Salts of indole derivatives and uses thereof

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to salts of indole derivatives and uses thereof. The present invention also relates to crystalline forms of the salts, pharmaceutical compositions comprising the salts and / or their crystalline forms, and the use of the salts, their crystalline forms, and / or their pharmaceutical compositions in the preparation of medicaments for preventing, treating, or allergic diseases mediated by PGD2 on CRTH2 receptors, particularly asthma and allergic rhinitis.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to salts of indole derivatives and uses thereof, and specifically to salts of 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indol-1-yl)acetic acid, crystal forms of the salts, and pharmaceutical compositions containing the same, and further relates to uses of the salts, crystal forms of the salts, or pharmaceutical compositions. Background Art

[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, 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 for 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 through 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. There are reports that CRTH2 receptor antagonists are also useful in treating other eosinophil-related diseases, such as allergic granulomatosis with polyangiitis and sinusitis.

[0004] International application WO2016037591A1 discloses a compound, 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indol-1-yl)acetic acid (compound represented by formula (I)), which exhibits CRTH2 receptor antagonist activity and its crystalline forms. However, no prior art studies have examined the salts of this compound or their crystalline forms.

[0005]

[0006] Different salts and solid forms of active pharmaceutical ingredients may exhibit distinct properties. These salts and solid forms may significantly differ in appearance, solubility, melting point, dissolution rate, and bioavailability, and may also have varying effects on drug stability, bioavailability, and efficacy. Therefore, comprehensive consideration of the salt and / or solid form of a drug should be considered during drug development.

[0007] While researching this compound, the inventors discovered that the compound and its crystalline form had poor water solubility and poor drugability, necessitating the search for a solid form with improved drugability. Through extensive experimental research, the inventors discovered that after the compound represented by formula (I) is formed into salts, the physical and chemical properties of different salts vary significantly, with some salts not performing better than the free form. However, the triethanolamine salt of the compound represented by formula (I), prepared according to the method of the present invention, exhibits significantly improved physical and chemical properties, making it more suitable for formulation development. Summary of the Invention

[0008] The present invention provides salts of a compound represented by formula (I), and studies have been conducted on the preparation methods, solid forms, physicochemical properties, and pharmacological properties of the salts. It has been found that the physicochemical properties of the salts formed by the compound with different organic bases vary significantly; among them, the triethanolamine salt exhibits superior physicochemical properties compared to other salts. For example, the triethanolamine salt crystalline form I obtained by salifying the compound represented by formula (I) with triethanolamine exhibits superior pharmacokinetic properties compared to the corresponding diethylamine salt crystalline form I, diethanolamine salt crystalline form I, ethylenediamine salt crystalline form I, and tromethamine salt crystalline form I. Therefore, the triethanolamine salt crystalline form I of the present invention exhibits superior properties, including better pharmacokinetic properties, and thus has superior drugability.

[0009] Specifically, the present invention relates to a salt of a compound represented by formula (I), a crystalline form of the salt, and a pharmaceutical composition comprising the salt or the crystalline form of the salt, and further relates to the use of the salt, its crystalline form, and / or the pharmaceutical composition in the preparation of a medicament for preventing, treating, or allergic rhinitis in patients with diseases mediated by PGD2 on the CRTH2 receptor. The salt of the present invention is a triethanolamine salt of the compound represented by formula (I). Furthermore, the salt of the present invention is a triethanolamine salt crystalline form I of the compound represented by formula (I). The crystalline form of the present invention may also be in the form of a solvate, such as a hydrate.

[0010] In one aspect, the present invention provides a salt of a compound represented by formula (I),

[0011]

[0012] In some embodiments, the salts described herein are organic base salts.

[0013] In other embodiments, the organic base salts of the present invention include, but are not limited to, triethanolamine salts, diethylamine salts, diethanolamine salts, ethylenediamine salts, or tromethamine salts.

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

[0015] In some embodiments, the salt described in the present invention is a triethanolamine salt, and the triethanolamine salt is triethanolamine salt crystalline form I. The X-ray powder diffraction pattern of the triethanolamine salt crystalline form I has diffraction peaks at the following 2θ angles: 14.39°±0.2°, 18.71°±0.2°, 19.71°±0.2°, 20.40°±0.2°, 21.34°±0.2°, 24.22°±0.2°, 25.49°±0.2°.

[0016] In some embodiments, the salt described in the present invention is a triethanolamine salt, characterized in that the triethanolamine salt is triethanolamine salt crystalline form I, and the X-ray powder diffraction pattern of the triethanolamine salt crystalline form I has diffraction peaks at the following 2θ angles: 14.39°±0.2°, 15.01°±0.2°, 16.19°±0.2°, 18.71°±0.2°, 19.71°±0.2°, 20.40°±0.2°, 21.34°±0.2°, 24.22°±0.2°, 25.49°±0.2°, 30.90°±0.2°.

[0017] In some embodiments, the salt of the present invention is a triethanolamine salt, characterized in that the triethanolamine salt is triethanolamine salt crystalline form I, and the X-ray powder diffraction pattern of the triethanolamine salt crystalline form I has diffraction peaks at the following 2θ angles: 5.46°±0.2°, 10.30°±0.2°, 11.90°±0.2°, 12.36°±0.2°, 13.07°±0.2°, 14.39°±0.2°, 15.01°± 0.2°,16.19°±0.2°,18.19°±0.2°,18.71°±0.2°,19.71°±0.2°,20.40°±0.2°,21.34°±0.2°,21.63°±0.2°,21.95°±0.2°,22.53°±0.2°,23.11°±0.2°,23.86°±0.2°,24.22°±0.2°,24.76°±0. 2°,25.49°±0.2°,26.19°±0.2°,27.07°±0.2°,27.67°±0.2°,28.15°±0.2°,28.91°±0.2°,29.27°±0.2°,29.63°±0.2°,30.00°±0.2°,30.90°±0.2°,32.03°±0.2°,32.25°±0.2°,32.61°±0.2 °,33.73°±0.2°,34.04°±0.2°,36.04°±0.2°,37.14°±0.2°,37.65°±0.2°,40.32°±0.2°,41.65°±0.2°,43.25°±0.2°,43.80°±0.2°,45.06°±0.2°,45.83°±0.2°,48.04°±0.2°,49.66°±0.2°.

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

[0019] In some embodiments, the salt described in the present invention is a triethanolamine salt, characterized in that the triethanolamine salt is triethanolamine salt crystal form I, and the differential scanning calorimetry diagram of the triethanolamine salt crystal form I comprises an endothermic peak at 178.24°C±3°C.

[0020] In some embodiments, the salt of the present invention is a triethanolamine salt, characterized in that the triethanolamine salt is a triethanolamine salt crystalline form I, and the triethanolamine salt crystalline form I has substantially the following Figure 2 Differential scanning calorimetry diagram shown.

[0021] In some embodiments, the salt of the present invention is a triethanolamine salt, characterized in that the triethanolamine salt is triethanolamine salt crystal form I, and when the triethanolamine salt crystal form I is heated to about 133.18° C., it loses about 0.01193% of its weight.

[0022] In some embodiments, the salt of the present invention is a triethanolamine salt, characterized in that the triethanolamine salt is a triethanolamine salt crystalline form I, and the triethanolamine salt crystalline form I has substantially the following Figure 3 Thermogravimetric analysis diagram shown.

[0023] In some embodiments, the salt of the compound represented by formula (I) of the present invention is an ethylenediamine salt.

[0024] In some embodiments, the salt described in the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is ethylenediamine salt crystal form I, and the X-ray powder diffraction pattern of the ethylenediamine salt crystal form I has diffraction peaks at the following 2θ angles: 12.19°±0.2°, 15.94°±0.2°, 20.60°±0.2°, 23.91°±0.2°, 29.09°±0.2°.

[0025] In some embodiments, the salt described in the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is ethylenediamine salt crystal form I, and the X-ray powder diffraction pattern of the ethylenediamine salt crystal form I has diffraction peaks at the following 2θ angles: 12.19°±0.2°, 15.94°±0.2°, 18.63°±0.2°, 20.60°±0.2°, 21.00°±0.2°, 21.30°±0.2°, 23.38°±0.2°, 23.91°±0.2°, 28.19°±0.2°, 29.09°±0.2°.

[0026] In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is ethylenediamine salt crystal form I, and the X-ray powder diffraction pattern of the ethylenediamine salt crystal form I has diffraction peaks at the following 2θ angles: 5.98°±0.2°, 7.99°±0.2°, 10.68°±0.2°, 10.98°±0.2°, 12.19°±0.2°, 13.01°±0.2°, 13.39°±0.2°, 14.04°±0.2°, 15.94°±0.2°, 16.80°±0.2° ,17.79°±0.2°,18.63°±0.2°,19.21°±0.2°,20.60°±0.2°,21.00°±0.2°,21.30°±0.2°,22.04°±0.2°,22.84°±0.2°,23.38°±0.2°,23.91°±0.2°,24.65°±0.2°,25.01°±0.2°,25.48°±0.2°,26.05°±0.2°,26.59°±0.2°,26.89°±0.2° ,27.33°±0.2°,27.84°±0.2°,28.19°±0.2°,28.44°±0.2°,29.09°±0.2°,29.76°±0.2°,30.85°±0.2°,31.18°±0.2°,31.69°±0.2°,32.17°±0.2°,32.69°±0.2°,33.09°±0.2°,33.90°±0.2°,34.30°±0.2°,34.80°±0.2°,35.54°±0.2° ,36.32°±0.2°,36.92°±0.2°,37.55°±0.2°,38.20°±0.2°,38.91°±0.2°,39.50°±0.2°,39.90°±0.2°,40.43°±0.2°,42.69°±0.2°,43.24°±0.2°,44.18°±0.2°,45.00°±0.2°,46.31°±0.2°,47.13°±0.2°,48.05°±0.2°,48.96°±0.2°.

[0027] In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is an ethylenediamine salt crystalline form I, and the ethylenediamine salt crystalline form I has substantially the following Figure 4 The X-ray powder diffraction pattern is shown.

[0028] In some embodiments, the salt described in the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is ethylenediamine salt crystal form I, and the differential scanning calorimetry diagram of the ethylenediamine salt crystal form I contains an endothermic peak at 206.72°C±3°C.

[0029] In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is an ethylenediamine salt crystalline form I, and the ethylenediamine salt crystalline form I has substantially the following Figure 5 Differential scanning calorimetry diagram shown.

[0030] In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is ethylenediamine salt crystal form I, and when the ethylenediamine salt crystal form I is heated to about 128.70° C., it loses about 0.6427% of its weight.

[0031] In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is an ethylenediamine salt crystalline form I, and the ethylenediamine salt crystalline form I has substantially the following Figure 6 Thermogravimetric analysis diagram shown.

[0032] In some embodiments, the salt of the compound represented by formula (I) of the present invention is a diethanolamine salt.

[0033] In some embodiments, the salt described in the present invention is a diethanolamine salt, characterized in that the diethanolamine salt is diethanolamine salt crystal form I, and the X-ray powder diffraction pattern of the diethanolamine salt crystal form I has diffraction peaks at the following 2θ angles: 13.37°±0.2°, 20.98°±0.2°, 21.26°±0.2°, 21.85°±0.2°, 24.64°±0.2°.

[0034] In some embodiments, the salt described in the present invention is a diethanolamine salt, characterized in that the diethanolamine salt is diethanolamine salt crystal form I, and the X-ray powder diffraction pattern of the diethanolamine salt crystal form I has diffraction peaks at the following 2θ angles: 13.37°±0.2°, 15.09°±0.2°, 17.33°±0.2°, 19.50°±0.2°, 20.98°±0.2°, 21.26°±0.2°, 21.85°±0.2°, 24.64°±0.2°, 25.51°±0.2°, 26.42°±0.2°.

[0035] In some embodiments, the salt of the present invention is a diethanolamine salt, characterized in that the diethanolamine salt is a diethanolamine salt crystal form I, and the X-ray powder diffraction pattern of the diethanolamine salt crystal form I has diffraction peaks at the following 2θ angles: 5.49°±0.2°, 9.33°±0.2°, 10.52°±0.2°, 10.71°±0.2°, 10.98°±0.2°, 11.73°±0.2°, 12.14°±0.2°, 13.37°±0.2°, 15.09°±0.2°, 16. .39°±0.2°,17.33°±0.2°,17.88°±0.2°,18.40°±0.2°,18.70°±0.2°,19.50°±0.2°,19.97°±0.2°,20.98°±0.2°,21.26°±0.2°,21.56°±0.2°,21.85°±0.2°,22.84°±0.2°,23.14°±0.2°,23.76°±0.2°,24.42°±0.2°,24.64°±0. 2°,24.99°±0.2°,25.25°±0.2°,25.51°±0.2°,26.08°±0.2°,26.42°±0.2°,26.95°±0.2°,28.18°±0.2°,28.50°±0.2°,29.65°±0.2°,30.15°±0.2°,30.70°±0.2°,30.99°±0.2°,31.79°±0.2°,32.21°±0.2°,32.78°±0.2°,33.3 1°±0.2°,34.16°±0.2°,35.08°±0.2°,35.78°±0.2°,36.95°±0.2°,37.33°±0.2°,37.93°±0.2°,38.24°±0.2°,38.52°±0.2°,39.33°±0.2°,40.44°±0.2°,41.89°±0.2°,43.15°±0.2°,44.80°±0.2°,45.74°±0.2°,46.36°±0.2°.

[0036] In some embodiments, the salt of the present invention is a diethanolamine salt, characterized in that the diethanolamine salt is a diethanolamine salt crystalline form I, and the diethanolamine salt crystalline form I has substantially the following Figure 7 The X-ray powder diffraction pattern is shown.

[0037] In some embodiments, the salt described in the present invention is a diethanolamine salt, characterized in that the diethanolamine salt is diethanolamine salt crystal form I, and the differential scanning calorimetry diagram of the diethanolamine salt crystal form I comprises an endothermic peak at 224.74°C±3°C.

[0038] In some embodiments, the salt of the present invention is a diethanolamine salt, characterized in that the diethanolamine salt is a diethanolamine salt crystalline form I, and the diethanolamine salt crystalline form I has substantially the following Figure 8 Differential scanning calorimetry diagram shown.

[0039] In some embodiments, the salt of the present invention is a diethanolamine salt, characterized in that the diethanolamine salt is diethanolamine salt crystal form I, and when the diethanolamine salt crystal form I is heated to about 122.79° C., it loses about 2.186% of its weight.

[0040] In some embodiments, the salt of the present invention is a diethanolamine salt, characterized in that the diethanolamine salt is a diethanolamine salt crystalline form I, and the diethanolamine salt crystalline form I has substantially the following Figure 9 Thermogravimetric analysis diagram shown.

[0041] In some embodiments, the salt of the compound represented by formula (I) of the present invention is a diethylamine salt.

[0042] In some embodiments, the salt described in the present invention is a diethylamine salt, characterized in that the diethylamine salt is diethylamine salt crystal form I, and the X-ray powder diffraction pattern of the diethylamine salt crystal form I has diffraction peaks at the following 2θ angles: 12.08°±0.2°, 17.12°±0.2°, 18.71°±0.2°, 20.83°±0.2°, 21.18°±0.2°.

[0043] In some embodiments, the salt described in the present invention is a diethylamine salt, characterized in that the diethylamine salt is diethylamine salt crystalline form I, and the X-ray powder diffraction pattern of the diethylamine salt crystalline form I has diffraction peaks at the following 2θ angles: 12.08°±0.2°, 14.33°±0.2°, 15.63°±0.2°, 17.12°±0.2°, 18.71°±0.2°, 20.83°±0.2°, 21.18°±0.2°, 24.28°±0.2°, 25.14°±0.2°, 27.07°±0.2°.

[0044] In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt crystalline form I, and the X-ray powder diffraction pattern of the diethylamine salt crystalline form I has diffraction peaks at the following 2θ angles: 5.78°±0.2°, 7.82°±0.2°, 10.57°±0.2°, 11.04°±0.2°, 12.08°±0.2°, 12.65°±0.2°, 14.33°±0.2°, 15 .17°±0.2°,15.63°±0.2°,16.05°±0.2°,17.12°±0.2°,18.12°±0.2°,18.71°±0.2°,19.42°±0.2°,19.62°±0.2°,20.12°±0.2°,20.83°±0.2°,21.18°±0.2°,21.80°±0.2°,22.13°±0.2°,22.86 °±0.2°,23.37°±0.2°,24.28°±0.2°,25.14°±0.2°,25.91°±0.2°,27.07°±0.2°,27.59°±0.2°,27.83°±0.2°,28.36°±0.2°,28.84°±0.2°,29.13°±0.2°,29.45°±0.2°,29.68°±0.2°,30.55°±0 .2°,31.48°±0.2°,31.89°±0.2°,32.43°±0.2°,33.08°±0.2°,33.47°±0.2°,35.27°±0.2°,35.78°±0.2°,36.15°±0.2°,36.77°±0.2°,37.06°±0.2°,37.91°±0.2°,38.57°±0.2°,39.33°±0.2°.

[0045] In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt crystalline form I, and the diethylamine salt crystalline form I has substantially the following Figure 10 The X-ray powder diffraction pattern is shown.

[0046] In some embodiments, the salt described in the present invention is a diethylamine salt, characterized in that the diethylamine salt is diethylamine salt crystal form I, and the differential scanning calorimetry diagram of the diethylamine salt crystal form I comprises an endothermic peak at 250.56°C±3°C.

[0047] In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt crystalline form I, and the diethylamine salt crystalline form I has substantially the following Figure 11 Differential scanning calorimetry diagram shown.

[0048] In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is diethylamine salt crystal form I, and when the diethylamine salt crystal form I is heated to about 132.37° C., it loses about 0.2436% of its weight.

[0049] In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt crystalline form I, and the diethylamine salt crystalline form I has substantially the following Figure 12 Thermogravimetric analysis diagram shown.

[0050] In some embodiments, the salt of the compound represented by formula (I) of the present invention is a tromethamine salt.

[0051] In some embodiments, the salt described in the present invention is a tromethamine salt, characterized in that the tromethamine salt is a tromethamine salt crystal form I, and the X-ray powder diffraction pattern of the tromethamine salt crystal form I has diffraction peaks at the following 2θ angles: 10.54°±0.2°, 16.79°±0.2°, 17.64°±0.2°, 19.70°±0.2°, 20.26°±0.2°.

[0052] In some embodiments, the salt described in the present invention is a tromethamine salt, characterized in that the tromethamine salt is a tromethamine salt crystal form I, and the X-ray powder diffraction pattern of the tromethamine salt crystal form I has a diffraction peak at the following 2θ angles: 10.54°±0.2°, 13.84°±0.2°, 15.89°±0.2°, 16.79°±0.2°, 17.64°±0.2°, 19.70°±0.2°, 20.26°±0.2°, 21.61°±0.2°, 22.03°±0.2°, 26.21°±0.2°.

[0053] In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a tromethamine salt crystal form I, and the X-ray powder diffraction pattern of the tromethamine salt crystal form I has diffraction peaks at the following 2θ angles: 3.98°±0.2°, 6.48°±0.2°, 7.81°±0.2°, 10.54°±0.2°, 11.88°±0.2°, 13.04°±0.2°, 13.37° ±0.2°,13.84°±0.2°,14.57°±0.2°,15.14°±0.2°,15.69°±0.2°,15.89°±0.2°,16.79°±0.2°,17.11°±0.2°,17.64°±0.2°,18.77°±0.2°,19.08°±0.2°,19.70°±0.2°,20.26°±0.2°,20.70°±0 .2°,21.02°±0.2°,21.61°±0.2°,22.03°±0.2°,22.16°±0.2°,22.65°±0.2°,23.07°±0.2°,24.06°±0.2°,24.64°±0.2°,25.28°±0.2°,26.21°±0.2°,26.84°±0.2°,27.16°±0.2°,27.94°±0.2 °,28.37°±0.2°,28.90°±0.2°,30.05°±0.2°,30.53°±0.2°,31.25°±0.2°,31.67°±0.2°,32.95°±0.2°,34.10°±0.2°,35.21°±0.2°,35.85°±0.2°,36.86°±0.2°,38.18°±0.2°,39.82°±0.2°.

[0054] In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a tromethamine salt crystal form I, and the tromethamine salt crystal form I has substantially Figure 13 The X-ray powder diffraction pattern is shown.

[0055] In some embodiments, the salt described in the present invention is a tromethamine salt, characterized in that the tromethamine salt is a tromethamine salt crystal form I, and the differential scanning calorimetry diagram of the tromethamine salt crystal form I comprises an endothermic peak at 197.93°C ± 3°C.

[0056] In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a tromethamine salt crystal form I, and the tromethamine salt crystal form I has substantially Figure 14 Differential scanning calorimetry diagram shown.

[0057] In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a tromethamine salt crystal form I, and when the tromethamine salt crystal form I is heated to about 149.69° C., it loses about 0.3987% of its weight.

[0058] In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a tromethamine salt crystal form I, and the tromethamine salt crystal form I has substantially Figure 15 Thermogravimetric analysis diagram shown.

[0059] In another aspect, the present invention relates to a pharmaceutical composition comprising any one of the salts described in the present invention and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.

[0060] In one aspect, the present invention relates to use of the salt or the pharmaceutical composition in preparing a medicament for preventing, treating or alleviating a disease mediated by PGD2 on the CRTH2 receptor in a patient.

[0061] In some of the embodiments, the disease mediated by PGD2 on the CRTH2 receptor described in the present invention is 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, mastocytosis, autoimmune disease, acne or reperfusion injury.

[0062] In some embodiments, the autoimmune disorder described herein is psoriasis, multiple sclerosis, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or osteoarthritis.

[0063] On the other hand, the present invention also relates to a method for preparing a salt of the compound represented by formula (I) or a crystalline form thereof.

[0064] The solvent used in the method for preparing the salt or its crystal form described in the present invention is not particularly limited. Any solvent that can dissolve the starting material to a certain extent and does not affect its properties is included in the present invention. In addition, many similar modifications, equivalent substitutions, or solvents equivalent to those described in the present invention, solvent combinations, and different ratios of solvent combinations in the art are considered to be within the scope of the present invention. The present invention provides preferred solvents for use in each reaction step.

[0065] The preparation experiments of the salt or its crystal form of the present invention are described in detail in the Examples section. Furthermore, the present invention provides pharmacological property testing experiments (e.g., pharmacokinetic experiments), solubility experiments, stability experiments, and hygroscopicity experiments of the salt or its crystal form. Experiments have demonstrated that the triethanolamine salt crystal form I of the present invention has unexpected technical advantages:

[0066] 1. The triethanolamine salt crystal form I has good stability and good water solubility, which can solve the problem that the free acid compound represented by formula (I) is easy to change color and reduce purity when placed.

[0067] 2. Compared with other salts or their crystal forms, such as diethylamine salt crystal form I, diethanolamine salt crystal form I, ethylenediamine salt crystal form I and / or tromethamine salt crystal form I, the triethanolamine salt crystal form I has a higher blood concentration and a longer half-life in beagle dogs, thereby having better pharmacokinetic properties.

[0068] Therefore, the triethanolamine salt crystal form I of the present invention has good biological activity and high stability, and is more suitable for pharmaceutical use.

[0069] Definitions and General Terms

[0070] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications to which this invention pertains are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein.

[0071] "Crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and / or polymorphs, solvates, hydrates, inclusion compounds, co-crystals, salts, solvates of salts, and hydrates of salts of a compound. Crystalline forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in a confined space, for example, in a nanopore or capillary, crystallization on a surface or template, for example, on a polymer, crystallization in the presence of an additive such as a co-crystallizing countermolecule, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding, etc.

[0072] "Amorphous" or "amorphous form" refers to a substance formed when the particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity, characterized by a diffuse, unsharp X-ray powder diffraction pattern. Amorphous is a special physical form of solid matter, and its locally ordered structure suggests that it is inextricably linked to crystalline forms. Amorphous forms of substances can be obtained by a variety of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques.

[0073] "Solvent" refers to a substance (typically a liquid) that can completely or partially dissolve another substance (typically a solid). Solvents useful in the practice of the present 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, and the like.

[0074] "Anti-solvent" refers to a fluid that promotes precipitation of a product (or product precursor) from a solvent. The anti-solvent can include a cold gas, or a fluid that promotes precipitation by a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

[0075] "Solvate" refers to a compound having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, and the solvent may 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, methylpyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof. A specific example of a solvate is a hydrate, in which the solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice is water. A hydrate may or may not have other solvents other than water on the surface, in the crystal lattice, or both on the surface and in the crystal lattice of the substance.

[0076] The crystal form can be identified by a variety of technical means, 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, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.

[0077] X-ray powder diffraction (XRPD) can detect information such as changes in crystal form, crystallinity, and crystalline state, and is a common means of identifying crystal forms. The peak position of the XRPD pattern depends primarily on the structure of the crystal form and is relatively insensitive to experimental details, while its relative peak height depends 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 substantially as shown in the XRPD pattern provided in the accompanying drawings of the present invention. At the same time, the measurement of 2θ of the XRPD pattern may have experimental errors, and the measurement of 2θ of the XRPD pattern may be slightly different between different instruments and different samples, so the numerical value of the 2θ cannot be considered absolute. According to the instrument conditions used in this experiment, there is an error tolerance of ±0.2° for the diffraction peak.

[0078] Differential Scanning Calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference material (usually α-Al2O3) as a function of temperature by continuously heating or cooling the sample under program control. The height of the endothermic peak of the 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 crystalline form of the present invention is characterized by a DSC graph with a characteristic peak position, which is substantially as shown in the DSC graph provided in the accompanying drawings of the present invention. At the same time, DSC spectra may have experimental errors, and the peak positions and peak values ​​of the DSC spectra may vary slightly between different instruments and different samples. Therefore, the peak position or peak value of the DSC endothermic peak cannot be considered absolute. According to the instrument conditions used in this experiment, the endothermic peak has an error tolerance of ±3°C.

[0079] Thermogravimetric analysis (TGA) is a technique that measures the mass change of a substance with temperature under program control. It is suitable for examining the loss of solvent from crystals or the sublimation or decomposition of a sample, and can infer the presence of water of crystallization or solvent in the crystals. 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 samples. Due to the instrumentation used in this test, the mass change has an error tolerance of ±0.1%.

[0080] In the context of the present invention, the 2θ values ​​in the X-ray powder diffraction pattern are all in degrees (°).

[0081] The term "substantially 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 the X-ray powder diffraction pattern, or the DSC pattern, or the Raman spectrum pattern, or the infrared spectrum pattern are shown in the pattern.

[0082] When referring to a spectrum and / or data appearing in a graph, a "peak" is a feature that one skilled in the art can identify and that cannot be attributed to background noise.

[0083] The present invention relates to salts of 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indol-1-yl)acetic acid and / or crystalline forms thereof, which exist in substantially pure crystalline form.

[0084] "Substantially pure" means that one crystalline form is substantially free of one or more other crystalline forms, that is, the purity of the crystalline 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 crystalline form contains other crystalline forms, and the percentage of the other crystalline forms in the total volume or total weight of the crystalline 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%.

[0085] "Substantially free" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is 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%.

[0086] The "relative intensity" (or "relative peak height") in the XRPD pattern refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in the X-ray powder diffraction pattern when the intensity of the first strongest peak is 100%.

[0087] In the context of the present invention, when or whether the word "about" or "approximately" is used, it means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is expressly disclosed, where "+ / -" means plus or minus.

[0088] In the present 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.

[0089] Pharmaceutical compositions, preparations, administration and uses of the salt or its crystal form according to the present invention

[0090] The pharmaceutical composition of the present invention comprises a salt of a compound represented by formula (I) and / or a crystalline form thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the salt of the compound or its crystalline form in the pharmaceutical composition of the present invention is effective and detectable in treating or allergic rhinitis in a patient. The pharmaceutical composition of the present invention may optionally further comprise other therapeutic and / or preventive ingredients.

[0091] Suitable carriers, adjuvants, and excipients are well known to those skilled in the art and are described in detail in, 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.

[0092] The skilled artisan has the knowledge and skill to select a suitable pharmaceutically acceptable excipient in an appropriate amount for use in the present invention. In addition, there are a large number of resources available to the skilled artisan that describe pharmaceutically acceptable excipients and are useful in selecting suitable pharmaceutically acceptable excipients. 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).

[0093] 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, various carriers for configuring pharmaceutically acceptable compositions and the known technology for their preparation are disclosed, and the respective contents of these documents are incorporated into the present invention by reference. Except any conventional carriers such as those which are incompatible with the compounds of the present invention by producing any undesirable biological effect or interacting in a harmful manner with any other component in the pharmaceutically acceptable compositions, the application of the remaining carriers falls within the scope of the present invention.

[0094] The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. A description of some common methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0095] In another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof, the process comprising mixing the ingredients. The pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

[0096] The salts of the compounds of the present invention or crystalline forms thereof are typically formulated into dosage forms suitable for administration to a patient via a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (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.

[0097] The pharmaceutical composition provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as dry-filled capsule (DFC), consists of two sections, one section 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 adding glycerol, sorbitol or similar polyols. The soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those as described in the present invention, including methylparaben and propylparaben, and sorbic acid. The liquid, semisolid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semisolid 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. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or sustain dissolution of the active ingredient.

[0098] In one embodiment, the treatment methods of the present invention comprise administering to a patient in need thereof a safe and effective amount of a salt of a compound of the present invention, or a crystalline form thereof, or a pharmaceutical composition comprising a salt of a compound of the present invention, or a crystalline form thereof. Various embodiments of the present invention include treating the diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a salt of a compound of the present invention, or a crystalline form thereof, or a pharmaceutical composition comprising a salt of a compound of the present invention, or a crystalline form thereof.

[0099] In one embodiment, the salt of the compound of the present invention or its crystal form or the pharmaceutical composition comprising the salt of the compound of the present invention or its crystal form can be administered by any suitable route of administration, including systemic administration and topical 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. Topical administration includes application to the skin and intraocular, ear, vaginal, inhalation and intranasal administration. In one embodiment, the salt of the compound of the present invention or its crystal form or the pharmaceutical composition comprising the salt of the compound of the present invention or its crystal form can be oral administration. In another embodiment, the salt of the compound of the present invention or its crystal form or the pharmaceutical composition comprising the salt of the compound of the present invention or its crystal form can be inhalation administration. In another embodiment, the salt of the compound of the present invention or its crystal form or the pharmaceutical composition comprising the salt of the compound of the present invention or its crystal form can be intranasal administration.

[0100] In one embodiment, the salt of the compound of the present invention or its crystal form or the pharmaceutical composition comprising the salt of the compound of the present invention or its crystal form can be administered once, or according to the dosing regimen, several times at different time intervals within a specified time period. For example, it is administered once, twice, three times or four times a day. In one embodiment, it is administered once a day. In another embodiment, it is administered twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen of the salt of the compound of the present invention or its crystal form or the pharmaceutical composition comprising the salt of the compound of the present invention or its crystal form depends on the pharmacokinetic properties of the salt of the compound, such as absorption, distribution and half-life, which can be determined by technicians. In addition, the appropriate dosing regimen of the salt of the compound of the present invention or its crystal form or the pharmaceutical composition comprising the salt of the compound of the present invention or its crystal form, including the duration of implementation of the regimen, depends on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of the concurrent therapy, the desired therapeutic effect, etc., factors within the knowledge and experience of technicians. Such skilled artisans will also understand that appropriate adjustment of the dosing regimen may be required depending on an individual patient's response to the dosing regimen, or as an individual patient's needs change over time.

[0101] The salt of the compound of the present invention or its crystalline form can be administered simultaneously with one or more other therapeutic agents, or before or after the administration thereof. The salt of the compound of the present invention or its crystalline form can be administered separately with other therapeutic agents by the same or different administration routes, or administered with them in the form of the same pharmaceutical composition.

[0102] The salt of the compound of the present invention or its crystalline form can be used in combination with drugs for treating diseases and conditions mediated by PGD2 on the CRTH2 receptor, etc., that is, to form the drug combination described in the present invention, for example: salmeterol, fluticasone, loratadine, montelukast, omalizumab, fusidic acid, clotrimazole, tacrolimus, pimecrolimus, DP antagonists, cilomilast, TNF-α converting enzyme (TACE) inhibitors, IL-4 or IL-5 blocking monoclonal antibodies, IL-4 or IL-5 soluble receptors and zileuton and their salts and compositions, etc., or the salt of the compound of the present invention or its crystalline form can be used in combination with physical methods such as phototherapy or electrical stimulation at the same time of administration.

[0103] For individuals weighing approximately 50-70 kg, the pharmaceutical compositions and combinations of the present invention may be in unit dosage form containing approximately 1-1000 mg, or an appropriate dose, of the active ingredient. The therapeutically effective amount of the compound, salt of the compound, pharmaceutical composition, or combination thereof will depend on the species, weight, age, and individual circumstances of the individual, the disease or disorder being treated, or its severity. A skilled physician, clinician, or veterinarian can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a disease or disorder.

[0104] The above-cited dosage properties have been demonstrated in in vitro and in vivo tests using advantageous mammals (eg, mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof.

[0105] In one embodiment, a therapeutically effective dose of a salt of a compound of the invention is in an amount of about 0.1 mg to about 2,000 mg of the compound per day. A pharmaceutical composition thereof should provide a dose of about 0.1 mg to about 2,000 mg of the compound. In a specific embodiment, a pharmaceutical dosage unit form is prepared that provides about 1 mg to about 2,000 mg of the active ingredient or a combination of active ingredients per dosage unit form.

[0106] The salts of the compounds provided by the present invention, or their crystal forms and pharmaceutical compositions can be used to prepare medicines for preventing, treating or alleviating asthma and allergic rhinitis in mammals, including humans, and can also be used to prepare medicines for preventing, treating or alleviating diseases mediated by PGD2 on the CRTH2 receptor in mammals, including humans.

[0107] 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 or crystal form of the compound of the present invention can be used as a drug for treating diseases mediated by PGD2 on the CRTH2 receptor, such as asthma and allergic rhinitis.

[0108] The salts or crystal forms of the compounds of the present invention can be used, but are in no way limited to, for the prevention, treatment, or alleviation of diseases mediated by PGD2 on the CRTH2 receptor by administering an effective amount of the salts or crystal forms of the compounds of the present invention or pharmaceutical compositions to a patient. The diseases mediated by PGD2 on the CRTH2 receptor are asthma, chronic obstructive pulmonary disease, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity, conjunctivitis, eosinophilic bronchitis, food allergies, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, autoimmune diseases, acne, or reperfusion injury; wherein the autoimmune disease is psoriasis, multiple sclerosis, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or osteoarthritis.

[0109] An "effective amount" or "effective dose" of a salt of a compound of the invention, or a crystalline form thereof, or a pharmaceutically acceptable composition thereof, is an amount effective to treat or alleviate the severity of one or more of the conditions described herein. According to the methods of the present invention, a salt of a compound of the invention, or a crystalline form thereof, or a pharmaceutically acceptable composition thereof, may be administered in any amount and by any route of administration to effectively treat or alleviate the severity of the condition. The exact amount required will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of the infection, special factors, mode of administration, and the like. A salt of a compound of the invention, or a crystalline form thereof, or a pharmaceutically acceptable composition thereof, may be administered in combination with one or more other therapeutic agents, as discussed herein.

[0110] In addition to being beneficial for human treatment, the salts of the compounds of the present invention or their crystalline forms and pharmaceutical compositions can also be used in veterinary treatment of mammals such as pets, imported breeds, and farm animals. Other examples of animals include horses, dogs, and cats. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] Figure 1 The X-ray powder diffraction (XRPD) pattern of the triethanolamine salt crystalline form I of the compound represented by formula (I) is shown.

[0112] Figure 2 The differential scanning calorimetry (DSC) diagram of the triethanolamine salt form I of the compound represented by formula (I) is shown.

[0113] Figure 3 This is a thermogravimetric analysis (TGA) diagram of the triethanolamine salt form I of the compound represented by formula (I).

[0114] Figure 4 The X-ray powder diffraction (XRPD) pattern of the ethylenediamine salt form I of the compound represented by formula (I) is shown.

[0115] Figure 5The differential scanning calorimetry (DSC) diagram of the ethylenediamine salt form I of the compound represented by formula (I) is shown.

[0116] Figure 6 This is a thermogravimetric analysis (TGA) diagram of the ethylenediamine salt form I of the compound represented by formula (I).

[0117] Figure 7 The X-ray powder diffraction (XRPD) pattern of the diethanolamine salt crystalline form I of the compound represented by formula (I) is shown.

[0118] Figure 8 The differential scanning calorimetry (DSC) diagram of the diethanolamine salt form I of the compound represented by formula (I) is shown.

[0119] Figure 9 This is a thermogravimetric analysis (TGA) diagram of the diethanolamine salt form I of the compound represented by formula (I).

[0120] Figure 10 The X-ray powder diffraction (XRPD) pattern of the diethylamine salt crystalline form I of the compound represented by formula (I) is shown.

[0121] Figure 11 The differential scanning calorimetry (DSC) diagram of the diethylamine salt form I of the compound represented by formula (I) is shown.

[0122] Figure 12 This is a thermogravimetric analysis (TGA) diagram of the diethylamine salt form I of the compound represented by formula (I).

[0123] Figure 13 The X-ray powder diffraction (XRPD) pattern of the crystalline form I of the tromethamine salt of the compound represented by formula (I) is shown.

[0124] Figure 14 The differential scanning calorimetry (DSC) diagram of the tromethamine salt crystal form I of the compound represented by formula (I) is shown.

[0125] Figure 15 The thermogravimetric analysis (TGA) diagram of the crystalline form I of the tromethamine salt of the compound represented by formula (I). DETAILED DESCRIPTION

[0126] The present invention is further described below by way of examples, which do not limit the present invention to the scope of the examples.

[0127] The X-ray powder diffraction analysis method used in this invention is to obtain X-ray powder diffraction patterns using an Empyrean diffractometer using Cu-Kα radiation (45 kV, 40 mA). A thin layer of powdered sample was prepared on a single crystal silicon sample holder and placed on a rotating sample stage. Analysis was performed over a range of 3° to 60° with a step size of 0.0167°. Data were collected using Data Collector software, processed using HighScore Plus software, and read using Data Viewer software.

[0128] The differential scanning calorimetry (DSC) analysis method used in this invention is performed using a TA Q2000 module with a thermal analysis controller. Data are collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of sample is accurately weighed into a custom aluminum crucible with a lid. Samples are analyzed from room temperature to approximately 300°C using a linear heating device at 10°C / min. During use, the DSC cell is purged with dry nitrogen.

[0129] Thermogravimetric analysis (TGA) was performed using a TA Instruments Q500 thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 10-30 mg of sample was placed in a platinum crucible and analyzed using a linear heating device at 10°C / min from room temperature to approximately 300°C. The TGA chamber was purged with dry nitrogen during use.

[0130] The solubility of the present 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.

[0131] The hygroscopicity of the present invention is measured using a DVS INT-Std dynamic moisture and gas adsorption analyzer from Surface Measurement Systems, UK. The humidity test range is 0%-95%, the air flow is 200 mL / min, the temperature is 25°C, and the test point is one test point for every 5% humidity.

[0132] Specific implementation methods

[0133] Comparative Example

[0134] The inventors have found through experiments that among the several crystal forms disclosed in the prior art WO2016037591A1, the crystal form I of the compound represented by 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 better pharmacokinetic properties than other crystal forms. Therefore, in the present invention, the inventors selected the crystal form I of the compound represented by formula (I) with various better properties as a reference substance and studied the salt of the compound represented by formula (I) and its crystal form. Specifically, the synthesis method of the crystal form I of the compound represented by formula (I) refers to Example 24 in the international application WO2016037591A1.

[0135] Example

[0136] Example 1 Triethanolamine Salt Crystal Form I

[0137] 1. Preparation of triethanolamine salt crystal form I

[0138] At room temperature, Form I of the compound represented by Formula (I) (60.0 g, 127.3 mmol) was added to ethanol (500.0 mL) and slurried. A solution of triethanolamine (18.0 mL, 140.0 mmol) in ethanol (50.0 mL) was then added, resulting in the precipitation of a large amount of product. Additional ethanol (500.0 mL) was added, and the reaction was stirred for 9 h. The mixture was filtered, and the filter cake was washed with ethanol (10.0 mL x 5) and dried under vacuum at 80°C overnight to yield a white solid (3.8 g, 97.0%).

[0139] 2. Identification of Triethanolamine Salt Form I

[0140] (1) X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation revealed the following peaks expressed in degrees 2θ: 5.46°, 10.30°, 11.90°, 12.36°, 13.07°, 14.39°, 15.01°, 16.19°, 18.19°, 18.71°, 19.71°, 20.40°, 21.34°, 21.63°, 21.95°, 22.53°, 23.11°, 23.86°, 24.22°, 24.76°, 25.49° , 26.19°, 27.07°, 27.67°, 28.15°, 28.91°, 29.27°, 29.63°, 30.00°, 30.90°, 32.03°, 32.25°, 32.61°, 33.73°, 34.04°, 36.04°, 37.14°, 37.65°, 40.32°, 41.65°, 43.25°, 43.80°, 45.06°, 45.83°, 48.04° and 49.66°, with an error tolerance of ±0.2°. The XRPD pattern of the triethanolamine salt crystalline form I prepared according to the method of Example 1 of the present invention is substantially as follows Figure 1 shown.

[0141] (2) Analytical identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10°C / min, and the endothermic peak was 178.24°C with an error tolerance of ±3°C. The DSC graph of the triethanolamine salt crystal form I prepared according to the method of Example 1 of the present invention is substantially as follows: Figure 2 (3) Thermogravimetric analysis (TGA) was performed by TAQ500: the heating rate was 10°C / min, and when heated to 133.18°C, the weight loss was 0.01193%. The TGA graph of the triethanolamine salt crystal form I prepared according to the method of Example 1 of the present invention is basically as follows Figure 3 shown.

[0142] Example 2 Ethylenediamine Salt Crystal Form I

[0143] 1. Preparation of Ethylenediamine Salt Form I

[0144] Form I of the compound represented by Formula (I) (504.8 mg, 1.071 mmol) was added to tetrahydrofuran (5.0 mL) at room temperature and stirred to dissolve. A homemade 1.0 mol / L solution of ethylenediamine in tetrahydrofuran (1.2 mL, 1.2 mmol) was then added and stirred overnight. The mixture was filtered and the filter cake was dried under vacuum at 80°C for 8 h to yield a white solid (520.3 mg, 95.49%).

[0145] 2. Identification of Ethylenediamine Salt Form I

[0146] (1) X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation revealed the following peaks expressed in degrees 2θ: 5.98°, 7.99°, 10.68°, 10.98°, 12.19°, 13.01°, 13.39°, 14.04°, 15.94°, 16.80°, 17.79°, 18.63°, 19.21°, 20.60°, 21.00°, 21.30°, 22.04°, 22.84°, 23.38°, 23.91°, 24.65°, 25.01°, 25.48°, 26.05°, 26.59°, 26.89°, 27.33° ,27.84°,28.19°,28.44°,29.09°,29.76°,30.85°,31.18°,31.69°,32.17°,32.69°,33.09°,33.90°,34.30°,34.80°,35.54°,36.32°,36.92°,37.55°,38.20°,38.91°,39.50°,39.90°,40.43°,42.69°,43.24°,44.18°,45.00°,46.31°,47.13°,48.05° and 48.96°, there is an error tolerance of ±0.2°. The XRPD pattern of the ethylenediamine salt crystal form I prepared according to the method of Example 2 of the present invention is substantially as follows Figure 4 shown.

[0147] (2) Analytical identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10°C / min, and the endothermic peak was at 206.72°C, with an error tolerance of ±3°C. The DSC graph of the ethylenediamine salt crystal form I prepared according to the method of Example 2 of the present invention is substantially as follows: Figure 5 shown.

[0148] (3) Thermogravimetric analysis (TGA) was performed on a TAQ500: the temperature was raised at a rate of 10°C / min, and when heated to 128.70°C, the weight loss was 0.6427%. The TGA graph of the ethylenediamine salt crystal form I prepared according to the method of Example 2 of the present invention is substantially as follows: Figure 6 shown.

[0149] Example 3 Diethanolamine Salt Crystal Form I

[0150] 1. Preparation of diethanolamine salt crystal form I

[0151] Form I of the compound represented by formula (I) (502 mg, 1.065 mmol) was added to isopropanol (5.0 mL) and heated to 60°C for 1 h. A homemade 1.0 mol / L diethanolamine solution in ethanol (1.2 mL, 1.2 mmol) was then added. The mixture was stirred for 5.5 h and then naturally cooled to room temperature. Filtration was performed, and the filter cake was vacuum-dried at 60°C overnight to obtain a white solid (592.5 mg, 100.5%).

[0152] 2. Identification of Diethanolamine Salt Form I

[0153] (1) X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation revealed the following peaks expressed in degrees 2θ: 5.49°, 9.33°, 10.52°, 10.71°, 10.98°, 11.73°, 12.14°, 13.37°, 15.09°, 16.39°, 17.33°, 17.88°, 18.40°, 18.70°, 19.50°, 19.97°, 20.98°, 21.26°, 21.56°, 21.85°, 22.84°, 23.14°, 23.76°, 24.42°, 24.64°, 24.99° , 25.25°, 25.51°, 26.08°, 26.42°, 26.95°, 28.18°, 28.50°, 29.65°, 30.15°, 30.70°, 30.99°, 31.79°, 32.21°, 32.78°, 33.31°, 34.16°, 35.08°, 35.78°, 36.95°, 37.33°, 37.93°, 38.24°, 38.52°, 39.33°, 40.44°, 41.89°, 43.15°, 44.80°, 45.74° and 46.36°, with an error tolerance of ±0.2°. The XRPD pattern of the diethanolamine salt crystalline form I prepared according to the method of Example 3 of the present invention is substantially as follows Figure 7 shown.

[0154] (2) Analytical identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10°C / min, and the endothermic peak was at 224.74°C, with an error tolerance of ±3°C. The DSC graph of the diethanolamine salt crystal form I prepared according to the method of Example 3 of the present invention is substantially as follows: Figure 8 (3) Thermogravimetric analysis (TGA) was performed by TAQ500: the heating rate was 10°C / min, and when heated to 122.79°C, the weight loss was 2.186%. The TGA graph of the diethanolamine salt crystal form I prepared according to the method of Example 3 of the present invention is basically as follows Figure 9 shown.

[0155] Example 4 Diethylamine Salt Crystal Form I

[0156] 1. Preparation of diethylamine salt crystal form I

[0157] Form I of the compound represented by formula (I) (503.9 mg, 1.069 mmol) was added to tetrahydrofuran (5.0 mL) at room temperature and stirred to dissolve. A homemade 1.0 mol / L ethanolic solution of diethylamine (1.3 mL, 1.3 mmol) was then added and stirred overnight. The mixture was filtered, and the filter cake was washed with tetrahydrofuran (1.0 mL x 2) and dried under vacuum at 60°C overnight to yield a white solid (539 mg, 96.63%).

[0158] 2. Identification of diethylamine salt crystal form I

[0159] (1) X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation revealed the following peaks expressed in degrees 2θ: 5.78°, 7.82°, 10.57°, 11.04°, 12.08°, 12.65°, 14.33°, 15.17°, 15.63°, 16.05°, 17.12°, 18.12°, 18.71°, 19.42°, 19.62°, 20.12°, 20.83°, 21.18°, 21.80°, 22.13°, 22.86°, 23. , 37.28°, 25.14°, 25.91°, 27.07°, 27.59°, 27.83°, 28.36°, 28.84°, 29.13°, 29.45°, 29.68°, 30.55°, 31.48°, 31.89°, 32.43°, 33.08°, 33.47°, 35.27°, 35.78°, 36.15°, 36.77°, 37.06°, 37.91°, 38.57° and 39.33°, with an error tolerance of ±0.2°. The XRPD pattern of the diethylamine salt crystalline form I prepared according to the method of Example 4 of the present invention is substantially as follows Figure 10 shown.

[0160] (2) Analytical identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10°C / min, and the endothermic peak was at 250.56°C with an error tolerance of ±3°C. The DSC graph of the diethylamine salt crystal form I prepared according to the method of Example 4 of the present invention is substantially as follows: Figure 11 (3) Thermogravimetric analysis (TGA) was performed by TAQ500: the heating rate was 10°C / min, and when heated to 132.37°C, the weight loss was 0.2436%. The TGA graph of the diethylamine salt crystal form I prepared according to the method of Example 4 of the present invention is basically as follows Figure 12shown.

[0161] Example 5 Tromethamine Salt Crystal Form I

[0162] 1. Preparation of Tromethamine Salt Form I

[0163] Form I of the compound represented by formula (I) (814.7 mg, 1.816 mmol) was added to n-propanol (8.0 mL) at room temperature and stirred for 1 hour. Then, a solution of tromethamine (239.0 mg, 1.953 mmol) dissolved in n-propanol (5.0 mL) was slowly added and stirred for 24 hours. The mixture was filtered, washed with ethanol (5.0 mL x 2), and vacuum-treated at 80°C for 24 hours to obtain a white solid (899.0 mg, 86.89%).

[0164] 2. Identification of Tromethamine Salt Form I

[0165] (1) X-ray powder diffraction (XRPD) analysis using Cu-Kα radiation revealed the following peaks expressed in degrees 2θ: 3.98°, 6.48°, 7.81°, 10.54°, 11.88°, 13.04°, 13.37°, 13.84°, 14.57°, 15.14°, 15.69°, 15.89°, 16.79°, 17.11°, 17.64°, 18.77°, 19.08°, 19.70°, 20.26°, 20.70°, 21.02°, , 21.61°, 22.03°, 22.16°, 22.65°, 23.07°, 24.06°, 24.64°, 25.28°, 26.21°, 26.84°, 27.16°, 27.94°, 28.37°, 28.90°, 30.05°, 30.53°, 31.25°, 31.67°, 32.95°, 34.10°, 35.21°, 35.85°, 36.86°, 38.18° and 39.82°, with an error tolerance of ±0.2°. The XRPD pattern of the tromethamine salt crystalline form I prepared according to the method of Example 5 of the present invention is substantially as follows Figure 13 shown.

[0166] (2) Analytical identification by TA Q2000 differential scanning calorimetry (DSC): The scanning speed was 10°C / min, and the endothermic peak was at 197.93°C with an error tolerance of ±3°C. The DSC graph of the tromethamine salt crystal form I prepared according to the method of Example 5 of the present invention is substantially as follows: Figure 14 shown.

[0167] (3) Thermogravimetric analysis (TGA) was performed on a TAQ500: the temperature was raised at a rate of 10°C / min, and when heated to 149.69°C, the weight loss was 0.3987%. The TGA graph of the tromethamine salt crystal form I prepared according to the method of Example 5 of the present invention is substantially as follows: Figure 15 shown.

[0168] Example 6 Pharmacokinetics of the salt or its crystalline form according to the present invention

[0169] The test sample (ie, the salt or its crystal form of the present invention, or the crystal form I of the compound represented by formula (I) of the present invention as a control example) is filled into capsules for oral administration.

[0170] Male Beagle dogs weighing 8-12 kg were divided into six groups of three dogs each. The test sample was orally administered in capsules at a dose of 5 mg / kg. Blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24 hours. A standard curve with an appropriate range was established based on the sample concentrations. The concentrations of the test sample in plasma samples were determined and quantitatively analyzed using an AB SCIEX API4000 LC-MS / MS system in MRM mode. Pharmacokinetic parameters were calculated using the non-compartmental model using WinNonLin 6.3 software based on the drug concentration-time curves. The experimental results are shown in Table 1.

[0171] Table 1 Pharmacokinetic experimental data

[0172] Test samples <![CDATA[C max (ng / ml)]]> <![CDATA[T 1 / 2 (h)]]> <![CDATA[T max (h)]]> Example 1 7190 10.4 0.5 Example 2 2960 5.91 1.33 Example 3 3420 6.01 1.0 Example 4 5860 5.46 1.0 Example 5 6160 7.41 1.0 Comparative Example 5800 5.15 2.0

[0173] Experimental conclusion:

[0174] As shown in Table 1, (1) relative to the crystal form I of the compound represented by formula (I), the diethylamine salt crystal form I of the present invention has comparable blood drug concentration and half-life in beagle dogs, and the tromethamine salt crystal form I has a slightly higher blood drug concentration and a longer half-life in beagle dogs; (2) relative to the crystal form I of the compound represented by formula (I), the ethylenediamine salt crystal form I of the compound represented by formula (I), the diethanolamine salt crystal form I, the diethylamine salt crystal form I or the tromethamine salt crystal form I, the triethanolamine salt crystal form I of the present invention has a higher blood drug concentration and a longer half-life in beagle dogs. Therefore, the diethylamine salt crystal form I and the tromethamine salt crystal form I of the present invention have good pharmacokinetic properties, and the triethanolamine salt crystal form I has better pharmacokinetic properties.

[0175] Example 7 Stability test of the salt or its crystal form described in the present invention

[0176] High temperature experiments: Take a batch of test samples and put them into 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 day to test the key stability inspection items.

[0177] High humidity experiment: Take a batch of test samples and put them into a flat weighing bottle in an appropriate amount, spread them into a thin layer ≤5mm thick, and place them under the conditions of 25℃, RH90%±5% for 32 days. Take samples on the 5th, 11th and 32nd day to test the key stability inspection items.

[0178] The experimental results are shown in Table 2.

[0179] Table 2 Stability test of triethanolamine salt crystal form I of the compound represented by formula (I) of the present invention

[0180]

[0181]

[0182] Experimental conclusion:

[0183] As shown in Table 2, under high temperature and high humidity conditions, the appearance and purity of the triethanolamine salt crystalline form I of the compound represented by formula (I) of the present invention do not change significantly, and the stability effect is good, which is suitable for pharmaceutical use.

[0184] Example 8 Hygroscopicity test of the salt or its crystal form of the present invention

[0185] An appropriate 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 of the present invention is not easily affected by high humidity and deliquesces.

[0186] Example 9 Solubility Test of the Salt or Its Crystalline Forms of the Present Invention

[0187] The test sample was placed in 37°C water to form a supersaturated turbid solution. After shaking for 24 hours, the solution was filtered and the filtrate was tested for solubility in water using HPLC. The experiment showed that the salt or its crystalline form described in the present invention has high solubility in water, thus having good drugability and being suitable for formulation development.

[0188] The above contents are only basic descriptions of the concept of the present invention, and any equivalent transformations made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

[0189] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[0190] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A salt of a compound represented by formula (I), (I)， It is characterized by: The salt is a triethanolamine salt, wherein the triethanolamine salt is triethanolamine salt crystalline form I, and the X-ray powder diffraction pattern of the triethanolamine salt crystalline form I has diffraction peaks at the following 2θ angles: 14.39° ± 0.2°, 18.71° ± 0.2°, 19.71° ± 0.2°, 20.40° ± 0.2°, 21.34° ± 0.2°, 24.22° ± 0.2°, 25.49° ± 0.2°.

2. The salt according to claim 1, wherein The X-ray powder diffraction pattern of the triethanolamine salt crystalline form I has diffraction peaks at the following 2θ angles: 14.39° ± 0.2°, 15.01° ± 0.2°, 16.19° ± 0.2°, 18.71° ± 0.2°, 19.71° ± 0.2°, 20.40° ± 0.2°, 21.34° ± 0.2°, 24.22° ± 0.2°, 25.49° ± 0.2°, 30.90° ± 0.2°.

3. The salt according to claim 1 or 2, wherein The X-ray powder diffraction pattern of the triethanolamine salt crystalline form I has diffraction peaks at the following 2θ angles: 5.46° ± 0.2°, 10.30° ± 0.2°, 11.90° ± 0.2°, 12.36° ± 0.2°, 13.07° ± 0.2°, 14.39° ± 0.2°, 15.01° ± 0.2°, 16.19° ± 0.2°, 18.19° ± 0.2°, 18.71° ± 0.2°, 19.71° ± 0.2°, 20.40° ± 0.2°, 21.34° ± 0.2°, 21.63° ± 0.2°, 21.95° ± 0.2°, 22.53° ± 0.2°, 23. 0.2°, 23.11° ± 0.2°, 23.86° ±0.2°, 24.22° ± 0.2°, 24.76° ± 0.2°, 25.49° ± 0.2°, 26.19° ± 0.2°, 27.07°± 0.2°, 27.67° ± 0.2°, 28.15° ± 0.2°, 28.91° ± 0.2°, 29.27° ± 0.2°,29.63° ± 0.2°, 30.00° ± 0.2°, 30.90° ± 0.2°, 32.03° ± 0.2°, 32.25° ±0.2°, 32.61° ± 0.2°, .2°, 33.73° ± 0.2°, 34.04° ± 0.2°, 36.04° ± 0.2°, 37.14°± 0.2°, 37.65° ± 0.2°, 40.32° ± 0.2°, 41.65° ± 0.2°, 43.25° ± 0.2°,43.80° ± 0.2°, 45.06° ± 0.2°, 45.83° ± 0.2°, 48.04° ± 0.2°, 49.66° ±0.2°.

4. The salt according to claim 1, wherein The triethanolamine salt crystalline form I has an X-ray powder diffraction pattern substantially as shown in FIG1 .

5. The salt according to claim 1, wherein The differential scanning calorimetry diagram of the triethanolamine salt crystalline form I includes an endothermic peak at 178.24°C ± 3°C.

6. The salt according to claim 5, wherein The triethanolamine salt Form I has a differential scanning calorimetry diagram substantially as shown in FIG2 .

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

8. Use of the salt according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for preventing, treating or alleviating a disease mediated by PGD2 on the CRTH2 receptor in a patient.

9. The use according to claim 8, wherein The diseases mediated by PGD2 on the CRTH2 receptor are 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, mastocytosis, autoimmune diseases, acne or reperfusion injury.

10. The use according to claim 9, wherein The autoimmune disorder is psoriasis, multiple sclerosis, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus or osteoarthritis.

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