Salts of indole derivatives and their use

Abstract

The present application belongs to the technical field of medicine, and relates to a salt of an indole derivative and use thereof. The present application also relates to a crystal form of the salt, a pharmaceutical composition containing the salt and / or the crystal form thereof, and use of the salt, the crystal form thereof and / or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a disease mediated by PGD2 on a CRTH2 receptor, in particular asthma and allergic rhinitis.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology and relates to salts of indole derivatives and their uses, specifically to salts of 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indole-1-yl)acetic acid, crystal forms of said salts, and pharmaceutical compositions comprising them, and further relates to the uses of said salts, crystal forms of said salts, or pharmaceutical compositions thereof. Background Technology

[0002] CRTH2 is a G protein-coupled chemotactic receptor expressed on Th2 cells and eosinophils. Th2 polarization has been observed in allergic diseases such as asthma, allergic rhinitis, hereditary atopic dermatitis, and allergic conjunctivitis. Th2 cells regulate allergic diseases by producing Th2 cytokines, such as IL-4, IL-5, and IL-13. In allergic diseases, these Th2 cytokines directly or indirectly induce the migration, activation, triggering, and prolonged survival of effector cells, such as eosinophils and basophils.

[0003] PGD2 (prostaglandin D2), a ligand of CRTH2, is produced by mast cells and other important effector cells in allergic diseases. In human cells, PGD2 induces the migration and activation of Th2 cells, eosinophils, and basophils via CRTH2. Therefore, antagonizing PGD2 at the CRTH2 receptor is an attractive approach for treating Th2-dependent allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. CRTH2 receptor antagonists have also been reported to be useful in treating other eosinophil-related diseases, such as allergic granulomatous vasculitis and sinusitis.

[0004] International application WO2016037591A1 discloses a compound with CRTH2 receptor antagonistic activity, 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indol-1-yl)acetic acid (the compound shown in formula (I)) and its crystal form. However, there is no prior art research on the salts of this compound or the crystal forms of its salts.

[0005]

[0006] Different salts and solid forms of a drug's active ingredient may possess different properties. These variations can significantly impact appearance, solubility, melting point, dissolution rate, and bioavailability, and consequently, the drug's stability, bioavailability, and therapeutic efficacy. Therefore, the salt form and / or solid form of a drug should be comprehensively considered during drug development.

[0007] During their research on the compound, the inventors discovered that crystal form I exhibits superior properties compared to other crystal forms. However, all crystal forms, including crystal form I, suffer from poor water solubility and poor drug-forming properties, which is detrimental to drug development. Furthermore, through extensive experimental research, the inventors found that the physicochemical properties of different salts of the compound (I) change significantly after salt formation, with some salts not showing better properties than the free state of the compound. In contrast, the potassium salt of the compound (I) prepared according to the method of this invention exhibits significantly improved physical properties and various characteristics, making it more suitable for formulation development. Summary of the Invention

[0008] This invention provides a salt of the compound shown in formula (I), and studies the preparation method, solid form, physicochemical properties, and pharmacological properties of the salt. It was found that the physicochemical properties of the salts formed by the compound with different inorganic bases vary considerably. Among these, the physicochemical properties of potassium salt crystal form II are superior to those of other salts and other crystal forms. For example, the potassium salt crystal form II obtained by reacting the compound shown in formula (I) with potassium hydroxide exhibits better pharmacokinetic properties than the corresponding potassium salt crystal form I, potassium salt crystal form III, and calcium salt crystal form I. Therefore, the potassium salt crystal form II of this invention has superior properties and better pharmacokinetic properties, thus possessing better drug-like properties.

[0009] Specifically, this invention relates to salts of compounds of formula (I), crystal forms of said salts, and pharmaceutical compositions comprising said salts or crystal forms of said salts, and further to the use of said salts, their crystal forms, and / or pharmaceutical compositions comprising said salts or crystal forms of said salts in the preparation of medicaments for the prevention, treatment, or relief of diseases mediated by PGD2 on the CRTH2 receptor, particularly asthma and allergic rhinitis. The salts of this invention are potassium salts of compounds of formula (I). Further, the salts of this invention are potassium salt crystal form II of compounds of formula (I). The crystal forms of this invention can also be in solvate form, such as hydrate form.

[0010] On the one hand, the present invention provides a salt of the compound shown in formula (I),

[0011]

[0012] In some embodiments, the salt described in this invention is an inorganic alkaline salt.

[0013] In other embodiments, the inorganic alkaline salts described in this invention include, but are not limited to, potassium salts, sodium salts, calcium salts, or magnesium salts.

[0014] In some embodiments, the salt of the compound represented by formula (I) of the present invention is a potassium salt.

[0015] In some embodiments, the salt of the present invention is a potassium salt, wherein the potassium salt is potassium salt crystal form I, and the X-ray powder diffraction pattern of potassium salt crystal form I has diffraction peaks at the following 2θ angles: 5.99°±0.2°, 7.57°±0.2°, 15.88°±0.2°, 16.13°±0.2°, 21.98°±0.2°.

[0016] In some embodiments, the salt of the present invention is a potassium salt, wherein the potassium salt is potassium salt crystal form I, and the X-ray powder diffraction pattern of potassium salt crystal form I has diffraction peaks at the following 2θ angles: 4.84°±0.2°, 5.99°±0.2°, 7.57°±0.2°, 15.55°±0.2°, 15.88°±0.2°, 16.13°±0.2°, 18.86°±0.2°, 20.37°±0.2°, 21.98°±0.2°, 24.74°±0.2°.

[0017] In some embodiments, the salt of the present invention is a potassium salt, wherein the potassium salt is potassium salt crystal form I, and the X-ray powder diffraction pattern of potassium salt crystal form I has diffraction peaks at the following 2θ angles: 4.84°±0.2°, 5.99°±0.2°, 7.57°±0.2°, 7.83°±0.2°, 9.67°±0.2°, 10.15°±0.2°, 10.57°±0.2°, 11. 21°±0.2°, 11.57°±0.2°, 12.14°±0.2°, 12.78°±0.2°, 14.72°±0.2°, 15.05°±0.2°, 15.55°±0.2°, 15.88°±0.2°, 16.13°±0.2°, 17.31°±0.2°, 18.00°±0.2°, 18.20°±0.2°, 18 0.56°±0.2°, 18.86°±0.2°, 19.28°±0.2°, 19.78°±0.2°, 20.37°±0.2°, 20.80°±0.2°, 21.05°±0.2°, 21.41°±0.2°, 21.98°±0.2°, 22.26°±0.2°, 22.72°±0.2°, 23.02°±0.2°, 2 4.05°±0.2°, 24.37°±0.2°, 24.74°±0.2°, 25.24°±0.2°, 25.52°±0.2°, 26.21°±0.2°, 27.84°±0.2°, 28.71°±0.2°, 29.19°±0.2°, 29.60°±0.2°, 29.98°±0.2°, 30.84°±0.2°.

[0018] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form I, and potassium salt crystal form I has substantially the following properties:Figure 1 The X-ray powder diffraction pattern shown.

[0019] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form I, and the differential scanning calorimetry (DSC) of potassium salt crystal form I includes an endothermic peak at 151.98℃±3℃.

[0020] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form I, and potassium salt crystal form I has substantially the following properties: Figure 2 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0021] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form II, and the X-ray powder diffraction pattern of potassium salt crystal form II has diffraction peaks at the following 2θ angles: 13.28°±0.2°, 16.68°±0.2°, 17.77°±0.2°, 18.95°±0.2°, 19.56°±0.2°, 22.03°±0.2°, 29.48°±0.2°.

[0022] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form II, and the X-ray powder diffraction pattern of potassium salt crystal form II has diffraction peaks at the following 2θ angles: 10.61°±0.2°, 13.28°±0.2°, 16.68°±0.2°, 17.13°±0.2°, 17.77°±0.2°, 18.95°±0.2°, 19.56°±0.2°, 22.03°±0.2°, 26.65°±0.2°, 29.48°±0.2°.

[0023] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form II, and the X-ray powder diffraction pattern of potassium salt crystal form II has diffraction peaks at the following 2θ angles: 5.33°±0.2°, 8.92°±0.2°, 9.51°±0.2°, 10.61°±0.2°, 12.46°±0.2°, 13.28°±0.2°, 13.80°±0.2°. °, 14.28°±0.2°, 14.92°±0.2°, 16.07°±0.2°, 16.68°±0.2°, 17.13°±0.2°, 17.77°±0.2°, 18.95°±0.2°, 19.56°±0.2°, 20.12°±0.2°, 21.13°±0.2°, 21.55°±0.2°, 22.03°±0.2°, 22. 95°±0.2°, 23.32°±0.2°, 24.20°±0.2°, 25.07°±0.2°, 26.34°±0.2°, 26.65°±0.2°, 27.17°±0.2°, 27.63°±0.2°, 28.11°±0.2°, 28.65°±0.2°, 29.48°±0.2°, 30.20°±0.2°, 30.66°± 0.2°, 31.01°±0.2°, 31.69°±0.2°, 33.12°±0.2°, 33.51°±0.2°, 34.70°±0.2°, 37.28°±0.2°, 38.33°±0.2°, 39.66°±0.2°, 40.39°±0.2°, 41.12°±0.2°, 41.89°±0.2°, 42.90°±0.2°.

[0024] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form II, and the potassium salt crystal form II has substantially the following properties: Figure 3 The X-ray powder diffraction pattern shown.

[0025] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form II, and the differential scanning calorimetry (DSC) of potassium salt crystal form II includes an endothermic peak at 211.81℃ ± 3℃.

[0026] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form II, and the potassium salt crystal form II has substantially the following properties: Figure 4 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0027] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form II, and the potassium salt crystal form II loses about 0.5943% of its weight when heated to about 138.48°C.

[0028] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form II, and the potassium salt crystal form II has substantially the following properties: Figure 5 The thermogravimetric analysis diagram is shown.

[0029] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form III, and the X-ray powder diffraction pattern of the potassium salt crystal form III has diffraction peaks at the following 2θ angles: 4.79°±0.2°, 6.47°±0.2°, 11.67°±0.2°, 16.76°±0.2°, 21.68°±0.2°.

[0030] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form III, and the X-ray powder diffraction pattern of potassium salt crystal form III has diffraction peaks at the following 2θ angles: 4.79°±0.2°, 6.47°±0.2°, 7.81°±0.2°, 11.67°±0.2°, 13.45°±0.2°, 15.22°±0.2°, 16.76°±0.2°, 19.56°±0.2°, 21.68°±0.2°, 34.13°±0.2°.

[0031] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form III, and the X-ray powder diffraction pattern of potassium salt crystal form III has diffraction peaks at the following 2θ angles: 4.79°±0.2°, 6.47°±0.2°, 7.81°±0.2°, 8.18°±0.2°, 9.44°±0.2°, 10.54°±0.2°, 11.1°. 5°±0.2°, 11.67°±0.2°, 13.45°±0.2°, 14.57°±0.2°, 15.22°±0.2°, 15.79°±0.2°, 16.38°±0.2°, 16.76°±0.2°, 17.88°±0.2°, 18.18°±0.2°, 18.62°±0.2°, 18.81°±0.2°, 19. 56°±0.2°, 20.01°±0.2°, 20.27°±0.2°, 20.51°±0.2°, 20.88°±0.2°, 21.42°±0.2°, 21.68°±0.2°, 22.15°±0.2°, 22.52°±0.2°, 23.38°±0.2°, 24.16°±0.2°, 24.72°±0.2°, 2 5.18°±0.2°, 26.21°±0.2°, 27.64°±0.2°, 28.87°±0.2°, 29.24°±0.2°, 30.02°±0.2°, 30.96°±0.2°, 31.26°±0.2°, 32.43°±0.2°, 32.77°±0.2°, 33.27°±0.2°, 34.13°±0.2°.

[0032] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form III, and the potassium salt crystal form III has substantially the following properties: Figure 6 The X-ray powder diffraction pattern shown.

[0033] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form III, and the differential scanning calorimetry (DSC) of potassium salt crystal form III includes an endothermic peak at 199.81℃±3℃.

[0034] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form III, and the potassium salt crystal form III has substantially the following properties: Figure 7 The differential scanning calorimetry (DSC) heatmap shown is shown.

[0035] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form III, and the potassium salt crystal form III loses 3.571% of its weight when heated to 117.89°C, and loses another 0.8091% of its weight when heated to 206.36°C.

[0036] In some embodiments, the salt of the present invention is a potassium salt, characterized in that the potassium salt is potassium salt crystal form III, and the potassium salt crystal form III has substantially the following properties: Figure 8 The thermogravimetric analysis diagram is shown.

[0037] In some embodiments, the salt of the compound represented by formula (I) of the present invention is a calcium salt.

[0038] In some embodiments, the salt of the present invention is a calcium salt, characterized in that the calcium salt is calcium salt crystal form I, and the X-ray powder diffraction pattern of calcium salt crystal form I has diffraction peaks at the following 2θ angles: 9.69°±0.2°, 15.05°±0.2°, 18.48°±0.2°, 19.47°±0.2°, 19.91°±0.2°.

[0039] In some embodiments, the salt of the present invention is a calcium salt, characterized in that the calcium salt is calcium salt crystal form I, and the X-ray powder diffraction pattern of calcium salt crystal form I has diffraction peaks at the following 2θ angles: 9.69°±0.2°, 10.86°±0.2°, 14.65°±0.2°, 15.05°±0.2°, 18.48°±0.2°, 18.88°±0.2°, 19.47°±0.2°, 19.91°±0.2°, 21.81°±0.2°, 23.48°±0.2°.

[0040] In some embodiments, the salt of the present invention is a calcium salt, characterized in that the calcium salt is calcium salt crystal form I, and the X-ray powder diffraction pattern of calcium salt crystal form I has diffraction peaks at the following 2θ angles: 5.46°±0.2°, 9.69°±0.2°, 10.86°±0.2°, 12.40°±0.2°, 14.65°±0.2°, 15.05°±0.2°, 15.68°±0.2°, 16.37°±0.2°, 16.90°±0.2°, 17.61°±0.2°, 18.00°±0.2°, 18.48°±0.2°, 18.88°±0.2°, 19.47°±0.2°. 2°, 19.91°±0.2°, 20.41°±0.2°, 21.35°±0.2°, 21.81°±0.2°, 22.59°±0.2°, 23.48°±0.2°, 24.10°±0.2°, 24.90°±0.2°, 25.92°±0.2°, 27.07°±0.2°, 27.87°±0.2°, 29.09°±0.2°, 29.47°±0.2°, 31.18°±0.2°, 32.59°±0.2°, 33.08°±0.2°, 33.74°±0.2°, 34.84°±0.2°, 35.66°±0.2°.

[0041] In some embodiments, the salt of the present invention is a calcium salt, characterized in that the calcium salt is calcium salt crystal form I, and calcium salt crystal form I has substantially the following properties: Figure 9 The X-ray powder diffraction pattern shown.

[0042] In some embodiments, the salt of the present invention is a calcium salt, characterized in that the calcium salt is calcium salt crystal form I, and the differential scanning calorimetry (DSC) of calcium salt crystal form I includes endothermic peaks at 111.94℃±3℃ and 204.22℃±3℃.

[0043] In some embodiments, the salt of the present invention is a calcium salt, characterized in that the calcium salt is calcium salt crystal form I, and calcium salt crystal form I has substantially the following properties: Figure 10 The differential scanning calorimeter is shown.

[0044] In some embodiments, the salt of the present invention is a calcium salt, characterized in that the calcium salt is calcium salt crystal form I, and the calcium salt crystal form I loses 3.001% of its weight when heated to 88.54°C, and loses another 3.815% of its weight when heated to 168.04°C.

[0045] In some embodiments, the salt of the present invention is a calcium salt, characterized in that the calcium salt is calcium salt crystal form I, and calcium salt crystal form I has substantially the following properties: Figure 11 The thermogravimetric analysis diagram is shown.

[0046] On the other hand, the present invention relates to a pharmaceutical composition comprising any of the salts described herein, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

[0047] On one hand, the present invention relates to the use of the salt or the pharmaceutical composition thereof in the preparation of a medicament for the prevention, treatment or relief of a disease mediated by PGD2 on the CRTH2 receptor in a patient.

[0048] In some of the described embodiments, the diseases mediated by PGD2 on the CRTH2 receptor described in this invention are asthma, chronic obstructive pulmonary disease, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mast cell hyperplasia, autoimmune diseases, acne, or reperfusion injury.

[0049] In some of the embodiments described herein, the autoimmune disease is psoriasis, multiple sclerosis, allogeneic graft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or osteoarthritis.

[0050] On the other hand, the present invention also relates to a method for preparing a salt of the compound shown in formula (I) or a crystal form thereof.

[0051] The solvents used in the preparation methods of the salts or their crystal forms described in this invention are not particularly limited; any solvent capable of dissolving the starting material to a certain extent without affecting its properties is included in this invention. Furthermore, many similar modifications, equivalent substitutions, or solvents, solvent combinations, and different proportions of solvent combinations described in this invention are considered to be within the scope of this invention. This invention provides preferred solvents for each reaction step.

[0052] The preparation experiments of the salt or its crystal form described in this invention will be described in detail in the Examples section. Simultaneously, this invention provides pharmacological property testing experiments (e.g., pharmacokinetic experiments), solubility experiments, stability experiments, and hygroscopicity experiments for the salt or its crystal form. Experiments have demonstrated that the potassium salt crystal form II described in this invention possesses unexpected technical advantages:

[0053] 1. The potassium salt crystal form II has good stability and water solubility, which can solve the problem of easy discoloration and reduced purity of the free acid of the compound shown in formula (I) when placed.

[0054] 2. Compared to other crystal forms of the potassium salt of the compound shown in formula (I) and / or other salts or crystal forms of the compound shown in formula (I), such as potassium salt crystal form I, potassium salt crystal form III, and / or calcium salt crystal form I, the potassium salt crystal form II has higher blood concentrations and a longer half-life in beagle dogs, thus exhibiting better pharmacokinetic properties.

[0055] Therefore, the potassium salt crystal form II described in this invention has better bioactivity, higher stability, and is more suitable for pharmaceutical applications.

[0056] Definitions and general terms

[0057] Unless otherwise stated, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications related to this invention are incorporated herein by reference in their entirety. Although any methods and substances similar to or identical to those described herein may be used in the practice or testing of this invention, preferred methods, apparatus, and substances are described herein.

[0058] "Crystal form" or "crystalline shape" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs of compounds, solvates, hydrates, inclusion compounds, eutectics, salts, solvates of salts, and hydrates of salts. The crystalline form of a substance can be obtained by many methods known in the art. These methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, such as in nanopores or capillaries, crystallization on a surface or template, such as on a polymer, crystallization in the presence of additives such as co-crystallized antimolecules, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0059] "Amorphous" or "amorphous form" refers to matter formed when its particles (molecules, atoms, ions) are arranged non-periodically in three-dimensional space. It is characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous matter is a special physical form of solid matter; its locally ordered structural features suggest a close connection to crystalline substances. The amorphous form of matter can be obtained through many methods known in the art. These methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, etc.

[0060] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents used in the implementation of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, etc.

[0061] An antisolvent is a fluid that promotes the precipitation of a product (or product precursor) from a solvent. Antisolvents can include cold gases, fluids that promote precipitation through chemical reactions, or fluids that reduce the solubility of a product in a solvent; they can be the same liquid as the solvent but at a different temperature, or they can be a different liquid from the solvent.

[0062] A "solvent" is a compound that has a solvent on its surface, in its crystal lattice, or both on its surface and in its crystal lattice. The solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which water is the solvent on its surface, in its crystal lattice, or both on its surface and in its crystal lattice. A hydrate may or may not have other solvents besides water on its surface, in its crystal lattice, or both on its surface and in its crystal lattice.

[0063] Crystal forms can be identified using a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0064] X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, and crystal structure, and is a commonly used method for identifying crystal forms. The peak positions of XRPD spectra depend primarily on the crystal structure and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal form of the present invention is characterized by an XRPD pattern with certain peak positions, which is essentially as shown in the XRPD patterns provided in the accompanying drawings. Furthermore, the measurement of 2θ in the XRPD spectra can be subject to experimental error; the measurement of 2θ in XRPD spectra may vary slightly between different instruments and different samples, therefore the value of 2θ cannot be considered absolute. Based on the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

[0065] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al₂O₃) as a function of temperature by continuously heating or cooling under programmed control. The height of the endothermic peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details. Therefore, in some embodiments, the crystal form described in this invention is characterized by a DSC plot with characteristic peak positions, which is essentially as shown in the DSC plots provided in the accompanying drawings. However, DSC spectra can be subject to experimental error; the peak positions and peak values ​​may vary slightly between different instruments and different samples. Therefore, the peak positions or peak values ​​of the endothermic peaks in the DSC should not be considered absolute. Depending on the instrument used in this experiment, there is an error tolerance of ±3°C for the endothermic peaks.

[0066] Thermogravimetric analysis (TGA) is a technique used under programmed control to determine the change in mass of a substance with temperature. It is suitable for examining the loss of solvent in crystals or the sublimation and decomposition of samples, and can infer the presence of water of crystallization or crystallization solvent in the crystal. The mass change shown by the TGA curve depends on many factors, including sample preparation and instrumentation; the mass change detected by TGA varies slightly between different instruments and different samples. Based on the instrument used in this experiment, there is an error tolerance of ±0.1% for the mass change.

[0067] In the context of this invention, the 2θ values ​​in X-ray powder diffraction patterns are all in degrees (°).

[0068] The term “basically as shown” means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern, DSC pattern, Raman spectrum, or infrared spectrum are shown in the pattern.

[0069] When referring to a spectrum or / and the data appearing in the graph, a "peak" refers to a feature that a person skilled in the art can identify and that is not attributable to background noise.

[0070] The present invention relates to salts of 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indole-1-yl)acetic acid and / or their crystal forms, which exist in substantially pure crystalline form.

[0071] "Substantially pure" means that a crystal form substantially contains no other crystal forms, i.e., the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, or at least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms whose percentage in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

[0072] "Substantially free of" means that one or more other crystal forms account for less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01% of the total volume or weight of the crystal form.

[0073] In an XRPD diagram, "relative intensity" (or "relative peak height") refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak when the intensity of the first strongest peak in the X-ray powder diffraction pattern is 100%.

[0074] In the context of this invention, when the terms "about" or "approximately" are used, whether or not they are used, it means within 10% of a given value or range, appropriately within 5%, and particularly within 1%. Alternatively, for those skilled in the art, the term "about" or "approximately" means within an acceptable standard error of the average. Whenever a number with a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, or N+ / -10% is explicitly disclosed, where "+ / -" refers to addition or subtraction.

[0075] In this invention, "room temperature" refers to a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, etc.

[0076] Pharmaceutical compositions, formulations, administration and uses of the salt or its crystal form described in this invention.

[0077] The pharmaceutical compositions of the present invention are characterized by salts and / or crystal forms of compounds represented by formula (I) and pharmaceutically acceptable carriers, excipients, or excipients. The amounts of salts or crystal forms of the compounds in the pharmaceutical compositions of the present invention can effectively and detectably treat or alleviate asthma or allergic rhinitis in patients. The pharmaceutical compositions of the present invention may also optionally contain other therapeutic and / or preventative ingredients.

[0078] Suitable carriers, excipients, and formulations are well known to those skilled in the art and described in detail, for example, Ansel HC et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004), Lippincott, Williams & Wilkins, Philadelphia; Gennaro AR et al., Remington: The Science and Practice of Pharmacy (2000), Lippincott, Williams & Wilkins, Philadelphia; and Rowe RC, Handbook of Pharmaceutical Excipients (2005), Pharmaceutical Press, Chicago.

[0079] Those skilled in the art possess the knowledge and skills to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in this invention. Furthermore, numerous resources are available to those skilled in the art describing pharmaceutically acceptable excipients and for selecting suitable ones. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0080] Various carriers for preparing pharmaceutically acceptable compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of which are incorporated herein by reference. The use of any commonly used carriers that are incompatible with the compounds of this invention, except for those that would produce any undesirable biological effects or interact harmfully with any other component of a pharmaceutically acceptable composition, is within the scope of this invention.

[0081] The pharmaceutical compositions of this invention are prepared using techniques and methods known to those skilled in the art. Descriptions of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0082] On the other hand, the present invention relates to a process for preparing pharmaceutical compositions comprising a salt of a compound of the present invention or a crystal form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof, wherein the process includes mixing various components. Pharmaceutical compositions comprising a salt of a compound of the present invention or a crystal form thereof can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

[0083] Salts of the compounds of the present invention or their crystal forms are generally formulated into dosage forms suitable for administration to a patient via the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, sachets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and sachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

[0084] The pharmaceutical compositions provided by this invention can be provided in soft or hard capsules, which can be prepared from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described in this invention, including methylparaben and propylparaben, and sorbic acid. Liquid, semi-solid, and solid dosage forms provided by this invention can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patents US Pat. Nos. 4,328,245; 4,409,239, and 4,410,545. The capsules may also be coated as is known to those skilled in the art, thereby improving or maintaining the dissolution of the active ingredients.

[0085] In one embodiment, the treatment method of the present invention includes administering to a patient in need a safe and effective amount of a salt of the compound of the present invention or a crystalline form thereof, or a pharmaceutical composition comprising a salt of the compound of the present invention or a crystalline form thereof. Various embodiments of the present invention include treating the diseases mentioned in the present invention by administering to a patient in need a safe and effective amount of a salt of the compound of the present invention or a crystalline form thereof, or a pharmaceutical composition comprising a salt of the compound of the present invention or a crystalline form thereof.

[0086] In one embodiment, the salt of the compound of the present invention or its crystalline form, or a pharmaceutical composition comprising the salt of the compound of the present invention or its crystalline form, may be administered via any suitable route of administration, including systemic and local administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Local administration includes application to the skin, as well as intraocular, intravaginal, inhalation, and intranasal administration. In one embodiment, the salt of the compound of the present invention or its crystalline form, or a pharmaceutical composition comprising the salt of the compound of the present invention or its crystalline form, may be administered orally. In another embodiment, the salt of the compound of the present invention or its crystalline form, or a pharmaceutical composition comprising the salt of the compound of the present invention or its crystalline form, may be administered by inhalation. In yet another embodiment, the salt of the compound of the present invention or its crystalline form, or a pharmaceutical composition comprising the salt of the compound of the present invention or its crystalline form, may be administered intranasally.

[0087] In one embodiment, the salt of the compound of the present invention or its crystalline form, or a pharmaceutical composition comprising the salt of the compound of the present invention or its crystalline form, may be administered once, or, depending on the dosing regimen, several times at different time intervals within a specified period. For example, once, twice, three times, or four times daily. In one embodiment, it is administered once daily. In yet another embodiment, it is administered twice daily. The administration may continue until the desired therapeutic effect is achieved or to maintain the desired therapeutic effect indefinitely. A suitable dosing regimen for the salt of the compound of the present invention or its crystalline form, or a pharmaceutical composition comprising the salt of the compound of the present invention or its crystalline form, depends on the pharmacokinetic properties of the salt of the compound, such as absorption, distribution, and half-life, which can be determined by a person skilled in the art. Furthermore, a suitable dosing regimen for the salt of the compound of the present invention or its crystalline form, or a pharmaceutical composition comprising the salt of the compound of the present invention or its crystalline form, includes the duration of administration, depending on factors within the knowledge and experience of a person skilled in the art, such as the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the patient's medical history, the nature of concurrent therapies, and the desired therapeutic effect. Such technicians should also understand that they may request adjustments to the dosing regimen as needed to address individual patient responses to the regimen or as individual patient needs may change over time.

[0088] The salts or crystal forms of the compounds of the present invention may be administered simultaneously with, before or after one or more other therapeutic agents. The salts or crystal forms of the compounds of the present invention may be administered separately to other therapeutic agents via the same or different routes of administration, or administered with them in the same pharmaceutical composition.

[0089] Salts of the compounds of the present invention or their crystal forms can be used in combination with drugs for treating diseases and conditions mediated by PGD2 on the CRTH2 receptor, i.e., forming drug combinations as described in the present invention, such as: salmeterol, fluticasone, loratadine, montelukast, omalizumab, fusidic acid, clotrimazole, tacrolimus, pimecrolimus, DP antagonists, sillosterol, TNF-α converting enzyme (TACE) inhibitors, IL-4 or IL-5 blocking monoclonal antibodies, soluble receptors for IL-4 or IL-5 and zileutone, and their salts and combinations, etc., or salts of the compounds of the present invention or their crystal forms can be administered in combination with physical methods such as phototherapy or electrical stimulation.

[0090] For an individual weighing approximately 50-70 kg, the pharmaceutical compositions and combinations of the present invention may be in unit dose form containing approximately 1-1000 mg or a suitable dose of active ingredient. The therapeutically effective amount of the compound, salt of the compound, pharmaceutical composition, or combination thereof depends on the individual's species, weight, age, individual condition, the disease or disorder being treated, or its severity. A physician, clinician, or veterinarian with common skills can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the development of a disease or disorder.

[0091] The dosage characteristics cited above have been confirmed in in vitro and in vivo studies using favorable mammals (e.g., mice, rats, dogs, monkeys) or their ex vivo organs, tissues and specimens.

[0092] In one embodiment, the amount of the compound in a therapeutically effective dose of the salt of the compound of the present invention is from about 0.1 mg to about 2,000 mg per day. The pharmaceutical composition thereof should provide a dose of the compound from about 0.1 mg to about 2,000 mg. In a particular embodiment, the prepared pharmaceutical dosage unit form provides about 1 mg to about 2,000 mg, about 10 mg to about 1,000 mg of the main active ingredient, or a combination of the main ingredients per dosage unit form.

[0093] The salts of the compounds provided by this invention or their crystal forms and pharmaceutical compositions can be used to prepare medicaments for the prevention, treatment or relief of asthma and allergic rhinitis in mammals, including humans, and can also be used to prepare medicaments for the prevention, treatment or relief of diseases mediated by PGD2 on the CRTH2 receptor in mammals, including humans.

[0094] Specifically, the amount of the compound in the pharmaceutical composition of the present invention can effectively and detectably antagonize PGD2 on the CRTH2 receptor, and the salt of the compound of the present invention or its crystal form can be used as a drug for treating diseases mediated by PGD2 on the CRTH2 receptor, such as asthma and allergic rhinitis.

[0095] Salts of the compounds of the present invention or their crystal forms may be used, but are not limited to, administering effective amounts of salts of the compounds of the present invention or their crystal forms, or pharmaceutical compositions to patients to prevent, treat, or alleviate diseases mediated by PGD2 on the CRTH2 receptor. The diseases mediated by PGD2 on the CRTH2 receptor include asthma, chronic obstructive pulmonary disease, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity reactions, conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mast cell hyperplasia, autoimmune diseases, acne, or reperfusion injury; wherein, the autoimmune diseases include psoriasis, multiple sclerosis, allogeneic graft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or osteoarthritis.

[0096] The “effective amount” or “effective dose” of a salt of the compound of the present invention or its crystalline form or pharmaceutically acceptable composition refers to an effective amount for treating or reducing the severity of one or more of the conditions mentioned in the present invention. According to the method of the present invention, a salt of the compound of the present invention or its crystalline form or pharmaceutically acceptable composition can be administered at any dosage and via any route of administration to effectively treat or reduce the severity of the disease. The precise amount required will vary depending on the patient’s condition, which depends on race, age, the patient’s general condition, the severity of the infection, specific factors, route of administration, etc. A salt of the compound of the present invention or its crystalline form or pharmaceutically acceptable composition can be administered in combination with one or more other therapeutic agents, as discussed in the present invention.

[0097] The salts or crystal forms of the compounds of this invention, as well as pharmaceutical compositions, are beneficial not only for human treatment but also for veterinary treatment of mammals, including pets, introduced breeds of animals, and farm animals. Other examples of animals include horses, dogs, and cats. Attached Figure Description

[0098] Figure 1 The image shows the X-ray powder diffraction (XRPD) pattern of the potassium salt crystal form I of the compound shown in formula (I).

[0099] Figure 2 The differential scanning calorimetry (DSC) curve is shown for potassium salt crystal form I of the compound represented by formula (I).

[0100] Figure 3 The image shows the X-ray powder diffraction (XRPD) pattern of potassium salt crystal form II of the compound shown in formula (I).

[0101] Figure 4 The differential scanning calorimetry (DSC) curve is shown for potassium salt crystal form II of the compound represented by formula (I).

[0102] Figure 5The thermogravimetric analysis (TGA) diagram is shown for potassium salt crystal form II of the compound represented by formula (I).

[0103] Figure 6 The image shows the X-ray powder diffraction (XRPD) pattern of the potassium salt crystal form III of the compound shown in formula (I).

[0104] Figure 7 The differential scanning calorimetry (DSC) curve is shown for potassium salt crystal form III of the compound represented by formula (I).

[0105] Figure 8 The thermogravimetric analysis (TGA) diagram is shown for potassium salt crystal form III of the compound represented by formula (I).

[0106] Figure 9 The image shows the X-ray powder diffraction (XRPD) pattern of the calcium salt crystal form I of the compound shown in formula (I).

[0107] Figure 10 The differential scanning calorimetry (DSC) curve is shown for the calcium salt crystal form I of the compound represented by formula (I).

[0108] Figure 11 The thermogravimetric analysis (TGA) diagram is shown for calcium salt crystal form I of the compound represented by formula (I). Detailed Implementation

[0109] The present invention will be further illustrated by way of embodiments below, but the invention is not limited to the scope of the embodiments described herein.

[0110] The X-ray powder diffraction analysis method used in this invention is as follows: An Empyrean diffractometer was used to obtain X-ray powder diffraction patterns using Cu-Kα radiation (45 kV, 40 mA). The powdered sample was prepared into a thin layer on a single-crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.0167° steps within the range of 3°–60°. Data was collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

[0111] The differential scanning calorimetry (DSC) analysis method used in this invention is as follows: Differential scanning calorimetry is performed using a TA Q2000 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample is accurately weighed into a specially designed aluminum crucible with a lid, and sample analysis is performed using a linear heating device at 10 °C / min, from room temperature to approximately 300 °C. During use, the DSC chamber is purged with dry nitrogen.

[0112] The thermogravimetric analysis (TGA) method used in this invention is as follows: Thermogravimetric analysis is performed using a TA Q500 module with a thermal analysis controller. Data is collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10-30 mg of sample is placed in a platinum crucible and analyzed from room temperature to approximately 300°C using a linear heating device at 10°C / min. During use, the TGA chamber is purged with dry nitrogen.

[0113] The solubility of this invention was determined using an Agilent 1200 high-performance liquid chromatograph with a DAD / VWD detector and an Agilent XDB-C18 column (4.6 × 50 mm, 5 μm). The detection wavelength was 266 nm, the flow rate was 1.0 mL / min, the column temperature was 35 °C, the mobile phase A was acetonitrile / 0.01 M ammonium acetate = 10 / 90 (V / V), the analytical method was acetonitrile / mobile phase A = 70 / 30 (V / V), and the run time was 10 minutes.

[0114] The hygroscopicity of this invention was measured using a DVS INT-Std dynamic moisture and gas adsorption analyzer from Surface Measurement Systems, UK. The humidity test range was 0%-95%, the airflow was 200 mL / min, the temperature was 25°C, and the test point was one point for every 5% humidity.

[0115] Specific implementation methods

[0116] Comparative Examples

[0117] Through experiments, the inventors discovered that, compared to other crystal forms disclosed in prior art WO2016037591A1, crystal form I of the compound shown in formula (I) (2-(5-fluoro-3-(1-(((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indol-1-yl)acetic acid) is more stable and has superior pharmacokinetic properties. Therefore, in this invention, the inventors selected crystal form I of various compounds shown in formula (I) with superior properties as reference standards to study the salts and crystal forms of the compounds shown in formula (I). Specifically, the synthesis method of crystal form I of the compound shown in formula (I) is based on Example 24 in international application WO2016037591A1.

[0118] Example

[0119] Example 1 Potassium Salt Crystal Form I

[0120] 1. Preparation of potassium salt crystal form I

[0121] Compound I (51.8 mg, 0.11 mmol) and potassium isooctanoate (21.8 mg, 0.117 mmol) of formula (I) were added to methanol (1.0 mL), heated to 60 °C and stirred for 3.5 h, then allowed to cool naturally to room temperature. The mixture was filtered, and the filter cake was dried under vacuum at 60 °C overnight to obtain a white solid (29.7 mg, 55.5%).

[0122] 2. Identification of Potassium Salt Crystal Form I

[0123] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 4.84°, 5.99°, 7.57°, 7.83°, 9.67°, 10.15°, 10.57°, 11.21°, 11.57°, 12.14°, 12.78°, 14.72°, 15.05°, 15.55°, 15.88°, 16.13°, 17.31°, 18.00°, 18.20°, 18.5°. The XRPD patterns of potassium salt crystal form I prepared according to the method of Example 1 of the present invention are basically as follows: 6°, 18.86°, 19.28°, 19.78°, 20.37°, 20.80°, 21.05°, 21.41°, 21.98°, 22.26°, 22.72°, 23.02°, 24.05°, 24.37°, 24.74°, 25.24°, 25.52°, 26.21°, 27.84°, 28.71°, 29.19°, 29.60°, 29.98° and 30.84°, with an error tolerance of ±0.2°. Figure 1 As shown.

[0124] (2) Differential scanning calorimetry (DSC) analysis using a TA Q2000 revealed a scan rate of 10 °C / min, including an endothermic peak at 151.98 °C, with an error tolerance of ±3 °C. The DSC chromatogram of potassium salt crystal form I prepared according to the method of Example 1 of this invention is essentially as follows: Figure 2 As shown.

[0125] Example 2 Potassium Salt Crystal Form II

[0126] 1. Preparation of potassium salt crystal form II

[0127] At room temperature, crystalline form I of compound (I) (6004.3 mg, 12.74 mmol) was added to ethanol (60.0 mL) and stirred for 40 min. Then, a solution of potassium hydroxide (856 mg, 12.97 mmol) in ethanol (20.0 mL) was added, producing a large amount of solid. Ethanol (20.0 mL) was added, and the mixture was stirred overnight to induce crystallization. The mixture was filtered, and the filter cake was dried under vacuum at 60 °C for 2 days to obtain a white solid (5049.7 mg, 81.44%).

[0128] 2. Identification of Potassium Salt Crystal Form II

[0129] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 5.33°, 8.92°, 9.51°, 10.61°, 12.46°, 13.28°, 13.80°, 14.28°, 14.92°, 16.07°, 16.68°, 17.13°, 17.77°, 18.95°, 19.56°, 20.12°, 21.13°, 21.55°, 22.03°, 22.95°. The XRPD patterns of potassium salt crystal form II prepared by the method of Example 2 of this invention are basically as follows: 23.32°, 24.20°, 25.07°, 26.34°, 26.65°, 27.17°, 27.63°, 28.11°, 28.65°, 29.48°, 30.20°, 30.66°, 31.01°, 31.69°, 33.12°, 33.51°, 34.70°, 37.28°, 38.33°, 39.66°, 40.39°, 41.12°, 41.89°, 42.90°, with an error tolerance of ±0.2°. Figure 3 As shown.

[0130] (2) Differential scanning calorimetry (DSC) analysis using a TA Q2000 revealed a scan rate of 10 °C / min, including an endothermic peak at 211.81 °C, with an error tolerance of ±3 °C. The DSC chromatogram of potassium salt crystal form II prepared according to the method of Example 2 of this invention is essentially as follows: Figure 4 As shown.

[0131] (3) Thermogravimetric analysis (TGA) using a TA Q500 was performed: at a heating rate of 10 °C / min, the weight loss was 0.5943% when heated to 138.48 °C. The TGA chart of potassium salt crystal form II prepared according to the method of Example 2 of this invention is basically as follows. Figure 5 As shown.

[0132] Example 3 Potassium Salt Crystal Form III

[0133] 1. Preparation of potassium salt crystal form III

[0134] The crystalline form I of the compound shown in formula (I) (6.01 g, 12.75 mmol) was added to isopropanol (50.0 mL), heated to 85 °C and stirred. Then, a solution of potassium hydroxide (860.0 mg, 13.03 mmol) in ethanol (8.0 mL) was added, and the mixture was stirred for 5 h. The mixture was then allowed to cool naturally to room temperature. The mixture was filtered, and the filter cake was dried under vacuum at 60 °C overnight to obtain a white solid (5.65 g, 91.1%).

[0135] 2. Identification of Potassium Salt Crystal Form III

[0136] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, were observed: 4.79°, 6.47°, 7.81°, 8.18°, 9.44°, 10.54°, 11.15°, 11.67°, 13.45°, 14.57°, 15.22°, 15.79°, 16.38°, 16.76°, 17.88°, 18.18°, 18.62°, 18.81°, 19.56°. The XRPD patterns of potassium salt crystal form III prepared according to the method of Example 3 of this invention are basically as follows: 20.01°, 20.27°, 20.51°, 20.88°, 21.42°, 21.68°, 22.15°, 22.52°, 23.38°, 24.16°, 24.72°, 25.18°, 26.21°, 27.64°, 28.87°, 29.24°, 30.02°, 30.96°, 31.26°, 32.43°, 32.77°, 33.27°, and 34.13°, with an error tolerance of ±0.2°. Figure 6 As shown.

[0137] (2) Differential scanning calorimetry (DSC) analysis using a TA Q2000 revealed a scan rate of 10 °C / min, including an endothermic peak at 199.81 °C, with an error tolerance of ±3 °C. The DSC chromatogram of potassium salt crystal form III prepared according to the method of Example 3 of this invention is essentially as follows: Figure 7 As shown.

[0138] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: at a heating rate of 10℃ / min, the weight loss was 3.571% when heated to 117.89℃, and another 0.8091% when heated to 206.36℃. The TGA chart of potassium salt crystal form III prepared according to the method of Example 3 of this invention is basically as follows. Figure 8 As shown.

[0139] Example 4 Calcium Salt Crystal Form I

[0140] 1. Preparation of calcium salt crystal form I

[0141] Method 1: At room temperature, 503 mg (1.067 mmol) of the compound in crystal form I of formula (I) was added to 1.0 mL of ethanol and stirred for 40 min. Then, 0.5 mL of water solution containing calcium hydroxide suspension (44.8 mg, 0.574 mmol) was added, and a large amount of solid precipitated. 10.0 mL of ethanol was added and the mixture was stirred overnight. The mixture was filtered and dried under vacuum at 60 °C overnight to obtain a white solid (500 mg, 50.1%).

[0142] Method 2: The potassium salt crystal form III of the compound shown in formula (I) (101.2 mg, 0.21 mmol) was added to isopropanol (1.0 mL), stirred at 60 °C for 0.5 h, and then a water solution of calcium chloride (12.8 mg, 0.113 mmol) (1.0 mL) was added, resulting in the precipitation of a large amount of solid. Water (2.0 mL) was added, and the mixture was kept warm and stirred for 3 h before naturally cooling to room temperature. The mixture was filtered, and the filter cake was washed with water (2.0 mL × 2), and dried under vacuum at 80 °C overnight to obtain a white solid (53.4 mg, 27.7%).

[0143] 2. Identification of calcium salt crystal form I

[0144] (1) Identification by Empyrean X-ray powder diffraction (XRPD): Using Cu-Kα radiation, the following characteristic peaks, expressed in terms of angle 2θ, are observed: 5.46°, 9.69°, 10.86°, 12.40°, 14.65°, 15.05°, 15.68°, 16.37°, 16.90°, 17.61°, 18.00°, 18.48°, 18.88°, 19.47°, 19. The XRPD patterns of calcium salt crystal form I prepared according to the method of Example 4 of the present invention are basically as follows: 91°, 20.41°, 21.35°, 21.81°, 22.59°, 23.48°, 24.10°, 24.90°, 25.92°, 27.07°, 27.87°, 29.09°, 29.47°, 31.18°, 32.59°, 33.08°, 33.74°, 34.84° and 35.66°, with an error tolerance of ±0.2°. Figure 9 As shown.

[0145] (2) Differential scanning calorimetry (DSC) analysis using a TA Q2000 revealed endothermic peaks at a scan rate of 10 °C / min, with a tolerance of ±3 °C. The DSC chromatogram of calcium salt crystal form I prepared according to the method of Example 4 of this invention is essentially as follows: Figure 10 As shown.

[0146] (3) Thermogravimetric analysis (TGA) was performed using a TA Q500: at a heating rate of 10℃ / min, the weight loss was 3.001% when heated to 88.54℃, and another 3.815% weight loss was observed when heated further to 168.04℃. The TGA chart of calcium salt crystal form I prepared according to the method of Example 4 of this invention is basically as follows. Figure 11 As shown.

[0147] Example 5: Pharmacokinetic experiment of the salt or its crystal form described in this invention.

[0148] The test sample (i.e., the salt of the present invention or its crystal form, or the crystal form I of the compound shown in formula (I) of the present invention as a control example) is filled into capsules for oral administration.

[0149] Male Beagle dogs weighing 8-12 kg were divided into 6 groups of 3 dogs each. Each dog was orally administered capsules containing the test sample at a dose of 5 mg / kg. Blood samples were collected at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24 hours. A standard curve was established based on the sample concentration. The concentration of the test sample in plasma samples was determined using an AB SCIEX API4000 LC-MS / MS in MRM mode, and quantitative analysis was performed. Pharmacokinetic parameters were calculated using the non-compartmental model method in WinNonLin 6.3 software based on the drug concentration-time curve. The experimental results are shown in Table 1.

[0150] Table 1 Pharmacokinetic Experimental Data

[0151] Test sample <![CDATA[C max (ng / ml)]]> <![CDATA[T 1 / 2 (h)]]> <![CDATA[T max (h)]]> Example 2 7120 8.49 1.0 Example 4 995 6.87 1.33 Comparative Examples 5800 5.15 2.0

[0152] Experimental conclusion:

[0153] As shown in Table 1, compared with the crystal form I of the compound shown in Formula (I) and the calcium salt crystal form I of the compound shown in Formula (I), the potassium salt crystal form II of the present invention has a higher blood concentration and a longer half-life in beagle dogs, and has better pharmacokinetic properties.

[0154] Example 6: Stability experiment of the salt or its crystal form described in this invention.

[0155] High temperature experiment Take an appropriate amount of a batch of test samples and place them in a flat weighing bottle, spread them into a thin layer ≤5mm thick, and place them at 40℃ and RH75% for 32 days. Take samples on the 5th, 11th and 32nd days to test the stability of key test items.

[0156] High humidity experiment:Take an appropriate amount of a batch of test samples and place them in a flat weighing bottle, spread them into a thin layer ≤5mm thick, and place them at 25℃ and RH 90%±5% for 32 days. Take samples on the 5th, 11th and 32nd days to test the stability of key test items.

[0157] Experiments show that under high temperature and high humidity conditions, the appearance and purity of the salt or its crystal form described in this invention do not change significantly, and it has good stability, making it suitable for pharmaceutical applications.

[0158] Example 7 Hygroscopicity test of the salt or its crystal form described in this invention

[0159] A suitable amount of the test sample was taken, and its hygroscopicity was tested using a dynamic moisture adsorption instrument. The experiment showed that the salt or its crystal form described in this invention is not easily deliquescent due to high humidity.

[0160] Example 8: Solubility test of the salt or its crystal form described in this invention.

[0161] The test sample was dissolved in water at 37°C to prepare a supersaturated turbid solution. After shaking for 24 hours, the solution was filtered, and the filtrate was collected. The solubility of the target sample in water was determined by HPLC. The experiment showed that the salt or its crystal form described in this invention has high solubility in water, thus exhibiting good drug-like properties and being suitable for formulation development.

[0162] The above description is merely a basic explanation of the concept of this invention, and any equivalent modifications made based on the technical solution of this invention shall fall within the protection scope of this invention.

[0163] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0164] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. Salts of the compound shown in formula (I), Its features are, The salt mentioned is a potassium salt. The potassium salt is potassium salt crystal form II, and the X-ray powder diffraction pattern of potassium salt crystal form II has diffraction peaks at the following 2θ angles: 13.28°±0.2°, 16.68°±0.2°, 17.77°±0.2°, 18.95°±0.2°, 19.56°±0.2°, 22.03°±0.2°, 29.48°±0.2°.

2. The salt according to claim 1, characterized in that, The potassium salt is potassium salt crystal form II, and the X-ray powder diffraction pattern of potassium salt crystal form II has diffraction peaks at the following 2θ angles: 10.61°±0.2°, 13.28°±0.2°, 16.68°±0.2°, 17.13°±0.2°, 17.77°±0.2°, 18.95°±0.2°, 19.56°±0.2°, 22.03°±0.2°, 26.65°±0.2°, 29.48°±0.2°.

3. The salt according to claim 1 or 2, characterized in that, The potassium salt is potassium salt crystal form II, and the X-ray powder diffraction pattern of potassium salt crystal form II has diffraction peaks at the following 2θ angles: 5.33°±0.2°, 8.92°±0.2°, 9.51°±0.2°, 10.61°±0.2°, 12.46°±0.2°, 13.28°±0.2°, 13.80°±0.2°, 14.28°±0.2°, 14.92° ±0.2°, 16.07°±0.2°, 16.68°±0.2°, 17.13°±0.2°, 17.77°±0.2°, 18.95°±0.2°, 19.56°±0.2°, 20.12°±0.2°, 21.13°±0.2°, 21.55°±0.2°, 22.03°±0.2°, 22.95°±0.2°, 23.3 2°±0.2°, 24.20°±0.2°, 25.07°±0.2°, 26.34°±0.2°, 26.65°±0.2°, 27.17°±0.2°, 27.63°±0.2°, 28.11°±0.2°, 28.65°±0.2°, 29.48°±0.2°, 30.20°±0.2°, 30.66°±0.2°, 31 0.01°±0.2°, 31.69°±0.2°, 33.12°±0.2°, 33.51°±0.2°, 34.70°±0.2°, 37.28°±0.2°, 38.33°±0.2°, 39.66°±0.2°, 40.39°±0.2°, 41.12°±0.2°, 41.89°±0.2°, 42.90°±0.2°.

4. The salt according to claim 1, characterized in that, The potassium salt is potassium salt crystal form II, which has an X-ray powder diffraction pattern substantially as shown in Figure 3.

5. The salt according to claim 1, characterized in that, The potassium salt is potassium salt crystal form II, and the differential scanning calorimetry (DSC) of potassium salt crystal form II includes an endothermic peak at 211.81℃ ± 3℃.

6. The salt according to claim 5, characterized in that, The potassium salt is potassium salt crystal form II, which has a differential scanning calorimeter essentially as shown in FIG4.

7. A pharmaceutical composition comprising the salt of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

8. Use of the salt of any one of claims 1-6 or the pharmaceutical composition of claim 7 in the preparation of a medicament for the prevention, treatment or relief of a disease mediated by PGD2 on the CRTH2 receptor.

9. The use according to claim 8, wherein, The diseases mediated by PGD2 on the CRTH2 receptor include asthma, chronic obstructive pulmonary disease, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mast cell hyperplasia, autoimmune diseases, acne, or reperfusion injury.

10. The use according to claim 9, wherein, The autoimmune diseases mentioned are psoriasis, multiple sclerosis, allogeneic graft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or osteoarthritis.

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