the model control group). This suggests that PTE-2 can effectively alleviate weight loss in mice with DSS-induced acute colitis.

[0060] The experimental results are summarized in Table 1 below:

[0061] Result analysis:

[0062] 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 the colorectal length of the PTE-2-100 mg / kg group was (6.4 ± 0.7 cm) (P < 0.01). There was no statistical difference in the pterostilbene-100 mg / kg group.

[0063] The DAI score of the model control group was (2.5±0.4), and the DAI score 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).

[0064] HE staining results 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-2-100mg / kg group (4.9±4.5) was statistically different (P<0.05).

[0065] Through the above analysis, it was found that PTE-2 can effectively improve the symptoms of DSS-induced colitis in mice, such as colon shortening, diarrhea, bloody stools, and weight loss, and has a significant inhibitory effect on intestinal inflammation and pathological changes.

[0066] Example 4 Distribution experiment of PTE-2 and pterostilbene in brain and other tissues

[0067] (1) 102 healthy Bar b / c mice weighing approximately 20 g were divided into five groups, including a blank group of 12 mice.

[0068] A. PTE-2 oral administration group (dose: 100 mg / kg): 21 mice;

[0069] B. PTE-2 tail vein injection group (dose: 20 mg / kg), 24 mice.

[0070] C. Pterostilbene oral administration group (dose: 100 mg / kg): 21 mice;

[0071] D. Pterostilbene tail vein injection group (dose: 20 mg / kg), 24 mice.

[0072] E. Blank plasma was used as blank matrix, 12 mice.

[0073] (2) Blood samples were collected from the oral 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 mouse eyeballs and placed in an anticoagulant tube containing sodium heparin. The blood was quickly centrifuged at 5000 rpm (4°C) for 10 min to obtain plasma samples. The samples were stored in a -80°C refrigerator and awaited testing. Three mice were included at each time point.

[0074] (3) Fix the mouse on a foam board, pull up the chest skin with tweezers, and use scissors to cut the chest skin and ribs to expose the heart and liver, and cut open the heart and ears. Insert the syringe needle into the left ventricle of the mouse and perfuse with normal saline for 1 minute (10-20 ml) of normal saline until the mouse's limbs, liver, and tongue turn white. Remove the mouse brain: Cut the skin on the head to expose the white skull, cut the cartilage, carefully open the skull cap to expose the white brain, and peel out the brain completely. At the same time, take the pancreas, liver, lung and other tissues (only brain tissue was taken in the pterostilbene group). Store in a -80℃ refrigerator and wait for detection.

[0075] (4) LC / MS was used to detect the contents of PTE-2 and pterostilbene in tissues.

[0076] Main instruments

[0077] ExionLC high performance liquid chromatography, SCIEX;

[0078] Triple Quad TM 4500 tandem triple quadrupole mass spectrometer, SCIEX;

[0079] MS105DU microbalance (100,000 parts per million), Teller-Toledo Instruments;

[0080] S1-0256 orbital oscillator mixer, IKA;

[0081] JXFSTPRP-CL frozen tissue grinder, Shanghai Jingxin;

[0082] Eppendorf Centrifuge 5425R small desktop high-speed refrigerated centrifuge, Eppendorf;

[0083] Detection conditions

[0084] Liquid phase conditions: Autosampler: ExionLC-AD Liquid chromatograph: ExionLC-AD Column oven: ExionLC-AC System control module: ExionLC Chromatographic column: C18, 2.7 μm (2.1 × 50 mm) Column temperature: 40°C Injection volume: PTE-2: brain tissue 2 μL; other tissues (liver, lung, pancreas) 1 μL Pterostilbene: 8 μL Mobile phase: A: H2O (containing 0.1% formic acid) B: acetonitrile (containing 0.1% formic acid)

[0085] PTE-2 gradient:

[0086] Pterostilbene gradient:

[0087] Mass spectrometry conditions: Instrument: Triple Quad TM 4500 (Sciex; Framingham, MA, USA) Ion source: Electrospray ionization source Ionization mode: Electrospray scanning mode: MRM Ion mode: PTE-2: positive ion mode; Pterostilbene: negative ion mode

[0088] MS / MS Information Note: Tolbutamide is the internal standard for peak area ratio calculation.

[0089] Test results

[0090] The comparison of plasma and tissue exposure levels of PTE-2 and pterostilbene after single oral gavage and intravenous injection is shown in the table below.

[0091] Example 5 Pharmacokinetic Study of PTE-2 and Pterostilbene

[0092] (1) 102 healthy Bal b / c mice weighing approximately 20 g were divided into five groups, including a blank group of 12 mice.

[0093] A. PTE-2 oral administration group (dose: 100 mg / kg): 21 mice;

[0094] B. PTE-2 tail vein injection group (dose: 20 mg / kg), 24 mice.

[0095] C. Pterostilbene oral administration group (dose: 100 mg / kg): 21 mice;

[0096] D. Pterostilbene tail vein injection group (dose: 20 mg / kg), 24 mice.

[0097] E. Blank plasma was used as blank matrix, 12 mice.

[0098] (2) Blood samples were collected from the oral 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 mouse eyeballs and placed in an anticoagulant tube containing sodium heparin. The blood was quickly centrifuged at 5000 rpm (4°C) for 10 min to obtain plasma samples. The samples were stored in a -80°C refrigerator and awaited testing. Three mice were included at each time point.

[0099] (3) LC / MS was used to detect the levels of PTE-2 and pterostilbene in peripheral blood.

[0100] Main instruments

[0101] ExionLC high performance liquid chromatography, SCIEX;

[0102] Triple Quad TM 4500 tandem triple quadrupole mass spectrometer, SCIEX;

[0103] MS105DU microbalance (100,000 parts per million), Teller-Toledo Instruments;

[0104] S1-0256 orbital oscillator mixer, IKA;

[0105] JXFSTPRP-CL frozen tissue grinder, Shanghai Jingxin;

[0106] Eppendorf Centrifuge 5425R small desktop high-speed refrigerated centrifuge, Eppendorf.

[0107] Detection conditions

[0108] Liquid phase conditions: Autosampler: ExionLC-AD Liquid chromatograph: ExionLC-AD Column oven: ExionLC-AC System control module: ExionLC Chromatographic column: C18, 2.7 μm (2.1 × 50 mm) Column temperature: 40°C Injection volume: PTE-2: 1 μL Pterostilbene: 8 μL Mobile phase: A: H2O (containing 0.1% formic acid) B: Acetonitrile (containing 0.1% formic acid)

[0109] PTE-2 gradient:

[0110] Pterostilbene gradient:

[0111] Mass spectrometry conditions: Instrument: Triple Quad TM 4500 (Sciex; Framingham, MA, USA) Ion source: Electrospray ionization source Ionization mode: Electrospray scanning mode: MRM Ion mode: PTE-2: positive ion mode; Pterostilbene: negative ion mode

[0112] MS / MS Information Note: Tolbutamide is the internal standard for peak area ratio calculation.

[0113] The main pharmacokinetic parameters of pterostilbene after single oral gavage and intravenous injection are shown in the table below.

[0114] It can be seen from this that the compounds of the present invention have significantly higher bioavailability.

[0115] The above is an exemplary description of the implementation methods of the technical solutions disclosed herein. It should be understood that the scope of protection of the present disclosure is not limited to the above-mentioned implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the scope of protection of the claims of this application.

Claims

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

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, 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, hemisulfuric acid 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 shown in 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) and an acid in a solvent; The acid has the definition as described in claim 2.

6. The preparation method according to claim 5, wherein, 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 as 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 its pharmaceutically acceptable salt.

9. Use of the compound according to any one of claims 1-3 or its pharmaceutically acceptable salt 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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