Preparation of compound containing heterocyclic compound or compound formed by heterocyclic compound and pharmaceutically acceptable salt as well as preparation method and application of preparation

Abstract

The invention relates to a preparation containing a heterocyclic compound or a compound formed by the heterocyclic compound and pharmaceutically acceptable salt as well as a preparation method and application of the preparation. The preparation comprises an active component and a pharmaceutically acceptable carrier, the content of the active component is 1 wt%-50 wt%; the active component is a compound as shown in a formula I-3B or a compound thereof; the compound of the compound as shown in the formula I-3B is a compound formed by the compound as shown in the formula I-3B and pharmaceutically acceptable acid. The application comprises the following steps: preparing a 15-PGDH inhibitor, and / or preparing a medicine, a pharmaceutical composition or a preparation for preventing and / or treating 15-PGDH related diseases. .

Description

Technical Field

[0001] This invention relates to a formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt, a method for its preparation, and its application. Background Technology

[0002] The 15-hydroxyprostaglandin dehydrogenase (15-PGDH) gene is located on chromosome 4, 4q34-q35, spanning approximately 31 kb, and contains 7 exons with a molecular weight of 29 kDa. Composed of 266 amino acids, 15-PGDH belongs to the short-chain dehydrogenase (SDR) family. It is a dimer composed of two identical subunits, although some believe it only exhibits enzymatic activity when present as a monomer. 15-PGDH is a key enzyme in the degradation and inactivation of prostaglandins (PGs) and related eicosane bioactive substances. It is widely found in normal tissues of humans and mammals, including the lungs, kidneys, gastrointestinal tract, thyroid gland, prostate, and placenta. On one hand, it catalyzes the oxidation of active 15-hydroxyprostaglandins to the significantly less active 15-ketoprostaglandins; on the other hand, it can also be activated by NAD+. + In the presence of coenzyme factors, some other non-prostaglandin polycyclic aromatic hydrocarbons are degraded, and carcinogens and pre-carcinogens produced under physiological or pathological conditions are reduced through oxidation reactions.

[0003] Chinese invention patent application No. 202211449273.5 describes a heterocyclic compound with 15-PGDH inhibitory activity:

[0004] .

[0005] The chemical name of this heterocyclic compound is 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]pyridin-3(2H)-one (numbered I-3), and the structure contains the following two isomers:

[0006] .

[0007] Chinese invention patent application No. 202410557122.4 describes a fumaric acid complex of a heterocyclic compound with 15-PGDH inhibitory activity. Based on the good biological activity of this compound, it is necessary to develop a suitable dosage form to obtain a product suitable for development and industrialization. Summary of the Invention

[0008] To address the deficiencies in the prior art, this invention provides a formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt, a method for its preparation, and its application.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] In a first aspect, the present invention provides a formulation comprising a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt, comprising an active ingredient and a pharmaceutically acceptable carrier; wherein the content of the active ingredient is 1 wt%-50 wt%.

[0011] .

[0012] The active ingredient is a compound of formula I-3B or a complex thereof; the complex is a complex formed by a compound of formula I-3B and a pharmaceutically acceptable acid.

[0013] In this invention, the weight percentage of each substance in the preparation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt refers to the ratio of the weight of that substance to the total weight of the preparation.

[0014] In this invention, 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.

[0015] In this invention, the formulation may be a formulation for treating or preventing 15-PGDH-related diseases; the 15-PGDH-related diseases are preferably idiopathic pulmonary fibrosis, liver regeneration, liver injury, or inflammatory bowel disease; the inflammatory bowel disease is preferably 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 preferably selected from one or more of ulcerative proctitis, ulcerative rectosigmoid colitis, left colitis, and pancolitis.

[0016] In this invention, the compounds or their complexes represented by formulas I-3B may be amorphous or crystalline.

[0017] In this invention, the complex of the compound represented by Formula I-3B is a fumaric acid complex of the compound represented by Formula I-3B. Preferably, the molar ratio of the compound represented by Formula I-3B to fumaric acid in the fumaric acid complex is 1:1. Preferably, the fumaric acid complex of Formula I-3B is a eutectic of the compound represented by Formula I-3B.

[0018] In this invention, the complex of the compound shown in Formula I-3B is the crystal form of the fumaric acid complex of the compound shown in Formula I-3B.

[0019] The crystal form of the fumaric acid complex shown in Formula I-3B may have the following unit cell parameters: orthorhombic, space group P212121; a = 6.4400(4) Å, α = 90°, b = 11.9376(8) Å, β = 90°, c = 33.139(2) Å, γ = 90°, unit cell volume = 2547.7(3) Å 3 The number of asymmetric units within the unit cell is Z=4, and the crystal density is 1.451 mg / m³. 3 .

[0020] The crystal form of the fumaric acid complex shown in Formula I-3B has diffraction peaks at 20.5±0.2º, 15.9±0.2º, 26.6±0.2º, 18.9±0.2º and 22.5±0.2º when X-ray powder diffraction is performed using Cu-Kα radiation and expressed at an angle of 2θ.

[0021] The crystal form of the fumaric acid complex shown in Formula I-3B, when subjected to Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle, may have diffraction peaks at one or more of the following locations: 22.3±0.2º, 26.4±0.2º, 10.8±0.2º, 17.4±0.2º, and 17.5±0.2º.

[0022] The crystal form of the fumaric acid complex shown in Formula I-3B, when subjected to Cu-Kα radiation and X-ray powder diffraction pattern expressed in 2θ angle, exhibits diffraction peaks at 20.5±0.2º, 15.9±0.2º, 26.6±0.2º, 18.9±0.2º, 22.5±0.2º, 22.3±0.2º, and 26.4±0.2º.

[0023] The crystal form of the fumaric acid complex shown in Formula I-3B, when subjected to Cu-Kα radiation and X-ray powder diffraction pattern expressed at an angle of 2θ, exhibits diffraction peaks at 20.5±0.2º, 15.9±0.2º, 26.6±0.2º, 18.9±0.2º, 22.5±0.2º, 22.3±0.2º, 26.4±0.2º, 10.8±0.2º, 17.4±0.2º, and 17.5±0.2º.

[0024] In certain specific embodiments of the present invention, the crystal form of the fumaric acid complex of Formula I-3B, when subjected to Cu-Kα radiation and X-ray powder diffraction patterns expressed at 2θ angles, exhibits the diffraction peaks shown in the table below:

[0025]

[0026] In a specific embodiment of the present invention, the crystal form of the fumaric acid complex represented by Formula I-3B is obtained by Cu-Kα radiation, and its X-ray powder diffraction (XRPD) pattern is essentially as follows: Figure 2 As shown.

[0027] The differential scanning calorimetry (DSC) curve of the fumaric acid complex of Formula I-3B shows an endothermic peak starting at 165.2±3℃.

[0028] The differential scanning calorimetry (DSC) curve of the fumaric acid complex of Formula I-3B reaches the peak value of the endothermic peak at 167.2±3℃.

[0029] In a specific embodiment of the present invention, the differential scanning calorimetry (DSC) curve of the fumaric acid complex of formula I-3B is essentially as follows: Figure 3 As shown.

[0030] 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°C to 120±3°C.

[0031] 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 is essentially as follows: Figure 3 As shown.

[0032] 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.

[0033] The preparation method of the fumaric acid complex represented by formula I-3B may include:

[0034] 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 and crystallize it to prepare the fumaric acid complex of the compound shown in Formula I-3B, wherein the good solvent is acetone or ethanol.

[0035] In one aspect of the present invention, in method 1, the volume-to-mass ratio of the good solvent to the compound shown in formula I-3B in the good solvent solution is 2-6 mL / g, for example, 3 mL / g.

[0036] In one aspect of the present invention, in method 1, the molar ratio of the compound shown in formula I-3B to the amount of fumaric acid is 1:(0.9-1.5), preferably 1:(1.1-1.5), and more preferably 1:1.1 or 1:1.2.

[0037] In one aspect of the present invention, in method 1, the good solvent is ethanol.

[0038] In one aspect of the present invention, in method 1, the good solvent is ethanol, and when the mixture is mixed with fumaric acid, the temperature of the good solvent solution of the compound shown in formula I-3B is 30-60°C, for example, 50°C.

[0039] In one aspect of the present invention, in method 1, the good solvent is ethanol. Method 1 further uses seed crystals of the fumaric acid complex of the compound shown in formula I-3B, for example, by adding the seed crystals 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 0.5% or greater than 0.5%, for example, 0.5%-1.5%, and further, for example, 1%. When the seed crystals are added, the temperature of the solution can be 30-60°C, for example, 50°C.

[0040] In one embodiment of the present invention, in method 1, the good solvent is ethanol, and method 1 specifically includes the following steps: mixing a good solvent solution of the compound shown in formula I-3B with fumaric acid at 30-60°C (e.g., 50°C), stirring at this temperature for 0.5-1.5 h, filtering while hot, collecting the filtrate, adding seed crystals of the fumaric acid complex of the compound shown in formula I-3B to the filtrate, stirring at this temperature for 0.5-3 h, slowly cooling to 0-10°C (e.g., 5°C), stirring for 1-3 h (e.g., 2 h), filtering, taking the filter cake, and drying at 50-70°C (e.g., 60°C); the mass ratio of the seed crystals to the compound shown in formula I-3B can be 0.5%-1.5% (e.g., 1%); preferably, when the seed crystals are added, the temperature of the filtrate is 30-60°C, e.g., 50°C; the drying method can be forced air drying; the drying time can be 4-8 h, e.g., 6 h.

[0041] In one embodiment of the present invention, in method 1, the good solvent is acetone.

[0042] In one embodiment of the present invention, in method 1, the good solvent is acetone, and method 1 specifically includes the following steps: mixing a good solvent solution of the compound shown in formula I-3B with fumaric acid, heating and stirring to fully dissolve, and cooling to crystallize; the heating can be to 50-55°C, for example, to 55°C; the stirring can be to stir for 1-3 hours, for example, 2 hours; the cooling to crystallize can be to cool to 0-10°C and stir for 1-3 hours, for example, to cool to 5°C and stir for 2 hours; after crystallization, the mixture can be filtered, and the filter cake can be dried, the drying can be by forced air drying, the drying temperature can be 50-70°C (for example, 60°C), and the drying time can be 1-3 hours, for example, 2 hours.

[0043] Method 2 comprises 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, 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.

[0044] In one aspect of the present invention, in method 2, the volume-to-mass ratio of the good solvent to the compound shown in formula I-3B in the good solvent solution is 2-4 mL / g, for example, 3 mL / g.

[0045] In one embodiment of the present invention, in method 2, the molar ratio of the compound shown in formula I-3B to the fumaric acid is 1:(0.9-1.5), preferably 1:1.

[0046] In one aspect of the present invention, in method 2, the volume ratio of the poor solvent to the good solvent is (2-4):1, for example, 3:1.

[0047] In one aspect of the present invention, in method 2, after the good solvent solution of the compound shown in formula I-3B is mixed with fumaric acid, the bad solvent is added in batches. Preferably, the bad solvent is added in two batches, and the volume ratio of the first batch to the second batch of bad solvent is 1:(3-4), for example, 1:3.5.

[0048] In one aspect of the present invention, method 2 specifically includes the following steps: mixing a good solvent solution of the compound shown in formula I-3B with fumaric acid, heating, adding the poor solvent dropwise, and cooling to crystallize; the heating can be raised to 40-55°C, for example 50°C; after cooling and crystallization, the mixture can be filtered, and the filter cake can be dried.

[0049] In any of the above schemes, the good solvent solution of the compound shown in Formula I-3B can be prepared by adding the compound shown in Formula I-3B to the good solvent.

[0050] In this invention, "fully dissolved" is not the same as "completely dissolved". "Fully dissolved" means that after a substance is placed in a solvent, it may have completely dissolved or it may have reached saturation and have some residue.

[0051] In this invention, the content of the active ingredient can be 8wt%-10wt%, for example 9wt% or 9.03wt%.

[0052] In this invention, the D90 of the active ingredient can be ≤100 μm, for example, D90=76.3-87.0 μm.

[0053] In this invention, the pharmaceutically acceptable carrier may include a first filler. The first filler may be selected from one or more of microcrystalline cellulose, lactose, and pregelatinized starch. The content of the first filler may be 5wt%-30wt%, preferably 15wt%-25wt%, for example 20wt%.

[0054] In this invention, the pharmaceutically acceptable carrier may include a second filler. The second filler may be selected from one or more of mannitol, lactose, and pregelatinized starch. The content of the second filler may be 10wt%-80wt%, preferably 60wt%-70wt%, for example 61.47wt%, 61.5wt%, or 61.97wt%.

[0055] In this invention, the pharmaceutically acceptable carrier may include an adhesive. The adhesive may be selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone. The content of the adhesive is preferably 1 wt%-5 wt%, for example, 3 wt%.

[0056] In this invention, the pharmaceutically acceptable carrier may include a disintegrant. The disintegrant may be selected from one or more of croscarmellose sodium, croscarmellose, croscarmellose calcium, and carboxymethyl starch sodium. The content of the disintegrant is preferably 2wt%-8wt%, for example, 5wt%.

[0057] In this invention, the pharmaceutically acceptable carrier may include a lubricant. The lubricant may be selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, sodium docusate, and calcium stearate. The content of the lubricant is preferably 0.5wt%-2wt%, more preferably 1wt%-2wt%, for example, 1wt% or 1.5wt%.

[0058] In certain specific embodiments of the present invention, the heterocyclic compound fumaric acid complex formulation may contain the following components in the following amounts: active ingredient 1wt%-50wt%, first filler 5wt%-30wt%, second filler 10wt%-80wt%, binder 1wt%-5wt%, disintegrant 2wt%-8wt%, and lubricant 1wt%-2wt%.

[0059] In a specific embodiment of the present invention, the heterocyclic compound fumaric acid complex formulation may contain the following components in the following amounts: 9.03 wt% fumaric acid eutectic of Formula I-3B, 20 wt% microcrystalline cellulose, 61.47 wt% mannitol, 3 wt% hydroxypropyl cellulose, 5 wt% croscarmellose sodium, and 1.5 wt% magnesium stearate.

[0060] In a specific embodiment of the present invention, the heterocyclic compound fumaric acid complex formulation may contain the following components in the following amounts: 9.03 wt% fumaric acid eutectic of Formula I-3B, 20 wt% microcrystalline cellulose, 61.97 wt% mannitol, 3 wt% hydroxypropyl cellulose, 5 wt% croscarmellose sodium, and 1 wt% magnesium stearate.

[0061] In this invention, the dosage form of the preparation containing the heterocyclic compound or its complex with a pharmaceutically acceptable salt may be a tablet or a capsule.

[0062] In a second aspect, the present invention provides a method for preparing a formulation of the heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt as described above, comprising the following steps:

[0063] S1. Under a first stirring state, the first mixture and the second mixture are mixed to obtain a granulation mixture; the first mixture includes a first filler, a disintegrant, an active ingredient, and a second filler, and the second mixture includes a binder and water;

[0064] S2. The granulation mixture is granulated under a second stirring state, and then dried to obtain dry granules;

[0065] S3. Fill the hollow capsule with the third mixture; the third mixture includes the lubricant and the dry granules.

[0066] In this invention, in step S1, the stirring speed of the first stirring state can be 100-300 r / min, for example 180 r / min.

[0067] In this invention, in step S1, the cutting speed of the first stirring state can be 500-2500 r / min, for example 1000 r / min.

[0068] In this invention, in step S1, the first filler may be as defined above.

[0069] In this invention, in step S1, the second filler may be as defined above.

[0070] In this invention, in step S1, the disintegrant can be as defined above.

[0071] In this invention, in step S1, the active ingredient may be as defined above.

[0072] In this invention, in step S1, the adhesive may be as defined above.

[0073] In this invention, in step S2, the stirring speed in the second stirring state can be 100-300 r / min, for example 200 r / min.

[0074] In this invention, in step S2, the cutting speed of the second stirring state can be 500-2500 r / min, for example 1500 r / min.

[0075] In this invention, the granulation time in step S2 can be 0.5-3 min, for example 1 min.

[0076] In this invention, in step S2, the drying process can employ fluidized bed drying. The inlet air temperature for drying can be 50-80℃, for example, 65℃. The fluidized air volume for drying can be 20-140 m³ / h. 3 / h.

[0077] In this invention, in step S2, the drying process can be carried out until the LOD of the material is ≤3.0%.

[0078] In this invention, before drying in step S2, wet particle granulation can be performed. The wet particle granulation can be carried out using a 5.0 mm × 5.0 mm sieve. The vibration frequency of the wet particle granulation can be 25 ± 10 Hz.

[0079] In this invention, after drying in step S2, dry granulation can be performed. The dry granulation can be carried out using a 0.8-1.2 mm sieve; for example, a 1.2 mm and / or 1 mm and / or 0.8 mm sieve. The vibration frequency of the dry granulation can be 25±10 Hz.

[0080] In this invention, in step S3, the content of the third mixture is determined based on HPLC, using C0.05... 22 H 22 The F2N6O2 content can be 95.0%-105.0% of the labeled amount.

[0081] In this invention, in step S3, the lubricant may be as defined above.

[0082] In this invention, in step S3, the amount of filling can be 63-77 mg / capsule, preferably 65.1-74.9 mg / capsule.

[0083] In this invention, in step S3, the amount of filling can be 325.5-374.5 mg / capsule.

[0084] In this invention, in step S3, the filling rate can be 5000-20000 particles / hour.

[0085] Thirdly, the present invention provides the use of a formulation of a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt as described above, for the purpose of inhibiting 15-PGDH; and / or, preventing and / or treating 15-PGDH-related diseases.

[0086] In this invention, the 15-PGDH-related diseases may include idiopathic pulmonary fibrosis (IPF).

[0087] In this invention, the prevention and / or treatment of 15-PGDH-related diseases may include liver regeneration.

[0088] In this invention, the 15-PGDH-related diseases may include liver damage.

[0089] In this invention, the 15-PGDH-related diseases may include: inflammatory bowel disease (IBD); the inflammatory bowel disease is preferably 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 preferably selected from one or more of ulcerative proctitis, ulcerative rectosigmoid colitis, left colitis, and pancolitis.

[0090] Terminology Explanation:

[0091] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of definitions and compound structures should fall within the scope of this application specification. Unless otherwise specified, the terms used in this invention have the following meanings:

[0092] The term "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that is permitted by the relevant government regulatory authority to be acceptable for human or animal use.

[0093] 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.

[0094] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0095] The term "inflammatory bowel disease" refers to IBD, used to describe a condition involving chronic inflammation of the digestive tract. The main types include ulcerative colitis and Crohn's disease. Ulcerative colitis causes inflammation and ulcers in the superficial lining of the large intestine (colon) and rectum. Crohn's disease is characterized by inflammation of the digestive tract lining, which often extends to the deeper layers of the digestive tract.

[0096] 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.

[0097] The reagents and raw materials used in this invention are all commercially available.

[0098] The positive and progressive effects of this invention lie in having one or more of the following advantages:

[0099] (1) The formulation of the present invention enables the rapid release of the active pharmaceutical ingredient and has good compatibility;

[0100] (2) The formulation of the present invention has good stability and dissolution characteristics, which can meet the relevant requirements for clinical administration;

[0101] (3) The formulation of the present invention has excellent uniformity of active ingredient content;

[0102] (4) The complex in the formulation of the present invention can be used to treat inflammatory bowel disease. After application, it is specifically distributed in the intestinal tissue and has good safety. Attached Figure Description

[0103] Figure 1 This is a single-crystal structure diagram of compound R1.

[0104] Figure 2 The X-ray powder diffraction pattern of the fumaric acid complex of formula I-3B is shown.

[0105] Figure 3 Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) curves of the fumaric acid complex shown in Formula I-3B.

[0106] Figure 4 The image shows an ellipsoidal diagram of the molecular structure of the fumaric acid complex crystal shown in I-3B.

[0107] Figure 5 This is a comparison between the fitted XRPD plot of the fumaric acid complex crystal shown in I-3B and the measured XRPD plot.

[0108] Figure 6 The XRPD plot shows the dynamic solubility of the fumaric acid complex of Formula I-3B in H2O.

[0109] Figure 7 XRPD plot of the dynamic solubility of the fumaric acid complex of Formula I-3B in SGF.

[0110] Figure 8 XRPD plot of the dynamic solubility of the fumaric acid complex of Formula I-3B in FaSSIF.

[0111] Figure 9 XRPD plot of the dynamic solubility of the fumaric acid complex of Formula I-3B in FeSSIF.

[0112] Figure 10 XRPD plot of the fumaric acid complex of Formula I-3B as an example of its crystal stability assessment.

[0113] Figure 11 The image shows XRPD images of the fumaric acid complex of Formula I-3B before and after the hygroscopicity test. Detailed Implementation

[0114] 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.

[0115] Symbols or units:

[0116] IC 50 The half-maximum inhibitory concentration (MCI) is the concentration at which half of the maximum inhibitory effect is achieved.

[0117] M: mol / L, for example, n-butyllithium (14.56 mL, 29.1 mmol, 2.5 M n-hexane solution) means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol / L.

[0118] N: Equivalent concentration, for example, 2N hydrochloric acid means a 2 mol / L hydrochloric acid solution.

[0119] Reagents:

[0120] A table of Chinese and English names of solvents used in the preparation examples and embodiments.

[0121]

[0122] Instrument and method for detecting crystal form:

[0123] 1. X-ray powder diffraction (XRPD)

[0124] XRPD images were acquired using a PANalytacal X-ray powder diffractometer, and the scanning parameters are shown in the table below:

[0125]

[0126] 2. X-ray single crystal diffraction

[0127] Test environment: Test temperature: 200(2)K, room temperature 24℃, relative humidity 34%, X-ray single crystal diffraction method as follows:

[0128]

[0129] 3. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

[0130] TGA and DSC plots were acquired using a TA 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively. The test parameters are listed in the table below:

[0131]

[0132] 4. Liquid NMR:

[0133] Liquid NMR spectra were acquired using a Bruker 400M NMR spectrometer with DMSO-d6 as the solvent.

[0134] 5. High Performance Liquid Chromatography (HPLC):

[0135] Purity, dynamic solubility, and stability tests were performed using UPLC (ultra-high performance liquid chromatography), and the analytical conditions are shown in the table below:

[0136]

[0137] 6. Dynamic Moisture Adsorption (DVS):

[0138] Dynamic moisture adsorption (DVS) curves were acquired using SMS (Surface Measurement Systems) DVSIntrinsic Plus. Relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. DVS test parameters are listed in the table below:

[0139]

[0140] 7. Ion chromatography (IC):

[0141] The instrument parameters for determining the molar ratio of the anti-charged ions in ion chromatography (IC) are listed in the analytical conditions below:

[0142]

[0143] Preparation Example 1: Preparation of the compound shown in Formula I-3B

[0144] The synthetic route for the target compound is as follows:

[0145] .

[0146] 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).

[0147] .

[0148] (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) were added to the reaction flask. After purging with nitrogen three times, anhydrous solvent 1,4-dioxane (4 mL) was added, and the reaction was carried out at 85 °C for 12 hours. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, concentrated the organic phase to dryness, mixed the sample, 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%).

[0149] LC-MS, M / Z (ESI): 352.1 [M+H] + .

[0150] Ligand L: .

[0151] 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).

[0152] .

[0153] 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 1 M 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.

[0154] LC-MS, M / Z (ESI): 338.1 [M+H] + .

[0155] 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).

[0156] .

[0157] 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, the organic phase was concentrated to dryness and then mixed. The sample was 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-cyclopropyl[c][1,8]naphthidin-3-yl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (5) (132 mg, yield: 75%)

[0158] LC-MS, M / Z (ESI): 441.1 [M+H] +

[0159] 1 H NMR (400 MHz, DMSO-d6): δ 8.09 (d, 1 H), 7.71 (d, 1 H), 7.59 (d, 1H), 6.55-6.52 (m, 2 H), 3.95 (d, 1 H), 3.75-3.69 (m, 5 H), 3.63 (s, 3 H),2.10-2.03 (m, 6 H), 1,22-1.12 (m, 2 H) ppm.

[0160] The product was subjected to SFC (column: Chiralpak AD-3 50×4.6 mm ID, 3μm, mobile phase: mobile phase A: CO2, mobile phase B: IPA+ACN (0.05 v% DEA)).

[0161] 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 compound I-3B (i.e., the compound represented by formula I-3B in this application) was 1.674 min.

[0162] 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; the single crystal structure of compound R1 is shown below. Figure 1 As shown, its main crystal parameters are as follows:

[0163]

[0164] 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.

[0165] Preparation Example 2: Fumaric acid complex of the compound shown in Formula I-3B

[0166] Preparation Example 2.1 Preparation of the fumaric acid complex of the compound shown in Formula I-3B

[0167] 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 the product, with a yield of 90.0% (the characterization data of the crystal form of the prepared product are the same as those in Preparation Example 3).

[0168] Preparation Example 2.2 Preparation of the fumaric acid complex of the compound shown in Formula I-3B

[0169] Preparation method: Weigh 20.00 g of free base 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 base 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 the table below:

[0170]

[0171] 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%.

[0172] Preparation Example 3: Crystal form of the fumaric acid complex of the compound shown in Formula I-3B

[0173] 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; "1% co-crystal seed crystals" means that the mass of the added co-crystal seed crystals is 1% of the free base feed amount), 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%. The fumaric acid content is 20.4%.

[0174] The XRPD diffraction peak data of the fumaric acid complex of Formula I-3B are shown in the table below:

[0175]

[0176]

[0177] The crystal form characterization data of the fumaric acid complex shown in Formula I-3B are shown in the table below:

[0178]

[0179] The NMR data for the crystal form of the fumaric acid complex shown in Formula I-3B are as follows:

[0180]

[0181] 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.

[0182] Method 2: Weigh ~15 mg of the fumaric acid complex (formula I-3B) obtained in Method 1 into an EP tube, add acetone (0.75 mL), shake until the sample dissolves, filter the solution through a microporous membrane into a 2 mL transparent glass bottle, add n-heptane (0.75 mL), the solution separates into layers, seal with sealing film, make two small holes, allow to stand at room temperature for about 2 days to evaporate, and transparent crystals will precipitate, thus obtaining the fumaric acid complex (single crystal) shown in Formula I-3B.

[0183] 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:

[0184]

[0185] According to the X-ray single-crystal diffraction results, fumaric acid is connected 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 indicates that the single-crystal sample forms 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.

[0186] The hydrogen bonding interactions (Å and °) of the fumaric acid complex of Formula I-3B are shown in the table below:

[0187]

[0188] The molecular structure ellipsoidal model of the fumaric acid complex shown in Formula I-3B in a single crystal is as follows: Figure 4 As shown, the comparison between the fitted XRPD diffraction pattern and the measured XRPD diffraction pattern of the crystal obtained by Method 1 is as follows. Figure 5 As shown, the results indicate that the composite crystals obtained by Method 1 and Method 2 are of the same crystal form.

[0189] The dosage forms of Examples 1 and 2 of this invention are capsules, with specifications of 25 mg and 5 mg, respectively. The capsule shells used are gelatin empty capsules (manufacturer: Suzhou Capsule, model 0#, 4#, or 5#). The active ingredient API in the formulation is the fumaric acid cocrystal (hereinafter referred to as fumaric acid cocrystal) of the compound shown in Formula I-3B obtained in Preparation Example 3. The excipients are mannitol (manufacturer: Roquette Freres, model 160C), microcrystalline cellulose (manufacturer: JRS, model VIVAPUR101), hydroxypropyl cellulose (manufacturer: Japan Soda, model HPC-SL), croscarmellose sodium cellulose (manufacturer: DuPont Nutrition USA, Inc., model SD 711, CAS: 74811-65-7), and magnesium stearate (manufacturer: Anhui Shanhe, model SH-YM-M).

[0190] Example 1: Specification 25 mg

[0191] Example 1-1, the prescription is shown in the table below:

[0192]

[0193] Examples 1-2, the prescriptions are shown in the table below:

[0194]

[0195] The active pharmaceutical ingredient (API) is a fumaric acid cocrystal. The specification is based on the base form of the API; 31.6 mg of fumaric acid cocrystal is equivalent to 25 mg of bases. The actual API feed rate is calculated based on the content of the raw material COA and the fumaric acid content (content and fumaric acid content are from the API manufacturer's COA). Actual API feed rate = Theoretical API usage 0.4740 kg ÷ 556.53 × 440.45 ÷ (1 - fumaric acid content) ÷ Raw material content. Since the raw material COA already includes moisture, only the content is considered for purification.

[0196] Purified water is used as a solvent in the preparation of adhesives, and is used in the process and eventually removed.

[0197] The specific preparation process is as follows:

[0198] 1. Ingredients

[0199] API pretreatment: Weigh approximately 510 g of API and pass it through a 40-mesh sieve. Collect the undersize material and discard the oversize material as waste. Use an FW135 medium-sized grinder to grind the undersize material into portions of approximately 255 g each for 15 seconds. Collect the ground material and pass it through an 80-mesh sieve. Discard the oversize material as waste. Mix all the ground and sieved materials together and transfer them to the next process.

[0200] Excipient pretreatment: Weigh the theoretical amounts of mannitol, microcrystalline cellulose, and croscarmellose sodium sequentially according to API conversion, pass them through a 20-mesh sieve, and collect the undersize material for the next process. Weigh the theoretical amounts of hydroxypropyl cellulose and purified water into the granulation room for later use. Weigh the theoretical amounts of magnesium stearate SH-YM-M and pass them through a 20-mesh sieve.

[0201] 2. Perform wet granulation according to the prescribed dosage.

[0202] Preparation of the slurry: Add purified water to a stainless steel bucket, and slowly add hydroxypropyl cellulose while stirring. Stir until completely dissolved and the solution is transparent. The stirring speed should be 1000-2000 rpm.

[0203] Premixing: Sifted microcrystalline cellulose, croscarmellose sodium, and pulverized and weighed API are sequentially poured into a 30 L granulator. Sifted mannitol is placed in a raw material bag and manually mixed for approximately 15 seconds before being poured into the granulator. The mixing process is premixed with a paddle speed of 200 rpm, a cutter speed of 1000 rpm, and a mixing time of 3 minutes.

[0204] Adding slurry: Set the agitator speed to 180 r / min and the cutter speed to 1000 r / min. Turn on the agitator and cutter, and simultaneously start the peristaltic pump to add slurry into the pellet mill (use two peristaltic pumps to add slurry simultaneously). The peristaltic pump speed is 600 rpm. After the slurry is added, record the slurry addition time and stop the machine. The slurry addition time should be ≤150 s. Open the pellet mill lid, clean the material on the lid and walls of the pellet mill, and close the pellet mill lid.

[0205] Granulation: Set the agitator speed to 200 r / min and the cutter speed to 1500 r / min. Turn on the agitator and cutter, granulate for 1 minute, and record the granulation time, as well as the total time for adding slurry and granulation.

[0206] Discharge: Set the speed of the granulator's mixing paddle and the slope rate of the mixing paddle, open the discharge valve, and collect the wet granules using a pharmaceutical polyethylene bag.

[0207] 3. Wet whole grain

[0208] The wet granules were granulated using a mobile granulator with a 5.0 mm × 5.0 mm screen at a granulation speed of 25 ± 10 Hz.

[0209] 4. Fluidized bed drying

[0210] Preheating: Set the fluidizing air volume to 160 m³ / h 3 / min, inlet air temperature 60℃, preheated fluidized bed.

[0211] Feeding: After the fluidized bed is heated for 10 minutes, the wet particles are poured directly into the fluidized bed product pot to begin drying.

[0212] Drying: At the start of drying, the fluidizing air volume is set to 140 m³ / h. 3 The fluidizing air volume is adjusted according to the material's drying state, with an adjustment range of 20-140 m³ / h. 3 / h. Observe the material temperature. When the material temperature reaches 30℃, take a sample to determine the LOD. If LOD > 3.0%, continue drying for 10 minutes and take a sample to determine the LOD again, until LOD ≤ 3.0%, at which point drying is complete.

[0213] Discharge: Open the discharge valve and collect the dry material using a pharmaceutical polyethylene bag. Then, use a brush to collect the material from the filter bag, the inside of the fluidized bed, and the filter of the buffer tank, and add it to the collected dry granules. Specific parameters for fluidized bed drying can be found in the table below.

[0214]

[0215] 5. Dry granulation

[0216] A mobile granulator is used, with 1.2 mm and 0.8 mm screens used sequentially (or with a 1.0 mm screen), and the granulation speed is 25 ± 10 Hz.

[0217] 6. Total Mixture

[0218] Add the dry granules and weighed magnesium stearate SH-YM-M (actual dosage = batch prescription amount × dry granule yield) to the mixing tank, set the mixer speed to 10 rpm, and mix for 3 min. The intermediate control parameters of the intermediate mixed powder are shown in the table below.

[0219]

[0220] 7. Capsule filling

[0221] Select a #0 mold and install the capsule filling machine. After installation, run the machine and confirm that there is no friction or abnormality. Add empty capsules to the capsule hopper and run the machine empty to check the quality of the capsule locking mechanism at the discharge point.

[0222] Randomly select 100 empty capsules and weigh them to calculate the average weight of each empty capsule. Control the fill weight range error to no more than 7.0% of 350 mg, i.e., a fill weight range of 325.5 mg to 374.5 mg. Fill the capsules using a capsule filling machine at a speed of 5000-20000 capsules / hour, and sample at least 20 capsules every 20 minutes to check the fill weight and appearance (for stains, powder leakage, damage, and wrinkles). All results must meet the requirements. Intermediate control indicators for filling are shown in the table below.

[0223]

[0224] 8. Double aluminum packaging

[0225] Solid pharmaceutical composite rigid sheets and pharmaceutical aluminum foil are cold-stamped using polyamide / aluminum / polyvinyl chloride. The heat-sealing temperature is set at 170±10℃, and the punching speed is 10~25 punches / min for inner packaging. The intermediate control of packaging is shown in the table below.

[0226]

[0227] Example 2: Specification 5 mg

[0228] Example 2-1, the prescription is shown in the table below:

[0229]

[0230] Example 2-2, the prescription is shown in the table below:

[0231]

[0232] The active pharmaceutical ingredient (API) is fumaric acid cocrystal. The specification is based on the base form of the API; 6.32 mg of fumaric acid cocrystal is equivalent to 5 mg of bases. The actual API feed rate is calculated based on the content of the raw material COA and the fumaric acid content (content and fumaric acid content are from the API manufacturer's COA). Actual API feed rate = Theoretical API usage 0.4740 kg ÷ 556.53 × 440.45 ÷ (1 - fumaric acid content) ÷ Raw material content. Since the raw material COA already includes moisture, only the content is considered for purification.

[0233] Purified water is used as a solvent in the preparation of adhesives, and is used in the process and eventually removed.

[0234] Compared with Example 1, the preparation process of Example 2 differs only in the capsule filling step, as follows:

[0235] 7. Capsule filling

[0236] Select mold #4 and install the capsule filling machine. After installation, run the machine and confirm that there is no friction or abnormality. Add empty capsules to the capsule hopper and run the machine empty to check the quality of the capsule locking at the discharge point.

[0237] Randomly select 100 empty capsules and weigh them to calculate the average weight of each empty capsule. Control the fill weight range to 70 mg ± 10.0% (63.0 mg - 77.0 mg). Fill the capsules using a capsule filling machine at a speed of 5000-20000 capsules / hour, and sample 10 capsules at least every 20 minutes to check the fill weight and appearance (for stains, powder leakage, damage, and wrinkles). All results must meet the requirements. Intermediate control standards for filling are shown in the table below.

[0238]

[0239] The remaining procedures and process parameters are the same as in Example 1.

[0240] Effect Example 1: Effect of the compound shown in Formula I-3B on the DSS-induced acute ulcerative colitis (UC) model in rats.

[0241] 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, respectively.

[0242] 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.

[0243] Mice in groups G2-G6 were given a 2% DSS solution for drinking from day 0 to 6, and normal water for drinking 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 the G4-formula I-3B group (2.5 mg / kg-bid) and the G5-formula I-3B group (5 mg / kg-bid) both showed increased body weight, with G5 animals showing a significant increase in body weight. Animals with DAI significantly decreased, CL significantly increased, and CW, CL / CW / BW, and CL / CW significantly decreased. Colon histopathological examination showed that inflammatory cell infiltration and tissue damage scores were significantly reduced.

[0244] The DAI scores of each group of animals from Day 0 to Day 9 are shown in the table below:

[0245]

[0246] Note: Statistical analysis was performed only on the DAI score for Day 9. P < 0.001: VS model group (One way ANOVA / Dunnett's).

[0247] The following table summarizes the colon length (CL), intestinal weight (CW), CL / CW / BW, and CW / CL:

[0248]

[0249] Experimental results showed that compound 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.

[0250] Example 2: Dynamic Solubility Stability Test of Crystal Form

[0251] The dynamic solubility of the fumaric acid complex of Formula I-3B obtained in Preparation Example 3 in H2O, SGF, FaSSIF and FeSSIF was tested at 37°C.

[0252] 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 solid samples after centrifugation were tested for XRPD.

[0253] The results of the dynamic solubility test are shown in the table below:

[0254]

[0255] S: Concentration of the compound shown in Formula I-3B (mg / mL); FC: Crystal form transformation; --: Not tested.

[0256] The results showed that the fumaric acid complex of formula I-3B exhibited good solubility in all solvents. XRPD results are as follows: Figure 6 to Figure 9 As shown, comparing the data at the start of testing, 1 hour, 4 hours, and 24 hours for each sample, it can be seen that the crystalline solid of the fumaric acid complex shown in Formula I-3B did not undergo any crystalline form change in any of the system tests, indicating that it has good stability.

[0257] Example 3: Solid-state stability evaluation experiment

[0258] The crystal samples of the fumaric acid complex of Formula I-3B obtained in Preparation Example 3 were placed at 60°C / closed / 1 day, 25°C / 60%RH / open / 1 week, and 40°C / 75%RH / open / 1 week, respectively, and their physical and chemical stability was evaluated by XRPD and HPLC.

[0259] The purity and stability test data of the samples are as follows:

[0260]

[0261] The HPLC test data of the crystal form of the fumaric acid complex shown in Formula I-3B are as follows:

[0262]

[0263] Note: A relative retention time of 1 min corresponds to the compound shown in sample formula I-3B.

[0264] The XRPD results are listed below.Figure 10 The results showed that all tested crystal forms maintained good purity after a period of storage, with virtually no significant change in HPLC purity. No crystal form changes were observed in any of the tested crystal forms, indicating high stability.

[0265] Example 4: Hygroscopicity Test

[0266] The hygroscopicity of the fumaric acid complex of Formula I-3B obtained in Preparation Example 3 was evaluated using DVS.

[0267] The results showed that the test samples had good hygroscopicity, and the XRPD results of the samples after DVS testing are listed below. Figure 11 In the comparison of data before and after the 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 there was no change in crystal form after the test.

[0268] Example 5: Effect of the fumaric acid complex of Formula I-3B on TNBS-induced acute Crohn's disease (CD) model in rats.

[0269] The fumaric acid complex of Formula I-3B obtained in Preparation Example 3 was verified to significantly improve the intestinal length and weight index, colonic crypt structure damage and regeneration repair in rat CD models, and showed significant therapeutic effect on TNBS-induced rat CD models.

[0270] Example 6: Dissolution Test

[0271] 1. Test subjects: Capsules prepared in Examples 1 and 2.

[0272] 2. Test method: According to the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0931, Method I, for the determination of dissolution and release.

[0273] 3. Test results: as shown in the table below.

[0274]

[0275] Where n=12 indicates that the average value of the dissolution curves was obtained using 12 formulation units. The data show that in pH=1.2 medium, Examples 1-1 (25 mg), 2-1 (5 mg), and 2-2 all exhibited extremely rapid release with a dissolution rate greater than 85% at 15 min; in pH=4.5 medium, Example 1-1 (25 mg) showed rapid release with a dissolution rate greater than 85% at 30 min, while Examples 2-1 and 2-2 (5 mg) showed extremely rapid release; in pH=6.8 medium, Example 1-1 (25 mg) showed rapid release with a dissolution rate greater than 85% at 30 min, while Examples 2-1 and 2-2 (5 mg) showed extremely rapid release.

[0276] Example 7: Stability Test

[0277] The samples from Examples 1 and 2 were placed at 40±2℃ / 75±5%RH for 6 months, 30±2℃ / 65±5%RH for 6 months, and 25±2℃ / 60±5%RH for 6 months, and all tests met the requirements. The results indicate that the product prepared by this invention has good stability.

[0278] Example 8: Canine PK Comparison Test

[0279] 1. Test subjects: API powder (fumaric acid eutectic of compound I-3B obtained in Preparation Example 3) and capsules prepared in Example 1-1.

[0280] 2. Test Methods: Six Beagle dogs weighing 9.08-9.32 kg were randomly divided into two groups: Group 1 received an API aqueous solution, and Group 2 received a formulation capsule, with three dogs in each group. The dogs were administered a single dose of 2.75 mg / kg via gavage or oral administration. The API aqueous solution was prepared using physiological saline as the solvent, with a concentration of 0.5 mg / mL, and the dosage was 2.75 mg / kg. In the formulation capsule group, each dog received 2.75 mg / kg (one capsule). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, and 72 hours after administration to prepare plasma. The concentration of the active ingredient in the plasma was determined by LC-MS-MS to investigate the absorption and exposure of the capsule formulation (the main pharmacokinetic parameter is T). max C max (Compared with AUC) Whether it meets the formulation requirements.

[0281] 3. Test results: As shown in the table below.

[0282]

[0283] The experimental results showed that the peak plasma concentration in dogs after administration of the 25 mg formulation capsules prepared in Example 1-1 was longer than that in the clear aqueous solution of API, but the systemic exposure C was lower. max and AUC 0-last Comparable to the clarified aqueous solution of API.

[0284] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt, characterized in that, It contains an active ingredient and a pharmaceutically acceptable carrier; the content of the active ingredient is 1wt%-50wt%. ； The active ingredient is a compound of formula I-3B or a complex thereof; the complex of the compound of formula I-3B is a complex formed by the compound of formula I-3B and a pharmaceutically acceptable acid.

2. The formulation of a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to 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; and (2) The compound or its complex shown in Formula I-3B is amorphous or crystalline; (3) The preparation is a preparation for treating or preventing 15-PGDH-related diseases; the 15-PGDH-related diseases are preferably idiopathic pulmonary fibrosis, liver regeneration, liver injury or inflammatory bowel disease; the inflammatory bowel disease is preferably 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 preferably selected from one or more of ulcerative proctitis, ulcerative rectosigmoid colitis, left colitis and pancolitis.

3. The formulation of a heterocyclic compound or its complex with a pharmaceutically acceptable salt according to claim 1, characterized in that, The complex of the compound shown in Formula I-3B is a fumaric acid complex of the compound shown in Formula I-3B, wherein the molar ratio of fumaric acid to the compound shown in Formula I-3B is preferably 1:1; more preferably, it is a eutectic of the compound shown in Formula I-3B.

4. A formulation of a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 1 or 3, characterized in that, The complex of the compound shown in Formula I-3B is the crystal form of the fumaric acid complex of the compound shown in Formula I-3B, and satisfies one or more of the following conditions: (1) The crystal form of the fumaric acid complex shown in Formula I-3B, when subjected to Cu-Kα radiation and expressed as 2θ angle X-ray powder diffraction patterns, has diffraction peaks at 20.5±0.2º, 15.9±0.2º, 26.6±0.2º, 18.9±0.2º and 22.5±0.2º; Preferably, the diffraction peaks are present at one or more of the following locations: 22.3±0.2º, 26.4±0.2º, 10.8±0.2º, 17.4±0.2º, and 17.5±0.2º; More preferably, diffraction peaks are present at 20.5±0.2º, 15.9±0.2º, 26.6±0.2º, 18.9±0.2º, 22.5±0.2º, 22.3±0.2º and 26.4±0.2º; More preferably, diffraction peaks are present at 20.5±0.2º, 15.9±0.2º, 26.6±0.2º, 18.9±0.2º, 22.5±0.2º, 22.3±0.2º, 26.4±0.2º, 10.8±0.2º, 17.4±0.2º, and 17.5±0.2º; For example, it has the diffraction peaks shown in the table below: ； For example, its X-ray powder diffraction pattern is shown in Figure 2; (2) The crystal form of the fumaric acid complex shown in Formula I-3B has an endothermic peak starting point at 165.2±3℃ in its differential scanning calorimetry curve; and / or, the endothermic peak can be reached at 167.2±3℃ in its differential scanning calorimetry curve. For example, its differential scanning calorimetry curve is shown in Figure 3; (3) The crystal form of the fumaric acid complex shown in Formula I-3B has a thermogravimetric analysis curve showing a weight loss of 0.36% in the temperature range of 26.2±3℃ to 120℃±3℃; For example, its thermogravimetric analysis curve is shown in Figure 3; (4) 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; a=6.4400(4) Å, α=90°, b=11.9376(8) Å, β=90°, c=33.139(2) Å, γ=90°, unit cell volume=2547.7(3) Å 3 The number of asymmetric units within the unit cell is Z=4, and the crystal density is 1.451 mg / m³. 3 ;and (5) 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.

5. A formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) The content of the active ingredient is 8wt%-10wt%, for example 9wt% or 9.03wt%; (2) The active ingredient has a D90 ≤ 100 μm, for example, D90 = 76.3-87 μm; (3) The pharmaceutically acceptable carrier includes a first filler; the first filler is preferably selected from one or more of microcrystalline cellulose, lactose and pregelatinized starch; the content of the first filler is 5wt%-30wt%, preferably 15wt%-25wt%, for example 20wt%; (4) The pharmaceutically acceptable carrier includes a second filler; the second filler is preferably selected from one or more of mannitol, lactose and pregelatinized starch; the content of the second filler is 10wt%-80wt%, preferably 60wt%-70wt%, for example 61.47wt%, 61.5wt% or 61.97wt%; (5) The pharmaceutically acceptable carrier includes an adhesive; the adhesive is preferably selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone; the content of the adhesive is preferably 1wt%-5wt%, for example 3wt%; (6) The pharmaceutically acceptable carrier may include a disintegrant; the disintegrant is preferably selected from one or more of croscarmellose sodium, croscarmellose, croscarmellose calcium and carboxymethyl starch sodium; the content of the disintegrant is preferably 2wt%-8wt%, for example 5wt%; (7) The pharmaceutically acceptable carrier includes a lubricant; the lubricant is preferably selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, sodium docusate, and calcium stearate; the content of the lubricant is preferably 0.5wt%-2wt%, more preferably 1wt%-2wt%, for example 1wt% or 1.5wt%; and (8) The dosage form of the preparation containing the heterocyclic compound or the complex thereof with a pharmaceutically acceptable salt is a tablet or a capsule.

6. A formulation of a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 5, characterized in that, It satisfies one of the following conditions: (1) It contains the following components in the following amounts: active ingredient 1wt%-50wt%, first filler 5wt%-30wt%, second filler 10wt%-80wt%, binder 1wt%-5wt%, disintegrant 2wt%-8wt%, lubricant 1wt%-2wt%; (2) It contains the following components in the following amounts: 9.03 wt% of fumaric acid eutectic as shown in Formula I-3B, 20 wt% of microcrystalline cellulose, 61.47 wt% of mannitol, 3 wt% of hydroxypropyl cellulose, 5 wt% of croscarmellose sodium, and 1.5 wt% of magnesium stearate; (3) It contains the following components: 9.03 wt% of fumaric acid eutectic, 20 wt% of microcrystalline cellulose, 61.97 wt% of mannitol, 3 wt% of hydroxypropyl cellulose, 5 wt% of croscarmellose sodium, and 1 wt% of magnesium stearate.

7. A method for preparing a formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt as described in any one of claims 1-6, characterized in that, It includes the following steps: S1. Under a first stirring state, the first mixture and the second mixture are mixed to obtain a granulation mixture; the first mixture includes a first filler, a disintegrant, the active ingredient and the second filler, and the second mixture includes a binder and water; S2. The granulation mixture is granulated under a second stirring state, and then dried to obtain dry granules; S3. Fill the hollow capsule with the third mixture; the third mixture includes the lubricant and the dry granules.

8. The method for preparing a formulation containing a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 7, characterized in that, It satisfies one or more of the following conditions: (1) In step S1, the stirring speed in the first stirring state is 100-300 r / min, for example 180 r / min; (2) In step S1, the cutting speed of the first stirring state is 500-2500 r / min, for example 1000 r / min; (3) In step S1, the active ingredient is as defined in any one of claims 1-5; (4) In step S1, the first filler is as defined in claim 5; (5) In step S1, the second filler is as defined in claim 5; (6) In step S1, the disintegrant is as defined in claim 5; (7) In step S1, the adhesive is as defined in claim 5; (8) In step S2, the stirring speed in the second stirring state is 100-300 r / min, for example 200 r / min; (9) In step S2, the cutting speed of the second stirring state is 500-2500 r / min, for example 1500 r / min; (10) In step S2, the granulation time is 0.5-3 min, for example 1 min; (11) In step S2, the drying is carried out using fluidized bed drying; the inlet air temperature of the drying is preferably 50-80℃, for example 65℃; the fluidized air volume of the drying is preferably 20-140 m³ / h. 3 / h; (12) In step S2, the drying process continues until the LOD of the material is ≤3.0%; (13) In step S2, before drying, wet particle sizing can be performed; the wet particle sizing is preferably performed using a 5.0 mm × 5.0 mm sieve; the vibration frequency of the wet particle sizing is preferably 25 ± 10 Hz. (14) In step S2, after drying, dry granulation can be performed; the dry granulation is preferably performed using a 0.8-1.2 mm sieve; for example, using a 1.2 mm and / or 1 mm and / or 0.8 mm sieve; the vibration frequency of the dry granulation is preferably 25±10 Hz; (15) In step S3, the content of the third mixture is determined by HPLC, using C0.05... 22 H 22 Based on F2N6O2, the content is 95.0%-105.0% of the labeled amount; (16) In step S3, the lubricant is as defined in claim 5; (17) In step S3, the amount of filling is 63-77 mg / capsule, preferably 65.1-74.9 mg / capsule or 325.5-374.5 mg / capsule; and (18) In step S3, the filling rate is 5000-20000 particles / hour.

9. Use of a formulation of a heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt as described in any one of claims 1-6, characterized in that, This includes: preparing 15-PGDH inhibitors, and / or preparing medicaments, pharmaceutical compositions or formulations for the prevention and / or treatment of 15-PGDH-related diseases.

10. The use of a formulation of the heterocyclic compound or a complex thereof with a pharmaceutically acceptable salt according to claim 9, characterized in that, The 15-PGDH-related diseases are idiopathic pulmonary fibrosis, liver regeneration, liver injury, or inflammatory bowel disease; the inflammatory bowel disease is preferably 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-related granulomatous colitis; ulcerative colitis is preferably selected from one or more of ulcerative proctitis, ulcerative rectosigmoid colitis, left colitis, and pancolitis.

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