Use of heterocyclic compound and complex formed by heterocyclic compound and pharmaceutically acceptable acid

Abstract

The present invention relates to use of a heterocyclic compound and a complex formed by the heterocyclic compound and a pharmaceutically acceptable acid. Specifically, provided is use of a compound represented by formula (I-3B) or a complex thereof in the preparation of a drug for treating and / or preventing inflammatory bowel diseases. The complex is a complex formed by the compound represented by formula I-3B and a pharmaceutically acceptable acid. The compound represented by formula I-3B or the complex thereof can significantly mitigate IBD symptoms and tissue injury, and possesses good safety.

Description

Uses of heterocyclic compounds and their complexes with pharmaceutically acceptable acids

[0001] This application claims priority to Chinese patent application 2024115879138, filed on 2024 / 11 / 07. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to the pharmaceutical field, and more specifically to the use of a heterocyclic compound and its complex with a pharmaceutically acceptable acid. Background Technology

[0003] Prostaglandin E2 (PGE2) is a type of prostaglandin with biological functions such as regulating blood pressure, inflammatory responses, and promoting cell proliferation and differentiation. In vivo, cell membrane phospholipids are converted into arachidonic acid (AA) by phospholipase A2 (PLA2). AA is then catalyzed by cyclooxygenase 1 / 2 (COX1 / 2) to produce the prostaglandin intermediate prostaglandin G2 (PGG2). Subsequently, PGG2 is rapidly reduced to prostaglandin H2 (PGH2), which is then metabolized into PGE2 by prostaglandin E synthase (PGES).

[0004] Numerous studies have shown that PGE2 can promote stem cell proliferation and play a role in tissue repair by activating downstream EP receptors. However, its short half-life in the blood limits its clinical use. Therefore, increasing the endogenous PGE2 content in tissue cells to promote stem cell proliferation is an ideal way to leverage PGE2's tissue repair function. 15-Prostaglandin Dehydrogenase (15-PGDH) is an important metabolic enzyme of intracellular PGE2, which can promote PGE2 degradation and inactivation, thereby blocking downstream signaling pathways. Inhibiting 15-PGDH can increase intracellular PGE2 levels and thus promote stem cell proliferation. However, because 15-PGDH is widely expressed systemically, excessively high levels of PGE2 in tissues may lead to adverse reactions such as fever and inflammation. Often, because it cannot be directed to the lesion site, it cannot achieve a therapeutic effect. Therefore, increasing the proportion of drugs distributed to target tissues and reducing systemic exposure can effectively improve drug efficacy and reduce the risks associated with its use.

[0005] Inflammatory bowel disease (IBD) is an idiopathic inflammatory bowel disease affecting the ileum, rectum, and colon. Clinical manifestations include diarrhea, abdominal pain, and even bloody stools. It includes ulcerative colitis (UC) and Crohn's disease (CD). Current treatments primarily focus on anti-inflammatory and immunomodulatory therapies to alleviate IBD symptoms, but these have drawbacks such as high treatment failure rates and poor tolerability.

[0006] Developing a drug that can be effectively used to treat inflammatory bowel disease, with the aim of improving drug distribution in intestinal tissue, enhancing drug safety, and reducing drug side effects, is of significant research value. Summary of the Invention

[0007] To address the deficiencies in the prior art, this invention provides the use of heterocyclic compounds and their complexes with pharmaceutically acceptable acids.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] This invention provides the use of compounds of formula I-3B or their complexes in the preparation of medicaments for treating and / or preventing inflammatory bowel disease;

[0010] in,

[0011] The complex is a complex formed by the compound of formula I-3B and a pharmaceutically acceptable acid.

[0012] The inflammatory bowel disease is Crohn's disease or ulcerative colitis; Crohn's disease is selected from one or more of ileocolitis, ileitis, gastroduodenal Crohn's disease, jejunoileitis, and Crohn's (granulomatous) colitis.

[0013] Ulcerative colitis is selected from one or more of ulcerative proctitis, ulcerative proctosigmoiditis, left-sided colitis, and pancolitis.

[0014] In this invention, the pharmaceutically acceptable acid is, for example, hydrochloric acid, phosphoric acid, fumaric acid, tartaric acid, malic acid, ethanedisulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or oxalic acid, preferably fumaric acid.

[0015] In this invention, the compounds or their complexes represented by formulas I-3B may be amorphous or crystalline.

[0016] In this invention, the complex may be a complex of the compound shown in Formula I-3B and fumaric acid, wherein the molar ratio of fumaric acid to the compound shown in Formula I-3B is 1:1; preferably, the compound shown in Formula I-3B and the fumaric acid complex are co-crystallized.

[0017] In this invention, the inflammatory bowel disease can be an inflammatory bowel disease that affects adolescents (onset before age 16), young adults (onset between age 17 and 40), or middle-aged and elderly people (onset after age 40).

[0018] In this invention, Crohn's disease may be one or more of the following areas: terminal ileum (ileum), colon, ileocolic region involving both terminal ileum and colon, and upper gastrointestinal tract (such as stomach or duodenum), preferably colon or ileocolic region involving both terminal ileum and colon.

[0019] In this invention, Crohn's disease may present with non-stenotic, non-penetrating, stenotic, penetrating, or perianal lesions.

[0020] In this invention, the Crohn's disease can be acute or non-acute (e.g., chronic) Crohn's disease, such as acute Crohn's disease, and more specifically, TNBS (2,4,6-trinitrobenzenesulfonic acid)-induced acute Crohn's disease.

[0021] In this invention, the ulcerative colitis can be rectal type, left-sided colon type, extensive colon type, or ileocolic type ulcerative colitis, preferably left-sided colon type, extensive colon type, or ileocolic type ulcerative colitis.

[0022] In this invention, the ulcerative colitis can be acute or non-acute (e.g., chronic) ulcerative colitis, such as acute ulcerative colitis, and more specifically, DSS (dextran sulfate sodium) induced acute ulcerative colitis.

[0023] In this invention, the inflammatory bowel disease can be an inflammatory bowel disease with high expression of interleukin-6, tumor necrosis factor-α, chemokine-2 and interferon-γ.

[0024] In this invention, preferably, the drug further comprises pharmaceutical excipients.

[0025] In this invention, the content of the compound or its complex represented by Formula I-3B in the drug can be the conventional content of such drugs in the art, for example 0.01%-90%, preferably 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%, wherein the percentage (%) is the mass ratio of the compound or its complex represented by Formula I-3B to the drug.

[0026] In this invention, the drug can be administered to patients via various routes, including but not limited to gastric administration (e.g., oral administration) and enema. Those skilled in the art can adjust the administration as needed, for example, by oral administration.

[0027] In this invention, the drug dosage is conventional in the art, and those skilled in the art can adjust it according to the condition or the target of administration. The single dose is 0.1 mg to 40 mg based on the mass of the compound or its complex shown in Formula I-3B.

[0028] In this invention, the drug can be administered according to the weight of the recipient. The single dose based on the mass of the compound or its complex shown in Formula I-3B is 0.01 mg / kg to 10 mg / kg, for example, 2.5 mg / kg, 5 mg / kg or 1.2 mg / kg.

[0029] In this invention, the drug can be administered according to the weight of the target, and the single dose based on the mass of the compound or its complex shown in Formula I-3B is 0.01 mg / kg to 10 mg / kg, for example 2.5 mg / kg, 5 mg / kg, 1.2 mg / kg, 0.6 mg / kg or 2.4 mg / kg (the target can be a rat).

[0030] In this invention, the drug can be administered according to the weight of the recipient. The single dose based on the mass of the compound or its complex shown in Formula I-3B is 0.001 mg / kg to 2 mg / kg, for example 0.1 to 1 mg / kg, preferably 0.2 mg / kg, 0.1 mg / kg, 0.4 mg / kg, 0.42 mg / kg, 0.83 mg / kg or 1.2 mg / kg (the recipient may be a human).

[0031] In this invention, those skilled in the art can administer the drug according to the condition of the disease (e.g., disease status, lesion site and disease behavior, etc.) (including selecting appropriate administration route, dosage, administration interval, etc.), and can choose long-term administration or short-term administration. The frequency of administration of the drug can be 1-3 times every 0.5-2 days, preferably once a day, and long-term administration is possible.

[0032] In this invention, the drug can be administered for 5-15 days as a course of treatment, for example, twice a day. Alternatively, the drug can be administered for 10 days or 7 days as a course of treatment.

[0033] In this invention, the complex can be the crystal form of the fumaric acid complex shown in Formula I-3B, which has diffraction peaks at 20.5±0.2°, 15.9±0.2°, 26.6±0.2°, 18.9±0.2° and 22.5±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angle.

[0034] In this invention, in the crystal form of the fumaric acid complex represented by Formula I-3B, the molar ratio of the compound represented by Formula I-3B to fumaric acid can be 1:1.

[0035] In this invention, the crystal form of the fumaric acid complex represented by Formula I-3B can be a fumaric acid eutectic or salt represented by Formula I-3B.

[0036] In this invention, the crystal form of the fumaric acid complex represented by Formula I-3B may have the following unit cell parameters: orthorhombic, space group P212121. α = 90° β = 90° γ = 90° The number of asymmetric units within the unit cell is Z = 4, and the crystal density is 1.451 mg / m³. 3 .

[0037] In this invention, the crystal form of the fumaric acid complex of the compound shown in Formula I-3B, when subjected to Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle, may also have diffraction peaks at one or more of the following locations: 22.3±0.2°, 26.4±0.2°, 10.8±0.2°, 17.4±0.2° and 17.5±0.2°.

[0038] In this invention, preferably, the crystal form of the fumaric acid complex of Formula I-3B has diffraction peaks at 20.5±0.2°, 15.9±0.2°, 26.6±0.2°, 18.9±0.2°, 22.5±0.2°, 22.3±0.2° and 26.4±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed at 2θ angle.

[0039] In this invention, more preferably, the crystal form of the fumaric acid complex of Formula I-3B has diffraction peaks at 20.5±0.2°, 15.9±0.2°, 26.6±0.2°, 18.9±0.2°, 22.5±0.2°, 22.3±0.2°, 26.4±0.2°, 10.8±0.2°, 17.4±0.2°, and 17.5±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed at 2θ angle.

[0040] In this invention, more preferably, the crystal form of the fumaric acid complex of formula I-3B, when subjected to Cu-Kα radiation and X-ray powder diffraction pattern expressed at 2θ angle, exhibits the diffraction peaks shown in Table A below:

[0041] Table A

[0042] In a specific embodiment of the present invention, the crystal form of the fumaric acid complex of Formula I-3B is obtained by Cu-Kα radiation, and its X-ray powder diffraction pattern (XRPD) can be basically as shown in Figure 2.

[0043] In this invention, the differential scanning calorimetry (DSC) curve of the fumaric acid complex of the compound shown in Formula I-3B may have an endothermic peak starting point at 165.2±3℃.

[0044] In this invention, the differential scanning calorimetry (DSC) curve of the fumaric acid complex of the compound shown in Formula I-3B reaches the peak value of the endothermic peak at 167.2±3℃.

[0045] In a specific embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the crystal form of the fumaric acid complex shown in Formula I-3B can be basically as shown in Figure 3.

[0046] In this invention, the thermogravimetric analysis (TGA) curve of the fumaric acid complex of Formula I-3B shows a weight loss of 0.36% in the temperature range of 26.2±3℃ to 120±3℃.

[0047] In a specific embodiment of the present invention, the thermogravimetric analysis (TGA) curve of the crystal form of the fumaric acid complex represented by Formula I-3B can be basically as shown in Figure 3.

[0048] In this invention, the crystal form of the fumaric acid complex represented by Formula I-3B can be a single crystal of the fumaric acid complex represented by Formula I-3B.

[0049] In this invention, the preparation method of the fumaric acid complex of the compound shown in Formula I-3B may include the following steps: mixing a good solvent solution of the compound shown in Formula I-3B with fumaric acid to fully dissolve the fumaric acid, crystallizing it, and thus preparing the fumaric acid complex of the compound shown in Formula I-3B.

[0050] The good solvent mentioned is ethanol.

[0051] Preferably, the method further uses seed crystals of the fumaric acid complex of the compound shown in Formula I-3B, for example, by adding the seed crystals (e.g., the fumaric acid cocrystal of the compound shown in Formula I-3B according to any embodiment of the present invention) to the solution obtained after the fumaric acid is fully dissolved. The mass ratio of the seed crystals to the amount of the compound shown in Formula I-3B can be more than 0.5%, for example, 0.5% to 1.5%, and more specifically, 1%. When the seed crystals are added, the temperature of the solution can be 30 to 60°C, for example, 50°C.

[0052] In the method described, the mass concentration of the compound represented by formula I-3B in a good solvent solution can be 50 / 125 g / mL.

[0053] In the method described, the mass ratio of fumaric acid to the compound represented by formula I-3B can be 15.81:50.

[0054] In the method described, it is preferable to mix a good solvent solution of the compound shown in Formula I-3B with fumaric acid at a temperature of 30–60°C (e.g., 50°C).

[0055] In the method described, the crystallization may include the following steps: after adding fumaric acid, adding seed crystals of the fumaric acid complex of the compound shown in Formula I-3B, and cooling to allow crystallization.

[0056] In this invention, the preparation method of the fumaric acid complex of the compound shown in Formula I-3B may include the following steps: mixing a good solvent solution of the compound shown in Formula I-3B sequentially with fumaric acid and a poor solvent, crystallizing, and preparing the fumaric acid complex of the compound shown in Formula I-3B.

[0057] Wherein, the good solvent is acetone or ethanol, the poor solvent is n-heptane, and the volume ratio of the poor solvent to the good solvent is greater than 1.

[0058] This invention provides a method for treating and / or preventing inflammatory bowel disease, comprising administering to an individual in need a therapeutically effective amount of a compound of formula I-3B or a compound thereof or the aforementioned drug;

[0059] The inflammatory bowel disease is as described in any embodiment of the present invention;

[0060] The compounds or their complexes represented by formulas I-3B are as described in any embodiment of the present invention.

[0061] The present invention provides a compound of formula I-3B or a complex thereof for the treatment and / or prevention of inflammatory bowel disease;

[0062] The inflammatory bowel disease is as described in any embodiment of the present invention;

[0063] The compounds or their complexes represented by formulas I-3B are as described in any embodiment of the present invention.

[0064] In this invention, the compounds of formula I-3B, their complexes, and the above-mentioned drugs can be administered to patients via various routes, including but not limited to gastric administration (e.g., oral administration) and enema administration. Those skilled in the art can make adjustments as needed, such as oral administration.

[0065] In this invention, the compounds shown in Formula I-3B, their complexes, and the dosage of the above-mentioned drugs are conventional in the art. Those skilled in the art can adjust them according to the disease or the target of administration. The single dose based on the mass of the compounds shown in Formula I-3B or their complexes is 0.1 mg to 40 mg.

[0066] In this invention, the dosage can be determined according to the weight of the target, with a single dose of 0.01 mg / kg to 10 mg / kg based on the mass of the compound or its complex shown in Formula I-3B, for example, 2.5 mg / kg, 5 mg / kg or 1.2 mg / kg.

[0067] In this invention, those skilled in the art can administer the drug according to the condition of the disease (e.g., disease state, lesion site and disease behavior, etc.) (including selecting appropriate administration route, dosage, administration interval, etc.), and can choose long-term administration or short-cycle administration. The frequency of administration of the drug can be 1-3 times every 0.5-2 days, preferably once a day, for long-term administration.

[0068] In this invention, the drug can be administered for 5-15 days as a course of treatment, for example, twice a day. Alternatively, the drug can be administered for 10 days or 7 days as a course of treatment.

[0069] In this invention, in the method and use described, the solubility of the complex after application (e.g., water, SGF, FaSSIF or FeSSIF) is preferably greater than 5 mg / mL, and preferably 5.1 mg / mL-6.7 mg / mL or more after 1 hour.

[0070] In this invention, in the methods and uses described herein, after applying the compound or its complex represented by formula I-3B, the DAI score can be 35.65 or less.

[0071] In this invention, in the methods and uses described herein, the application of the compound or its complex of formula I-3B preferably achieves substantially equivalent therapeutic effects (e.g., equivalent colon weight / length ratio) when the dosage is 4% of mesalazine.

[0072] In this invention, in the methods and uses described herein, after applying the compound or its complex represented by formula I-3B, the colon weight / length ratio is preferably 13.95 or less.

[0073] In this invention, when the compound or its complex of formula I-3B is applied, the (CW / CL)*10 is preferably less than 2.26, where CL represents the length of the colon and CW represents the weight of the intestine.

[0074] In this invention, in the method and use described herein, after applying the compound or its complex represented by formula I-3B, it is preferred that (CW / CL / BW)*1000 be less than 1.39, where CL represents colon length, CW represents intestinal weight, and BW represents body weight.

[0075] Terminology Explanation:

[0076] The term "pharmaceutically acceptable salt" refers to a salt formed by the compound and a pharmaceutically acceptable inorganic or organic acid, wherein the inorganic acid includes, but is not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid; and the organic acid includes, but is not limited to: formic acid, acetic acid, propionic acid, succinic acid, 1,5-naphthalenedisulfonic acid, linalool, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids;

[0077] The term "pharmaceuticalally acceptable" refers to a substance that is suitable for human use without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), i.e., a substance with a reasonable benefit / risk ratio.

[0078] The term "complex of the compound represented by Formula I-3B" refers to a complex formed by the compound represented by Formula I-3B with a pharmaceutically acceptable acid, comprising a crystalline form (e.g., a eutectic) and / or an amorphous solid form.

[0079] The term "therapeutic effective amount" refers to the amount of compound administered to a patient that is sufficient to effectively treat the disease. Therapeutic effective amount will vary depending on the compound, the type of disease, the severity of the disease, the patient's age, etc., but may be adjusted as appropriate by those skilled in the art.

[0080] The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the dispensing of prescriptions. It includes all substances contained in pharmaceutical preparations, excluding the active ingredient. See the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009) for details.

[0081] The term “treatment” refers to a therapeutic approach. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects or side effects associated with the condition, or one or more symptoms, effects or side effects associated with the condition or its treatment; or (4) slowing the development of the condition or one or more biological manifestations of the condition.

[0082] The term “prevention” refers to a reduced risk of acquiring or developing a disease or disorder (i.e., resulting in at least one clinical symptom of the disease in a subject who may have been exposed to a disease-causing agent or a pre-existing predisposition to the disease).

[0083] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0084] The reagents and raw materials used in this invention are all commercially available.

[0085] The positive and progressive effects of this invention are as follows: the compounds, complexes thereof, or drugs of formulas I-3B provided by this invention can be effectively used for the prevention and treatment of inflammatory bowel disease, and have one or more of the following advantages:

[0086] (1) Significantly improves IBD symptoms and tissue damage in mice.

[0087] (2) Increase the level of PEG2 in tissues, reduce intestinal inflammatory response, and improve the treatment effect of ulcerative colitis.

[0088] (3) Improves intestinal length and weight index, colonic tissue crypt structure damage and regeneration repair, and improves the treatment effect of Crohn's disease.

[0089] (4) After application, this compound is specifically distributed in some tissues (e.g., specifically in the stomach, liver and intestines), with very little entry into the brain, and has good safety.

[0090] (5) The eutectic dynamic solubility stability, solid-state stability and hygroscopicity are good, and it has good prospects for drug development.

[0091] (6) It can increase the level of PEG2 in intestinal tissue, reduce systemic exposure, promote intestinal tissue repair, and reduce systemic risk. Attached Figure Description

[0092] Figure 1 shows the single-crystal structure of compound R1.

[0093] Figure 2 shows the X-ray powder diffraction pattern of the fumaric acid complex of formula I-3B.

[0094] Figure 3 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of the fumaric acid complex of formula I-3B.

[0095] Figure 4 is an ellipsoidal diagram of the molecular structure of the fumaric acid complex crystal shown in Formula I-3B.

[0096] Figure 5 is a comparison between the fitted XRPD diagram of the fumaric acid complex crystal of Formula I-3B and the measured XRPD diagram.

[0097] Figure 6 shows the XRPD diagram of the dynamic solubility of the fumaric acid complex crystals shown in Formula I-3B in H2O.

[0098] Figure 7 shows the XRPD plot of the dynamic solubility of the fumaric acid complex crystals of Formula I-3B in SGF.

[0099] Figure 8 shows the XRPD plot of the dynamic solubility of the fumaric acid complex crystals of Formula I-3B in FaSSIF.

[0100] Figure 9 shows the XRPD plot of the dynamic solubility of the fumaric acid complex crystals of Formula I-3B in FeSSIF.

[0101] Figure 10 shows the XRPD diagram of the stability assessment of the fumaric acid complex of Formula I-3B.

[0102] Figure 11 shows the XRPD images of the fumaric acid complex crystals of Formula I-3B before and after the hygroscopicity test. Detailed Implementation

[0103] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0104] Symbols or units:

[0105] IC 50 The half-maximum inhibitory concentration (MCI) is the concentration at which half of the maximum inhibitory effect is achieved.

[0106] M: mol / L, for example, n-butyllithium (2.5M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L.

[0107] N: Equivalent concentration, for example, 2N hydrochloric acid means a 2 mol / L hydrochloric acid solution.

[0108] Reagents:

[0109] Table B: A list of English and Chinese names of solvents used in the preparation examples and embodiments.

[0110] Table B

[0111] Instruments and methods for detecting crystal forms:

[0112] 1. X-ray powder diffraction (XRPD)

[0113] XRPD images were acquired using a PANalytacal X-ray powder diffractometer, and the scanning parameters are shown in Table C below:

[0114] Table C

[0115] 2. X-ray single crystal diffraction

[0116] Test environment: Test temperature: 200(2)K, room temperature: 24℃, relative humidity: 34%, X-ray single crystal diffraction method is shown in Table D below:

[0117] Table D

[0118] 3. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0119] TGA and DSC plots were acquired using a TA5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively. The test parameters are shown in Table E below:

[0120] Table E

[0121] 4. Liquid NMR:

[0122] Liquid NMR spectra were acquired using a Bruker 400M NMR spectrometer with DMSO-d6 as the solvent.

[0123] 5. High Performance Liquid Chromatography (HPLC):

[0124] Purity, dynamic solubility, and stability tests were performed using UPLC (ultra-high performance liquid chromatography), and the analytical conditions are shown in Table F below:

[0125] Table F

[0126] 6. Dynamic Moisture Adsorption (DVS):

[0127] Dynamic moisture adsorption (DVS) curves were acquired using the DVS Intrinsic Plus of SMS (Surface Measurement Systems). Relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. The DVS test parameters are shown in Table G below.

[0128] Table G

[0129] 7. Ion chromatography (IC):

[0130] The instrument parameters for determining the molar ratio of the anti-charged ions in ion chromatography (IC) are listed in Table H below under the analytical conditions:

[0131] Table H

[0132] Preparation Example 1: Preparation of the compound shown in Formula I-3B

[0133] The synthetic route for the target compound is as follows:

[0134] Step 1: Synthesis of methyl(1aS,7bR)-3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthylpyridine-6-carboxylate (3).

[0135] To the reaction flask, add (1aS,7bR)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthyl-6-carboxylate (R1) (159.6 mg, 0.7 mmol), 7-bromo-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (2) (130 mg, 0.6 mmol), Pd2(dba)3 (91.6 mg, 0.1 mmol), ligand L (ligand L is Xantphos) (57.9 mg, 0.1 mmol), and cesium carbonate (488.7 mg, 1.5 mmol). After purging with nitrogen three times, add anhydrous solvent 1,4-dioxane (4 mL), and react at 85 °C for 12 hours. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, the organic phase was concentrated to dryness and then mixed, and purified by silica gel column chromatography (dichloromethane:methanol, V / V = 20:1) to give methyl(1aS,7bR)-3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthylpyridine-6-carboxylate (3) (200 mg, yield: 85.7%).

[0136] LC-MS, M / Z (ESI): 352.1 [M+H] + .

[0137] Ligand L:

[0138] Step 2: Synthesis of (1aS,7bR)-3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthylpyridine-6-carboxylic acid (4).

[0139] Methyl(1aS,7bR)-3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthylpyridine-6-carboxylate (3) (200 mg, 0.6 mmol) was dissolved in a mixture of tetrahydrofuran (4 mL), methanol (0.8 mL), and water (0.8 mL), and then lithium hydroxide monohydrate (100 mg, 2.4 mmol) was added. The reaction was carried out at room temperature for 12 hours. After the reaction was complete, water was added to quench the reaction. The pH was adjusted to 1 by adding 1M hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was concentrated to dryness to obtain (1aS,7bR)-3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthylpyridine-6-carboxylic acid (4), which was directly used in the next step of the reaction.

[0140] LC-MS, M / Z (ESI): 338.1 [M+H] + .

[0141] Step 3: Synthesis of 7-((1aS,7bR)-6-(4,4-difluoropiperidin-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropane[c][1,8]naphthidin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridine-3(2H)-one (5).

[0142] Under nitrogen protection, 4,4-difluoropiperidine hydrochloride (72.7 mg, 0.6 mmol) and pyridine (0.2 mL) were added to an ethyl acetate (2 mL) solution of (1aS,7bR)-3-(2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthylpyridine-6-carboxylic acid (4) (120 mg, 0.4 mmol), followed by the addition of T3P DMF solution (0.68 mL, 0.5 mmol). The reaction was carried out at room temperature for 3 hours. The reaction was quenched with water, extracted with ethyl acetate, and the organic phase was concentrated to dryness and then mixed. The mixture was then purified by silica gel column chromatography (dichloromethane:methanol, V / V = 20:1) to give 7-((1aS,7bR)-6-(4,4-difluoropiperidin-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropane[c][1,8]naphthidin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5) (132 mg, yield: 75%).

[0143] LC-MS, M / Z (ESI): 441.1 [M+H]+

[0144] 1 H NMR (400MHz, DMSO-d6): δ8.09(d,1H),7.71(d,1H),7.59(d,1H),6.55-6.52(m,2H),3 .95(d,1H),3.75-3.69(m,5H),3.63(s,3H),2.10-2.03(m,6H),1,22-1.12(m,2H)ppm.

[0145] The product was subjected to SFC (column: Chiralpak AD-3 50×4.6mm ID, 3μm, mobile phase: mobile phase A: CO2, mobile phase B: IPA+ACN (0.05 v% DEA);

[0146] Isocratic elution: 50 v / v IPA + ACN (0.05 v / v DEA) in CO2, flow rate: 3 mL / min; detector: PDA, column temperature: 35 °C; column pressure: 100 Bar. The retention time RT of the compound represented by Formula I-3B (i.e., the compound represented by Formula I-3B of this application) is 1.674 min.

[0147] Single crystal preparation method: Weigh 5 mg of (1aS,7bR)-1a,2,3,7b-tetrahydro-1H-cyclopropyl[c][1,8]naphthyl-6-carboxylic acid methyl ester (R1) into a 2 mL LC-MS flask, add 0.4 mL of ethyl acetate to dissolve it, then add 0.6 mL of petroleum ether and mix well. The LC-MS flask is then left to stand at room temperature until the solvent evaporates naturally, yielding colorless and transparent crystals (approximately 2 days). Single crystal structure analysis was performed, and the single crystal structure of compound R1 is shown in Figure 1. Its main crystal parameters are shown in Table I below.

[0148] Table I

[0149] Recrystallization of the free base is difficult, and it easily precipitates into a gel. The free base of the compound shown in Formula I-3B obtained in Preparation Example 1 dissolves completely in a toluene and dimethyl ether solvent system without precipitating any solids. Prolonged stirring in a THF / MTBE system can precipitate solids, but this requires a long time, which is not conducive to large-scale industrial production. Large solid clumps are easily generated during the curing process of the gel, resulting in severe sample agglomeration, which can easily clog the stir bar and make stirring difficult.

[0150] Preparation Example 2: Fumaric acid complex of the compound shown in Formula I-3B

[0151] Preparation Example 2.1 Preparation of the fumaric acid complex of the compound shown in Formula I-3B

[0152] Preparation method: The free base (40.00 g) of the compound shown in Formula I-3B and acetone (120 mL) were added to a reaction flask, stirred and dissolved, filtered, and the filtrate was collected. Fumaric acid (10.54 g) was added, and the system was heated to 50 °C. After stirring for 1 h, n-heptane (80 mL) was added, and the mixture was stirred for 10 min. Then, n-heptane (280 mL) was added, and the mixture was slowly cooled to room temperature and stirred for 16 h. The temperature was then lowered to 0-10 °C and stirred for 2 h. The mixture was filtered, and the filter cake was washed with a mixed solvent of acetone / n-heptane (64 mL, V / V = 1 / 3). The filter cake was collected and dried in a forced-air drying oven to obtain 45.50 g of product, with a yield of 90.0% (the crystal form of the prepared product was characterized by the same data as in Preparation Example 3).

[0153] Preparation Example 2.2 Preparation of the fumaric acid complex of the compound shown in Formula I-3B

[0154] Preparation method: Weigh 20.00 g of free alkali and add it to 50 mL of ethanol. Heat to 50 °C. After the sample dissolves, add fumaric acid (0.97-1.20 eq). After the fumaric acid dissolves, filter while hot and wash with 10 mL of ethanol. Collect the filtrate. While stirring, add 1% co-crystal seed crystals to the filtrate (the seed crystals are derived from the fumaric acid complex of formula I-3B prepared in Preparation Example 2.1 (i.e., the co-crystal seed crystals). "1% co-crystal seed crystals" means that the mass of the added co-crystal seed crystals is 1% of the amount of free alkali added). After solid precipitation, cool to 5 °C and stir for 2 h. Filter and dry the filter cake at 60 °C for 2 h. Collect the eutectic sample (the crystal form of the prepared product has the same characterization data as in Preparation Example 3). Specific data are shown in Table J below:

[0155] Table J

[0156] As shown in the table above, using ethanol as a solvent, the free alkali is first dissolved by heating, then excess fumaric acid is added to fully combine with the free alkali, followed by filtration to remove excess insoluble matter, and finally the filtrate is cooled to allow crystallization. The resulting products have fumaric acid contents close to the theoretical value, exhibiting good parallelism, and the yield can reach approximately 85%.

[0157] Preparation Example 3: Crystal form of the fumaric acid complex of the compound shown in Formula I-3B

[0158] Method 1: Weigh 50.00 g of free base (i.e., the compound shown in Formula I-3B) and add it to 125 mL of ethanol. Heat to 50 °C. After the sample dissolves, add fumaric acid (15.81 g) and stir for 1 h. Filter while hot, wash with 25 mL of ethanol, and collect the filtrate. Reheat the filtrate to 50 °C, add 1% co-crystal seed crystals (the seed crystals are derived from the fumaric acid complex shown in Formula I-3B prepared in Preparation Example 2.2 (i.e., the co-crystal seed crystals), "1% co-crystal seed crystals" means that the mass of the added co-crystal seed crystals is 1% of the amount of free base added), and stir for 0.5 h. Slowly cool to 5 °C and stir for 2 h. Filter, and dry the filter cake at 60 °C with forced air for 6 h. 51.22 g of off-white solid is obtained, with a yield of 80.3% and a fumaric acid content of 20.4%.

[0159] The XRPD diffraction peak data of the fumaric acid complex shown in Formula I-3B are shown in Table K below:

[0160] Table K

[0161] The crystal form characterization data of the fumaric acid complex shown in Formula I-3B are shown in Table L below:

[0162] Table L

[0163] The NMR data for the crystal form of the fumaric acid complex shown in Formula I-3B are as follows (Table M):

[0164] Table M

[0165] To further investigate the molecular structure of the above crystals, a single crystal of fumaric acid, the compound shown in I-3B, was obtained using method two.

[0166] Method 2: Weigh approximately 15 mg of the fumaric acid complex (I-3B) obtained in Method 1 into an EP tube, add 0.75 mL of acetone, shake until the sample dissolves, filter the solution through a microporous membrane into a 2 mL transparent glass bottle, add 0.75 mL of n-heptane, the solution separates into layers, seal with sealing film, make two small holes, and allow to stand at room temperature for about 2 days to evaporate until transparent crystals precipitate, thus obtaining the fumaric acid complex (single crystal) shown in Formula I-3B.

[0167] The single crystal of the fumaric acid complex shown in Formula I-3B obtained in Method 2 was subjected to X-ray single-crystal diffraction, and the crystallographic parameters were measured as follows (Table N):

[0168] Table N

[0169] According to the X-ray single-crystal diffraction results, fumaric acid is linked to the compound shown in formula I-3B by hydrogen bonds. The distance between the hydrogen atom and the oxygen atom is 0.84 Å, and the distance between the hydrogen atom and the nitrogen atom is 1.89 Å. The closer hydrogen atom is to the oxygen atom, the more likely it is a eutectic (i.e., (1aS,7bR)-7-(6-(4,4-difluoropiperidin-1-carbonyl)-1,1a,2,7b-tetrahydro-3H-cyclopropane[c][1,8]naphthidin-3-yl)-2-methyl-[1,2,4]triazolyl[4,3-a]pyridine-3(2H)-one fumaric acid eutectic). The molar ratio of fumaric acid to the compound shown in formula I-3B is 1.0:1.0, and no residual solvent signal was observed on NMR.

[0170] Hydrogen bonding in the crystal of the fumaric acid complex shown in Formula I-3B ( And °) are shown in Table O below:

[0171] Table O

[0172] Figure 4 shows the molecular structure ellipsoidal model of the single crystal of the fumaric acid complex shown in Formula I-3B. Figure 5 shows the comparison between its fitted XRPD diffraction pattern and the measured XRPD diffraction pattern of the crystal obtained by Method 1. The complex crystals obtained by Method 1 and Method 2 are of the same crystal form.

[0173] Effect Example 1: Effect of the compound shown in Formula I-3B on the DSS-induced acute ulcerative colitis (UC) model in rats.

[0174] Female C57BL / 6 mice aged 6-8 weeks were divided into 5 groups: G1-G5, which were the normal control group, the model control group, the positive control group, the low-dose group of the compound shown in Formula I-3B (the free base of the compound shown in Formula I-3B obtained in Preparation Example 1), and the high-dose group of the compound shown in Formula I-3B obtained in Preparation Example 1, respectively.

[0175] The solvent used in this experiment was physiological saline. The positive control drug cyclosporine A (supplier Novartis, batch number SFRU1) was prepared as follows: dissolved and diluted with physiological saline to a concentration of 2.5 mg / mL for gavage administration; the compound shown in Formula I-3B was dissolved in appropriate amounts of physiological saline and diluted to clear solutions of 0.25 and 0.5 mg / mL for low- and high-dose gavage administration. The administration volume was 10 ml / kg for all cases.

[0176] Mice in groups G2-G6 were given a 2% DSS solution for drinking from day 0 to 6, and normal water from day 0 to 10. From day 0 to 9, they were administered the solvent (physiological saline) / positive control (cyclosporine A) / test substance by gavage. On day 10, they were euthanized and dissected. Intestinal weight (CW), intestinal length (CL), and intestinal tissue (BW) were measured for histopathological examination. The results showed that compared with the G2 model group, the G3-positive control group (cyclosporine CsA 25 mg / kg-qd) had significantly increased body weight, significantly decreased DAI, significantly increased CL, and significantly decreased CW, CL / CW / BW, and CL / CW. Histopathological examination of the colon tissue of the model animals showed decreased inflammatory cell infiltration and tissue damage scores, but these differences were not statistically significant. Animals in groups treated with compound G4 (2.5 mg / kg bid) and compound G5 (5 mg / kg bid) showed increased body weight, with G5 animals showing a significant increase. DAI scores were significantly decreased in all groups, while CL scores were significantly increased, and CW, CL / CW / BW, and CL / CW scores were significantly decreased. Colon histopathological examination showed significantly reduced inflammatory cell infiltration and tissue damage scores. DAI scores for each group from Day 0 to Day 9 are shown in Table P below.

[0177] Table P Note: Statistical analysis was performed only on the DAI score for Day 9. *** P<0.001: VS model group (One way ANOVA / Dunnett's). Colon length (CL), intestinal weight (CW), CL / CW / BW, and CW / CL are summarized in Table Q below:

[0178] Table Q Note: **P<0.01, *** P<0.001: VS model group (One way ANOVA / Dunnett's).

[0179] Experimental results showed that the compounds shown in Formula I-3B (2.5 mg / kg and 5 mg / kg) could significantly improve IBD symptoms and tissue damage in mice, with better efficacy than positive results.

[0180] Example 2: Dynamic Solubility Stability Test of Crystal Form

[0181] The dynamic solubility of the fumaric acid complex of Formula I-3B in H2O, SGF, FaSSIF and FeSSIF was tested at 37 °C.

[0182] The above sample was mixed by rotation at 37°C with a feed concentration of 10 mg / mL, and the solubility of each sample was determined at different time points (1, 4, and 24 hours). After sampling at each time point, the samples were centrifuged (12000 rpm, 2 min) and filtered (0.45 μm PTFE membrane). The HPLC concentration and pH value of the filtrate were determined, and the XRPD of the solid samples after centrifugation was tested.

[0183] The results of the dynamic solubility test are shown in Table R below:

[0184] Table R

[0185] S: Concentration (mg / mL) of the compound as shown in Formula I-3B; FC: Crystal transformation; --: Not tested.

[0186] The results showed that the fumaric acid complex represented by Formula I-3B exhibited good solubility in all solvents. XRPD results are shown in Figures 6, 7, 8, and 9. Comparison of the initial, 1-hour, 4-hour, and 24-hour data for each sample indicates that the fumaric acid complex represented by Formula I-3B did not undergo any crystal form change during testing in any system, demonstrating excellent stability.

[0187] Example 3: Solid-state stability evaluation experiment

[0188] Crystallized samples of the fumaric acid complex shown in Formula I-3B were placed at 60°C / closed / 1 day, 25°C / 60%RH / open / 1 week, and 40°C / 75%RH / open / 1 week, and their physical and chemical stability was evaluated by XRPD and HPLC.

[0189] The purity and stability test data of the samples are shown in Table S below:

[0190] Table S

[0191] The HPLC test data of the fumaric acid complex of Formula I-3B are shown in Table T below:

[0192] Table T Note: A relative retention time of 1 min corresponds to the compound shown in Formula I-3B.

[0193] The XRPD results are shown in Figure 10. The results show that the fumaric acid complex of Formula I-3B maintained good purity after a period of storage, with virtually no significant change in HPLC purity. No changes in crystal form were observed in any of the tested crystal forms, indicating high stability.

[0194] Example 4: Hygroscopicity Test

[0195] The hygroscopicity of the fumaric acid complexes shown in Formula I-3B was evaluated using DVS.

[0196] The results showed that the test sample had good hygroscopicity. The XRPD results of the sample after DVS test are shown in Figure 11. Comparing the data before and after DVS test, the hygroscopicity assessment results showed that the crystal form of the fumaric acid complex shown in Formula I-3B had a moisture absorption weight gain of 0.0880% at 25℃ / 80%RH. The sample had no hygroscopicity and no crystal form change after the test.

[0197] Example 5: Effect of the fumaric acid complex of Formula I-3B on TNBS-induced acute Crohn's disease (CD) model in rats.

[0198] Forty male SD rats were randomly divided into six groups: normal group, model group, positive group (mesalazine - 30 mg / kg - qd), fumarate complex (fumarate cocrystal of compound I-3B obtained in Preparation Example 3) group (0.6 mg / kg - bid) (complex group - 0.6 mg / kg), fumarate complex (fumarate cocrystal of compound I-3B obtained in Preparation Example 3) group (1.2 mg / kg - bid) (complex group - 1.2 mg / kg), or fumarate complex (fumarate cocrystal of compound I-3B obtained in Preparation Example 3) group (2.4 mg / kg - bid) (complex group - 2.4 mg / kg), with 10 rats per group.

[0199] Except for the normal control group, which received the model induction solvent (37.5% ethanol solution), all other experimental groups were administered TNBS ethanol solution via enema (with animals fasted overnight the day before model induction). On the day following model induction (D1), treatment with fumarate complex (twice a day) and the positive control drug (once a day) was initiated for 10 consecutive days. The therapeutic effect of the compound of this invention on the rat model of acute Crohn's disease was evaluated based on changes in intestinal length and weight index and colonic histopathological scores. The test results are shown in Table U below:

[0200] Table U Note: All data are presented as mean ± standard deviation (SD) for statistical analysis. ****P<0.0001: Model group vs. normal group; ##P<0.01: Positive control group or fumarate complex group vs. model group (One-way ANOVA / Dunnett's). +P<0.05: Statistical analysis results between the 1.2 or 2.4 mg / kg fumarate complex group and the 0.6 mg / kg treatment group.

[0201] The experimental results showed that the fumarate complex group significantly improved the intestinal length and weight index, colonic crypt structure damage and regeneration repair in rat CD model at doses of 0.6, 1.2 and 2.4 mg / kg. It had a significant therapeutic effect on TNBS-induced rat CD model, and the therapeutic effect showed a certain degree of dose-relatedness.

[0202] Example 6: Specific tissue distribution of fumarate complex in SD rats

[0203] Twenty-four male and female SD rats were administered 10 mg / kg of fumaric acid complex (the fumaric acid cocrystal shown in Formula I-3B obtained in Example 3) by gavage. Following administration, rats were euthanized by exsanguination at corresponding time points (0.25 h, 1 h, 6 h, and 24 h, with six rats at each time point, half male and half female). Brain, liver, stomach, colon, and whole blood were collected. Except for plasma preparation by anticoagulation centrifugation of whole blood, all other tissues were homogenized in a homogenate solution (methanol: 15 mmol / L phosphate buffer (pH 7.4) = 1:2). The concentration of each matrix sample was determined by LC-MS / MS, and the tissue / plasma sample concentrations and AUC of each tissue were calculated at different time points. 0-24h The experimental results are shown in Table V below:

[0204] Table V

[0205] The experimental results showed that after rats were administered 10 mg / kg of fumaric acid complex by gavage, the peak concentration was reached in all tissues and plasma at 0.25 h. The drug exposure in each tissue from 0 to 24 h after administration was ranked as follows: stomach > liver > colon > plasma >> brain. The tissue distribution results of rats suggest that this compound is specifically distributed in the stomach, liver and intestines after gavage administration, with very little entry into the brain, and the potential systemic safety risk is low.

Claims

1. Use of a compound or a complex thereof of formula I-3B in the preparation of a medicament for treating and / or preventing inflammatory bowel disease; in, The complex is a complex formed by the compound of formula I-3B and a pharmaceutically acceptable acid. The inflammatory bowel disease is Crohn's disease or ulcerative colitis; Crohn's disease is selected from one or more of ileocolitis, ileitis, gastroduodenal Crohn's disease, jejunoileitis, and Crohn's disease granulomatous colitis. Ulcerative colitis is selected from one or more of ulcerative proctitis, ulcerative rectosigmoid colitis, left colitis, and pancolitis.

2. The use as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The pharmaceutically acceptable acid is hydrochloric acid, phosphoric acid, fumaric acid, tartaric acid, malic acid, ethanedisulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid or oxalic acid, preferably fumaric acid; The compounds or their complexes shown in formulas I-3B as described in (2) are amorphous or crystalline.

3. The use as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The inflammatory bowel disease mentioned refers to inflammatory bowel disease that affects adolescents, young adults, or middle-aged and elderly people; (2) Crohn's disease is a disease involving one or more of the terminal ileum, colon, or both the terminal ileum and colon and the upper gastrointestinal tract, preferably the colon or both the terminal ileum and colon. (3) The Crohn's disease described herein has pathological behaviors of non-stenotic non-penetrating, stenotic, penetrating, or perianal lesions; (4) The Crohn's disease is acute or non-acute Crohn's disease, such as acute Crohn's disease, and further, for example, TNBS-induced acute Crohn's disease; (5) The ulcerative colitis is rectal type, left hemicolon type, extensive colon type or ileocolic type ulcerative colitis, preferably left hemicolon type, extensive colon type or ileocolic type ulcerative colitis; (6) The ulcerative colitis is acute or non-acute ulcerative colitis, such as acute ulcerative colitis, and further, for example, DSS-induced acute ulcerative colitis. The inflammatory bowel disease described in (7) is an inflammatory bowel disease with high expression of interleukin-6, tumor necrosis factor-α, chemokine-2 and interferon-γ.

4. The use as described in claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The drug further comprises pharmaceutical excipients; (2) In the drug, the content of the compound or its complex shown in Formula I-3B is 0.01%-90%, preferably 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%, wherein the percentage is the mass ratio of the compound or its complex shown in Formula I-3B to the drug; (3) The drug is administered via gastric administration or enema, for example, orally; (4) The single dose of the drug is 0.1 mg to 40 mg based on the mass of the compound or its complex shown in Formula I-3B; (5) The drug is administered in a long-cycle or short-cycle manner, for example, long-cycle administration; The frequency of administration of the drug described in (6) is 1-3 times / 0.5-2 days, preferably once / day.

5. The use as described in claim 1, characterized in that, The complex is a complex of the compound shown in Formula I-3B and fumaric acid, wherein the molar ratio of fumaric acid to the compound shown in Formula I-3B is 1:1; preferably, the compound shown in Formula I-3B and the fumaric acid complex are co-crystallized.

6. The use as described in claim 1, characterized in that, It satisfies one or more of the following conditions: The complex is the crystal form of the fumaric acid complex shown in Formula I-3B, and its X-ray powder diffraction pattern, expressed in 2θ angles using Cu-Kα radiation, shows diffraction peaks at 20.5±0.2°, 15.9±0.2°, 26.6±0.2°, 18.9±0.2° and 22.5±0.2°. Preferably, the molar ratio of the compound shown in Formula I-3B to fumaric acid is 1:1; More preferably, the crystal form of the fumaric acid complex of Formula I-3B is the fumaric acid eutectic of Formula I-3B.

7. The use as described in claim 6, characterized in that, It satisfies one or more of the following conditions: (1) The crystal form of the fumaric acid complex of the compound shown in Formula I-3B, whose X-ray powder diffraction pattern using Cu-Kα radiation and expressed in 2θ angle also has diffraction peaks at one or more of the following locations: 22.3±0.2°, 26.4±0.2°, 10.8±0.2°, 17.4±0.2° and 17.5±0.2°; Preferably, the crystal form of the fumaric acid complex of the compound shown in Formula I-3B has diffraction peaks at 20.5±0.2°, 15.9±0.2°, 26.6±0.2°, 18.9±0.2°, 22.5±0.2°, 22.3±0.2° and 26.4±0.2° in the X-ray powder diffraction pattern expressed in 2θ angle using Cu-Kα radiation. More preferably, the crystal form of the fumaric acid complex of the compound shown in Formula I-3B has diffraction peaks at 20.5±0.2°, 15.9±0.2°, 26.6±0.2°, 18.9±0.2°, 22.5±0.2°, 22.3±0.2°, 26.4±0.2°, 10.8±0.2°, 17.4±0.2°, and 17.5±0.2° when X-ray powder diffraction is performed using Cu-Kα radiation and expressed in 2θ angle. For example, the crystal form of the fumaric acid complex of the compound shown in Formula I-3B has the following diffraction peaks as shown in Table W: X-ray powder diffraction pattern using Cu-Kα radiation and expressed at a 2θ angle. Table W For example, the crystal form of the fumaric acid complex of the compound shown in Formula I-3B, when subjected to Cu-Kα radiation, has an X-ray powder diffraction pattern that is basically as shown in Figure 2. (2) The differential scanning calorimetry curve of the fumaric acid complex of the compound shown in Formula I-3B has an endothermic peak at 165.2±3℃ and / or reaches the endothermic peak at 167.2±3℃. For example, the differential scanning calorimetry curve of the crystal form of the fumaric acid complex of the compound shown in Formula I-3B is basically as shown in Figure 3. (3) The thermogravimetric analysis curve of the fumaric acid complex of the compound shown in Formula I-3B shows a weight loss of about 0.36% in the temperature range of 26.2±3℃ to 120℃±3℃. For example, the thermogravimetric analysis curves of the fumaric acid complexes of the compounds shown in Formula I-3B are basically as shown in Figure 3.

8. The use as described in claim 5 or 6, characterized in that, It satisfies one or more of the following conditions: (1) The crystal form of the fumaric acid complex shown in Formula I-3B has the following unit cell parameters: orthorhombic crystal system, space group P212121; α＝90°， β＝90°， γ=90°, The number of asymmetric units within the unit cell is Z = 4, and the crystal density is 1.451 mg / m³. 3 ; (2) The crystal form of the fumaric acid complex of the compound shown in Formula I-3B is a single crystal of the fumaric acid complex of the compound shown in Formula I-3B.

9. The use as described in claim 1 or 6, characterized in that, The fumaric acid complex of the compound shown in Formula I-3B is prepared by either method 1 or method 2 as follows: Method 1 comprises the following steps: mixing a good solvent solution of the compound shown in Formula I-3B with fumaric acid to fully dissolve the fumaric acid, followed by crystallization, to prepare the fumaric acid complex of the compound shown in Formula I-3B. The good solvent mentioned above is ethanol; Method 2 comprises the following steps: sequentially mixing a good solvent solution of the compound shown in Formula I-3B with fumaric acid and a poor solvent, followed by crystallization to prepare the fumaric acid complex of the compound shown in Formula I-3B. Wherein, the good solvent is acetone or ethanol, the poor solvent is n-heptane, and the volume ratio of the poor solvent to the good solvent is greater than 1.

10. The use as described in claim 1 or 6, characterized in that, It satisfies one or more of the following conditions: (1) The single dose of the drug, based on the mass of the compound or its complex shown in Formula I-3B, is 0.01 mg / kg to 10 mg / kg, for example, 2.5 mg / kg, 5 mg / kg, 1.2 mg / kg, 0.6 mg / kg or 2.4 mg / kg, and is preferably administered to rats; (2) The single dose of the drug, based on the mass of the compound or its complex shown in Formula I-3B, is 0.001 mg / kg to 2 mg / kg, for example 0.1-1 mg / kg, preferably 0.2 mg / kg, 0.1 mg / kg, 0.4 mg / kg, 0.42 mg / kg, 0.83 mg / kg or 1.2 mg / kg, and is preferably administered to the human body; (3) After the compound is applied, the solubility is greater than 5 mg / mL, preferably 5.1 mg / mL-6.7 mg / mL or more after 1 hour; (4) After application of the compound or its complex shown in Formula I-3B, the DAI score is 35.65 or below; (5) When the dosage of the compound or its complex of formula I-3B is 4% of the dosage of mesalazine, substantially equivalent therapeutic effects are achieved, for example, equivalent colon weight / length ratios. (6) After administration of the compound or its complex of formula I-3B, the colon weight / length ratio is 13.95 or less; (7) After administration of the compound or its complex shown in Formula I-3B, (CW / CL)*10 is less than 2.26, where CL represents colon length and CW represents intestinal weight; (8) After administration of the compound or its complex shown in Formula I-3B, (CW / CL / BW)*1000 is less than 1.39, where CL represents colon length, CW represents intestinal weight, and BW represents body weight.

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