WO2022166638A1 - Salt of indole derivative and use thereof - Google Patents

Abstract

A salt of a compound, as represented by formula I, a crystal form thereof, a pharmaceutical composition containing the salt and/or the crystal form thereof, and the use of the salt, the crystal form thereof and/or the pharmaceutical composition in the preparation of a drug for preventing, treating or mitigating diseases mediated by PGD 2 on a CRTH2 receptor, in particular asthma and allergic rhinitis.

Description

Salts of indole derivatives and their uses

Related applications

This application claims the priority of Chinese Patent Application No. 202110140603.1, which was submitted to the State Intellectual Property Office on February 2, 2021, the entire contents of which are incorporated herein by reference.

technical field

The invention belongs to the technical field of medicine, relates to salts of indole derivatives and uses thereof, in particular to 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl) - Salts of 2-methyl-1H-indol-1-yl)acetic acid, crystalline forms of said salts and pharmaceutical compositions containing them, further related to said salts, crystalline forms of said salts or said pharmaceutical combinations use of things.

Background technique

CRTH2 is a G protein-coupled chemotaxis receptor expressed on Th2 cells, 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.

PGD2 ( _{prostaglandin} D2), the ligand for CRTH2, is produced by mast cells and other important effector cells in allergic disease. In human cells, PGD ₂ induces the migration and activation of Th2 cells, eosinophils and basophils through CRTH2. Thus, antagonism of PGD ₂ at the CRTH2 receptor is an attractive approach for the treatment of Th2-dependent allergic diseases such as asthma, allergic rhinitis and atopic dermatitis. CRTH2 receptor antagonists have also been reported to be useful in the treatment of other eosinophil-related diseases, such as allergic granulomatosis with vasculitis and sinusitis.

International application WO 2016037591 A1 discloses compound 2-(5-fluoro-3-(1-((4-fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl with CRTH2 receptor antagonistic activity -1H-indol-1-yl)acetic acid (the compound represented by formula (I)) and its crystalline form. However, there is no research on the salt of the compound or the crystal form of the salt in the prior art.

Different salts and solid forms of pharmaceutical active ingredients may have different properties. Different salts and solid forms may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and also have different effects on drug stability, bioavailability, and efficacy. Therefore, in drug development, the issue of salt and/or solid forms of drugs should be fully considered.

The inventors found that the compound and its crystalline form have poor water solubility and poor druggability during research on the compound, so it is necessary to find a solid form with better druggability. Through a large number of experimental studies, the inventor found that after the compound represented by the formula (I) forms a salt, the physicochemical properties of different salts change greatly, and the properties of some salts are not better than the properties of the compounds in the free state; and according to the method of the present invention. The physical properties and various properties of the prepared triethanolamine salt of the compound represented by formula (I) can be significantly improved, which is more favorable for formulation development.

SUMMARY OF THE INVENTION

The present invention provides the salt of the compound represented by the formula (I), and the preparation method of the salt, the solid form of the salt, its physicochemical properties and its pharmacological properties have been studied, and it is found that the compound formed with different organic bases Salt, their physical and chemical properties are quite different; wherein the various physical and chemical properties of triethanolamine salt are better than other salts, for example, the triethanolamine salt crystal form I obtained after the compound represented by formula (I) is salified with triethanolamine , its pharmacokinetic properties are better than the corresponding diethylamine salt crystal form I, diethanolamine salt crystal form I, ethylenediamine salt crystal form I, tromethamine salt crystal form I. Therefore, the triethanolamine salt crystal form I of the present invention has better properties, better pharmacokinetic properties, and thus better druggability.

Specifically, the present invention relates to a salt of the 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 salt, its crystalline form and /or use of the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating diseases mediated by PGD2 _on CRTH2 receptors in patients, especially asthma and allergic rhinitis. The salt of the present invention is the triethanolamine salt of the compound represented by formula (I). Further, the salt of the present invention is the triethanolamine salt crystal form I of the compound represented by formula (I). The crystalline forms of the present invention may also be in the form of solvates, such as hydrates.

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

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

In other embodiments, the organic base salts described in the present invention include, but are not limited to, triethanolamine salts, diethylamine salts, diethanolamine salts, ethylenediamine salts or tromethamine salts, and the like.

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

In some embodiments, the salt of the present invention is a triethanolamine salt, the triethanolamine salt is a triethanolamine salt form I, and the X-ray powder diffraction pattern of the triethanolamine salt form I has the following 2θ angles Diffraction peaks: 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°.

In some embodiments, the salt of the present invention is a triethanolamine salt, characterized in that, the triethanolamine salt is a triethanolamine salt crystal form I, and the X-ray powder diffraction pattern of the triethanolamine salt crystal form I is as follows Diffraction peaks at 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°.

In some embodiments, the salt of the present invention is a triethanolamine salt, characterized in that, the triethanolamine salt is a triethanolamine salt crystal form I, and the X-ray powder diffraction pattern of the triethanolamine salt crystal form I is as follows Diffraction peaks at 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°.

In some embodiments, the salt of the present invention is a triethanolamine salt, characterized in that the triethanolamine salt is a triethanolamine salt crystal form I, and the triethanolamine salt crystal form I has substantially as shown in FIG. 1 X-ray powder diffraction pattern.

In some embodiments, the salt of the present invention is a triethanolamine salt, wherein the triethanolamine salt is a triethanolamine salt crystal form I, and the differential scanning calorimetry of the triethanolamine salt crystal form I comprises Endothermic peak at 178.24°C ± 3°C.

In some embodiments, the salt of the present invention is a triethanolamine salt, characterized in that the triethanolamine salt is a triethanolamine salt crystal form I, and the triethanolamine salt crystal form I has substantially as shown in FIG. 2 . Differential Scanning Calorimetry.

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

In some embodiments, the salts of the present invention are triethanolamine salts, characterized in that the triethanolamine salts are triethanolamine salt crystal form I, and the triethanolamine salt crystal form I has substantially as shown in FIG. 3 . thermogravimetric analysis chart.

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

In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is an ethylenediamine salt crystal form I, and the X-ray powder of the ethylenediamine salt crystal form I The diffraction pattern 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°.

In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is an ethylenediamine salt crystal form I, and the X-ray powder of the ethylenediamine salt crystal form I The diffraction pattern 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°.

In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is an ethylenediamine salt crystal form I, and the X-ray powder of the ethylenediamine salt crystal form I The diffraction pattern 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°.

In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is ethylenediamine salt Form I, and the ethylenediamine salt Form I has substantially the same The X-ray powder diffraction pattern shown in Figure 4.

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

In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is ethylenediamine salt Form I, and the ethylenediamine salt Form I has substantially the same Differential scanning calorimetry map shown in Figure 5.

In some embodiments, the salt of the present invention is an ethylenediamine salt, wherein the ethylenediamine salt is an ethylenediamine salt crystal form I, and the ethylenediamine salt crystal form I is heated to 128.70° C. When left and right, the weight loss is about 0.6427%.

In some embodiments, the salt of the present invention is an ethylenediamine salt, characterized in that the ethylenediamine salt is ethylenediamine salt Form I, and the ethylenediamine salt Form I has substantially the same The thermogravimetric analysis chart shown in FIG. 6 .

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

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 is as follows There are diffraction peaks at 2θ angles: 13.37°±0.2°, 20.98°±0.2°, 21.26°±0.2°, 21.85°±0.2°, 24.64°±0.2°.

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 is as follows Diffraction peaks at 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°.

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 is as follows Diffraction peaks at 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°, 33.31°± 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°.

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 diethanolamine salt crystal form I has substantially as shown in FIG. 7 . X-ray powder diffraction pattern.

In some embodiments, the salt of the present invention is a diethanolamine salt, wherein the diethanolamine salt is a diethanolamine salt crystal form I, and the differential scanning calorimetry of the diethanolamine salt crystal form I comprises Endothermic peak at 224.74°C ± 3°C.

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 diethanolamine salt crystal form I has substantially as shown in FIG. 8 . Differential Scanning Calorimetry.

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 diethanolamine salt crystal form I loses weight when heated to about 122.79° C. About 2.186%.

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 diethanolamine salt crystal form I has substantially as shown in FIG. 9 . thermogravimetric analysis chart.

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

In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt crystal form I, and the X-ray powder of the diethylamine salt crystal form I The diffraction pattern 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°.

In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt crystal form I, and the X-ray powder of the diethylamine salt crystal form I The diffraction pattern 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°.

In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt crystal form I, and the X-ray powder of the diethylamine salt crystal form I The diffraction pattern 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°.

In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt Form I, and the diethylamine salt Form I has substantially the following The X-ray powder diffraction pattern shown in FIG. 10 .

In some embodiments, the salt of the present invention is a diethylamine salt, wherein the diethylamine salt is a diethylamine salt crystal form I, and the differential scanning of the diethylamine salt crystal form I The calorimetry contains an endothermic peak at 250.56°C ± 3°C.

In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt Form I, and the diethylamine salt Form I has substantially the following Differential scanning calorimetry map shown in Figure 11.

In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt crystal form I, and the diethylamine salt crystal form I is heated to 132.37° C. When left and right, the weight loss is about 0.2436%.

In some embodiments, the salt of the present invention is a diethylamine salt, characterized in that the diethylamine salt is a diethylamine salt Form I, and the diethylamine salt Form I has substantially the following The thermogravimetric analysis chart shown in FIG. 12 .

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

In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a trometamol salt crystal form I, and the tromethamine salt crystal form I The X-ray powder diffraction pattern of the 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°.

In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a trometamol salt crystal form I, and the tromethamine salt crystal form I The X-ray powder diffraction pattern has diffraction peaks 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°.

In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a trometamol salt crystal form I, and the tromethamine salt crystal form I The X-ray powder diffraction pattern 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°.

In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a trometamol salt crystal form I, and the tromethamine salt crystal form I Has an X-ray powder diffraction pattern substantially as shown in FIG. 13 .

In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a trometamol salt crystal form I, and the tromethamine salt crystal form I The differential scanning calorimetry of 197.93 °C ± 3 °C endothermic peak.

In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a trometamol salt crystal form I, and the tromethamine salt crystal form I There is a differential scanning calorimetry map substantially as shown in FIG. 14 .

In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a trometamol salt crystal form I, and the tromethamine salt crystal form I When heated to about 149.69 ℃, the weight loss is about 0.3987%.

In some embodiments, the salt of the present invention is a tromethamine salt, characterized in that the tromethamine salt is a trometamol salt crystal form I, and the tromethamine salt crystal form I Has a thermogravimetric analysis diagram substantially as shown in FIG. 15 .

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

In one aspect, the present invention relates to the use of the salt or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a disease in a patient mediated by PGD ₂ on the CRTH2 receptor.

In some such embodiments, the disease mediated by PGD ₂ on the CRTH2 receptor of the 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, mast cell hyperplasia disease, autoimmune disease, acne, or reperfusion injury.

In some such regimens, the autoimmune disorder of the invention is psoriasis, multiple sclerosis, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or osteoarthritis.

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.

The solvent used in the preparation method of the salt or its crystal form of the present invention is not particularly limited, and 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 in the art, equivalent replacements, or equivalents to the solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are all deemed to be within the scope of the present invention. The present invention provides the preferred solvent used in each reaction step.

The preparation experiments of the salts of the present invention or their crystalline forms will be described in detail in the Examples section. At the same time, the present invention provides pharmacological property testing experiments (such as pharmacokinetics experiments), solubility experiments, stability experiments and hygroscopicity experiments of the salt or its crystalline form. It has been proved by experiments that the triethanolamine salt crystal form I of the present invention has an unexpected technical advantage:

1. The triethanolamine salt crystal form I has good stability and good water solubility, and can solve the problems of easy discoloration and reduced purity of the free acid compound represented by formula (I) when placed.

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 three Ethanolamine salt crystal form I has higher plasma concentration and longer half-life in beagle dogs, so it has better pharmacokinetic properties.

Therefore, the triethanolamine salt crystal form I of the present invention has better biological activity, higher stability, and is more suitable for pharmaceutical use.

Definitions and General Terms

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or identical 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.

"Crystalline" or "crystalline form" refers to a solid with 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, hydrates of salts. Crystalline forms of materials 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 confined spaces, e.g., in nanopores or capillaries, crystallization on surfaces or templates, e.g., on polymers, Crystallization, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding in the presence of additives such as co-crystallizing anti-molecules, among others.

"Amorphous" or "amorphous form" refers to a substance formed when its particles (molecules, atoms, ions) are arranged aperiodically in three-dimensional space, characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural features suggest that it is inextricably linked with crystalline matter. Amorphous forms of substances can be obtained by a number 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, among others.

"Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents used 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.

"Antisolvent" refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The antisolvent may comprise a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.

"Solvate" means a compound having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, 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-dimethylmethane Amide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, Toluene, xylene and mixtures thereof, etc. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the lattice or both on the surface and in the lattice is water. Hydrates may or may not have solvents other than water on the surface of the substance, in the lattice, or both on the surface and in the lattice.

Crystal forms can be identified by various 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 Resonance method, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.

X-ray powder diffraction (XRPD) can detect the change of crystal form, crystallinity, crystal structure and other information, and is a common method to identify crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystal form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention. At the same time, there may be experimental errors in the measurement of the 2θ of the XRPD spectrum, and the measurement of the 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of the 2θ cannot be regarded as absolute. According to the condition of the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

Differential Scanning Calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al ₂ O ₃ ) as a function of temperature by continuously heating or cooling under program control. The endothermic peak heights of DSC curves depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by DSC patterns having characteristic peak positions substantially as shown in the DSC patterns provided in the accompanying drawings of the present invention. At the same time, the DSC spectrum may have experimental errors, and the peak positions and peaks of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. Depending on the condition of the instrument used in this experiment, there is a tolerance of ±3°C for the endothermic peak.

Thermogravimetric analysis (TGA) is a technique for measuring the change of the mass of a substance with temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains water of crystallization or crystallization solvent. Case. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments and between different samples. Depending on the condition of the instrumentation used for this test, there is a ±0.1% error tolerance for mass variation.

In the context of the present invention, the 2Θ values in an X-ray powder diffraction pattern are all in degrees (°).

The term "substantially as shown" means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least a 90%, or at least 95%, or at least 99% of the peaks are shown in their graph.

When referring to a spectrum or/and data appearing in a graph, a "peak" refers to a feature that would be recognized by those skilled in the art that would not be attributed to background noise.

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

"Substantially pure" means that a crystalline form is substantially free of one or more other crystalline forms, ie, the crystalline form is at least 80% pure, or at least 85% pure, or at least 90% pure, or at least 93% pure, 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, said The percentage of other crystal forms 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%.

"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%.

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

In the context of the present invention, when or whether the words "about" or "about" are used, it means within 10%, suitably within 5%, especially within 1% of the given value or range . Alternatively, to those of ordinary skill in the art, the terms "about" or "about" mean within an acceptable standard error of the mean. Whenever a number with a value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+ Numbers within the /-10% value are explicitly disclosed, where "+/-" means plus or minus.

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, and the like.

Pharmaceutical compositions, formulations, administrations and uses of the salts or their crystalline forms of the present invention

The characteristics of the pharmaceutical composition of the present invention include the salt of the compound represented by formula (I) and/or its crystal form and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the salt of the compound or its crystalline form in the pharmaceutical composition of the present invention is effective to detectably treat or alleviate asthma or allergic rhinitis in a patient. The pharmaceutical compositions of the present invention may also optionally contain other therapeutic and/or prophylactic ingredients.

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

The skilled artisan possesses the knowledge and skills in the art to enable them to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in the present invention. In addition, there are numerous resources available to the skilled artisan describing pharmaceutically acceptable excipients and for use 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).

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 formulating pharmaceutically acceptable compositions, and well-known techniques for their preparation, are disclosed, and the contents of each of these documents are incorporated herein by reference. Except for any conventional carrier which is incompatible with the compound of the present invention, such as by producing any undesired biological effect, or interacting in a deleterious manner with any other ingredient of the pharmaceutically acceptable composition, the use of such carriers belongs to the scope of the present invention.

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

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, vehicle or combination thereof, The process involves mixing the various ingredients. Pharmaceutical compositions 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.

The salts of the compounds of the present invention, or crystalline forms thereof, are generally formulated into dosage forms suitable for administration to patients by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration such as tablets, capsules, caplets, pills, troches, 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.

The pharmaceutical compositions 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 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 herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid 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 US 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 maintain active ingredient dissolution.

In one embodiment, the method of treatment of the present invention comprises 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. Embodiments of the present invention include treating the diseases referred to in the present invention 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 .

In one embodiment, 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, may be administered by any suitable route of administration, including systemic and topical administration . Systemic administration includes oral, parenteral, transdermal, 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 as well as intraocular, otic, intravaginal, inhalation and intranasal administration. In one embodiment, 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 may be administered orally. In another embodiment, 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 may be administered by inhalation. In yet another embodiment, 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 may be administered intranasally.

In one embodiment, 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 may be administered at one time, or, according to the dosing regimen, over a specified period of time, at different times administered several times at a time interval. For example, it is administered once, twice, three times or four times per day. In one embodiment, the administration is once a day. In yet another embodiment, the administration is twice daily. Administration can be performed until the desired therapeutic effect is achieved or maintained indefinitely. A suitable dosing regimen for 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 depends on the pharmacokinetic properties of the salt of the compound, such as absorption, distribution and half-life, These can be determined by the skilled person. In addition, a suitable dosing regimen 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, including the duration for which the regimen is carried out, depends on the disease being treated, being treated The severity of the disease, 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 treatment effect, etc. are factors within the knowledge and experience of the technician. Such skilled artisans will also appreciate that adjustments to appropriate dosing regimens may be required as individual patient responses to dosing regimens change, or as individual patient needs change over time.

A salt of a compound of the present invention, or a crystalline form thereof, may be administered simultaneously with, before or after one or more other therapeutic agents. The salts of the compounds of the present invention or their crystalline forms can be administered separately with other therapeutic agents through the same or different routes of administration, or in the same pharmaceutical composition.

The salts of the compounds of the present invention or their crystalline forms can be used in combination with drugs and the like for the treatment of diseases and conditions mediated by PGD ₂ on the CRTH2 receptor, that is, to form the drug combination of the present invention, such as: salmeterol, Fluticasone, Loratadine, Montelukast, Omalizumab, Fusidic Acid, Clotrimazole, Tacrolimus, Pimecrolimus, DP Antagonists, Cilolast, 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 and the like, or compounds of the invention The salts or crystalline forms thereof may be administered concurrently with physical methods such as light therapy or electrical stimulation.

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

The dosage characteristics cited above 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.

In one embodiment, a therapeutically effective dose of a salt of a compound of the present invention is in an amount of the compound from about 0.1 mg to about 2,000 mg per day. Pharmaceutical compositions thereof should provide a dose of about 0.1 mg to about 2,000 mg of the compound. In a particular embodiment, pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 2,000 mg of the principal active ingredient or a combination of principal ingredients per dosage unit form.

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 and treating Or a drug for alleviating diseases mediated by PGD ₂ on CRTH2 receptors in mammals, including humans.

In particular, the amount of the compound in the pharmaceutical composition of the present invention is effective to detectably antagonize PGD ₂ on the CRTH2 receptor, and the salt of the compound of the present invention or a crystalline form thereof can be used as a therapeutic mediated by PGD ₂ on the CRTH2 receptor induced diseases such as asthma and allergic rhinitis.

The salts of the compounds of the present invention or their crystalline forms can be applied, but in no way limited to, using an effective amount of the salts of the compounds of the present invention or their crystalline forms or pharmaceutical compositions to be administered to a patient to prevent, treat or alleviate the effects of CRTH2 receptors on CRTH2 receptors. Diseases mediated by PGD ₂ . The diseases mediated by PGD ₂ on the CRTH2 receptor are asthma, chronic obstructive pulmonary disease, allergic asthma, perennial allergic rhinitis, seasonal allergic rhinitis, atopic dermatitis, contact hypersensitivity Allergies, conjunctivitis, eosinophilic bronchitis, food allergy, eosinophilic gastroenteritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, autoimmune disease, acne or reperfusion injury; wherein the autoimmune disorder is psoriasis, multiple sclerosis, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus or osteoarthritis.

An "effective amount" or "effective dose" of a salt of a compound of the present invention, or a crystalline form or a pharmaceutically acceptable composition thereof, refers to an amount effective to treat or lessen the severity of one or more of the disorders referred to herein. According to the methods of the present invention, a salt of a compound of the present invention, or a crystalline form or a pharmaceutically acceptable composition thereof, may be administered in any amount and by any route of administration effective for treating or reducing the severity of a disease. The exact amount necessary will vary from patient to patient, depending on race, age, the general condition of the patient, the severity of the infection, particular factors, the mode of administration, and the like. A salt of a compound of the present invention, or a crystalline form or a pharmaceutically acceptable composition thereof, may be administered in combination with one or more other therapeutic agents, as discussed herein.

In addition to being beneficial to human therapy, 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 in pets, introduced breed animals and farm animals. Examples of other animals include horses, dogs and cats.

Description of drawings

Figure 1 is an X-ray powder diffraction (XRPD) pattern of the triethanolamine salt crystal form I of the compound represented by formula (I).

Figure 2 is a differential scanning calorimetry (DSC) chart of the triethanolamine salt crystal form I of the compound represented by formula (I).

Figure 3 is a thermogravimetric analysis (TGA) chart of the triethanolamine salt crystal form I of the compound represented by formula (I).

Figure 4 is an X-ray powder diffraction (XRPD) pattern of the ethylenediamine salt crystal form I of the compound represented by formula (I).

Figure 5 is a differential scanning calorimetry (DSC) chart of the ethylenediamine salt crystal form I of the compound represented by formula (I).

Figure 6 is a thermogravimetric analysis (TGA) chart of the ethylenediamine salt crystal form I of the compound represented by formula (I).

Figure 7 is an X-ray powder diffraction (XRPD) pattern of the diethanolamine salt crystal form I of the compound represented by formula (I).

Figure 8 is a differential scanning calorimetry (DSC) chart of the diethanolamine salt crystal form I of the compound represented by formula (I).

Figure 9 is a thermogravimetric analysis (TGA) chart of the diethanolamine salt crystal form I of the compound represented by formula (I).

Figure 10 is an X-ray powder diffraction (XRPD) pattern of the diethylamine salt crystal form I of the compound represented by formula (I).

Figure 11 is a differential scanning calorimetry (DSC) chart of the diethylamine salt crystal form I of the compound represented by formula (I).

Figure 12 is a thermogravimetric analysis (TGA) chart of the diethylamine salt crystal form I of the compound represented by formula (I).

Figure 13 is an X-ray powder diffraction (XRPD) pattern of the tromethamine salt crystal form I of the compound represented by formula (I).

Figure 14 is a differential scanning calorimetry (DSC) chart of the tromethamine salt crystal form I of the compound represented by formula (I).

Figure 15 is a thermogravimetric analysis (TGA) chart of the tromethamine salt form I of the compound represented by formula (I).

Detailed ways

The present invention is further described below by way of examples, and therefore the present invention is not limited to the scope of the described examples.

The X-ray powder diffraction analysis method used in the present invention is: Empyrean diffractometer, using Cu-Kα radiation (45KV, 40mA) to obtain the X-ray powder diffraction pattern. Powdered samples were prepared as thin layers on a single crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.0167° steps over a range of 3°-60°. Data was collected using Data Collector software, processed by HighScore Plus software, and read by Data Viewer software.

The differential scanning calorimetry (DSC) analysis method used in the present invention is: using a TA Q2000 module with a thermal analysis controller to carry out differential scanning calorimetry. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5 mg of sample was accurately weighed into a special aluminum crucible with a lid and analyzed from room temperature to about 300°C using a linear heating device at 10°C/min. During use, the DSC cell was purged with dry nitrogen.

The thermogravimetric (TGA) analysis method used in the present invention is: use a TA Q500 module with a thermal analysis controller to carry out thermogravimetric analysis. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 10-30 mg of the sample was placed in a platinum crucible, and the sample was analyzed from room temperature to about 300°C using a linear heating device at 10°C/min. During use, the TGA cell was purged with dry nitrogen.

The solubility of the present invention is measured by an Agilent 1200 high performance liquid chromatograph DAD/VWD detector, and the chromatographic column model is Agilent XDB-C18 (4.6×50mm, 5μm). Detection wavelength is 266nm, flow rate is 1.0mL/min, column temperature is 35℃, mobile phase A: acetonitrile/0.01M ammonium acetate=10/90 (V/V), analysis method: acetonitrile/mobile phase A=70/30 (V/V), run time: 10 minutes.

The hygroscopicity of the present invention is measured by the DVS INT-Std dynamic moisture and gas adsorption analyzer from Surface Measurement Systems, UK. Take a test point at 5% humidity.

Specific implementation method

Comparative Example

The inventors have found through experiments that among the several crystal forms disclosed in the prior art WO 2016037591 A1, compared with other crystal forms, the compound (2-(5-fluoro-3-(1-((4 -Fluorophenyl)sulfonyl)piperidin-4-yl)-2-methyl-1H-indol-1-yl)acetic acid) crystal form I is more stable and has better pharmacokinetic properties, therefore , In the present invention, the inventors selected various crystal forms I of the compound represented by formula (I) with better properties as the reference substance, and studied the salt of the compound represented by formula (I) and its crystal form. Specifically, for the synthesis method of the compound crystal form I represented by formula (I), refer to Example 24 in the international application WO 2016037591 A1.

Example

Embodiment 1 Triethanolamine salt crystal form I

1. Preparation of Triethanolamine Salt Form I

At room temperature, the compound crystal form I (60.0g, 127.3mmol) represented by the formula (I) was added to ethanol (500.0mL) to make a slurry, and then a solution of triethanolamine (18.0mL, 140.0mmol) in ethanol (50.0mL) was added to precipitate out. For a large amount of product, ethanol (500.0 mL) was added, and the reaction was stirred for 9 h. After suction filtration, the filter cake was washed with ethanol (10.0 mL×5), and dried under vacuum at 80° C. overnight to obtain a white solid (3.8 g, 97.0%).

2. Identification of Triethanolamine Salt Form I

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by angles 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 crystal form I prepared according to the method in Example 1 of the present invention is basically as shown in FIG. 1 .

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 178.24°C is included, and there is an error tolerance of ±3°C. The DSC chart of the triethanolamine salt crystal form I prepared according to the method of Example 1 of the present invention is basically as shown in FIG. 2 .

(3) Thermal weight loss (TGA) analysis and identification by TA Q500: the heating rate is 10°C/min, and the weight loss is 0.01193% when heated to 133.18°C. The TGA diagram of the triethanolamine salt crystal form I prepared according to the method of Example 1 of the present invention is basically as shown in FIG. 3 .

Embodiment 2 Ethylenediamine salt crystal form I

1. Preparation of Ethylenediamine Salt Form I

At room temperature, the compound crystal form I (504.8 mg, 1.071 mmol) represented by the formula (I) was added to tetrahydrofuran (5.0 mL) and stirred to dissolve, and then a self-made 1.0 mol/L ethylenediamine solution in tetrahydrofuran (1.2 mL, 1.2 mmol), and the reaction was stirred overnight. After suction filtration, the filter cake was dried under vacuum at 80° C. for 8 h to obtain a white solid (520.3 mg, 95.49%).

2. Identification of ethylenediamine salt crystal form I

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks represented by angle 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 basically as shown in FIG. 4 .

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 206.72°C is included, and there is an error tolerance of ±3°C. The DSC chart of the ethylenediamine salt crystal form I prepared according to the method of Example 2 of the present invention is basically as shown in FIG. 5 .

(3) Thermal weight loss (TGA) analysis and identification by TA Q500: the heating rate is 10°C/min, and the weight loss is 0.6427% when heated to 128.70°C. The TGA diagram of the ethylenediamine salt crystal form I prepared according to the method of Example 2 of the present invention is basically as shown in FIG. 6 .

Embodiment 3 Diethanolamine salt crystal form I

1. Preparation of diethanolamine salt crystal form I

The compound crystalline form I (502 mg, 1.065 mmol) represented by formula (I) was added to isopropanol (5.0 mL), heated to 60° C. for 1 h, and then a self-made 1.0 mol/L ethanolic solution of diethanolamine was added ( 1.2mL, 1.2mmol), kept stirring for 5.5h and then cooled to room temperature naturally. After suction filtration, the filter cake was vacuum dried at 60°C overnight to obtain a white solid (592.5 mg, 100.5%).

2. Identification of Diethanolamine Salt Form I

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks represented by the angle 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°, exist ±0.2° error tolerance. The XRPD pattern of the diethanolamine salt crystal form I prepared according to the method of Example 3 of the present invention is basically as shown in FIG. 7 .

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 224.74°C is included, and there is an error tolerance of ±3°C. The DSC chart of the diethanolamine salt crystal form I prepared according to the method of Example 3 of the present invention is basically as shown in FIG. 8 .

(3) Thermal weight loss (TGA) analysis and identification by TA Q500: the heating rate is 10°C/min, and the weight loss is 2.186% when heated to 122.79°C. The TGA diagram of the diethanolamine salt crystal form I prepared according to the method of Example 3 of the present invention is basically as shown in FIG. 9 .

Embodiment 4 Diethylamine salt crystal form I

1. Preparation of diethylamine salt crystal form I

At room temperature, the compound crystal form I (503.9 mg, 1.069 mmol) represented by the formula (I) was added to tetrahydrofuran (5.0 mL) and stirred to dissolve, and then a self-made 1.0 mol/L ethanolic solution of diethylamine (1.3 mL, 1.3 mmol), and the reaction was stirred overnight. After suction filtration, the filter cake was washed with tetrahydrofuran (1.0 mL×2), and dried under vacuum at 60° C. overnight to obtain a white solid (539 mg, 96.63%).

2. Identification of diethylamine salt crystal form I

(1) Identification by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by angles 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°,24.28°, 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 crystal form I prepared according to the method of Example 4 of the present invention is basically as shown in FIG. 10 .

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 250.56°C is included, and there is an error tolerance of ±3°C. The DSC chart of the diethylamine salt crystal form I prepared according to the method of Example 4 of the present invention is basically as shown in FIG. 11 .

(3) Thermal weight loss (TGA) analysis and identification by TA Q500: the heating rate is 10°C/min, and the weight loss is 0.2436% when heated to 132.37°C. The TGA diagram of the diethylamine salt crystal form I prepared according to the method of Example 4 of the present invention is basically as shown in FIG. 12 .

Embodiment 5 tromethamine salt crystal form I

1. Preparation of Tromethamine Form I

Compound crystal form I (814.7 mg, 1.816 mmol) of the compound represented by formula (I) was added to n-propanol (8.0 mL) at room temperature, stirred at room temperature for 1 h, and then slowly dissolved tromethamine (239.0 mg, 1.953 mmol) was added. The solution of n-propanol (5.0 mL) was stirred at room temperature for 24 h. Filtered with suction, washed with ethanol (5.0 mL×2), and vacuumed at 80° C. for 24 h to obtain a white solid (899.0 mg, 86.89%).

2. Identification of tromethamine salt form I

(1) Identification by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, it has the following characteristic peaks represented by angle 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 crystal form I prepared according to the method of Example 5 of the present invention is basically as shown in FIG. 13 .

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 197.93°C is included, and there is an error tolerance of ±3°C. The DSC chart of the tromethamine salt crystal form I prepared according to the method of Example 5 of the present invention is basically as shown in FIG. 14 .

(3) Thermal weight loss (TGA) analysis and identification by TA Q500: the heating rate is 10°C/min, and the weight loss is 0.3987% when heated to 149.69°C. The TGA diagram of the tromethamine salt crystal form I prepared according to the method of Example 5 of the present invention is basically as shown in FIG. 15 .

Example 6 Pharmacokinetic experiment of the salt of the present invention or its crystal form

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

Divide 8-12kg male Beagle dogs into 6 groups, with 3 dogs in each group, and orally administer capsules containing the test sample at a dose of 5mg/kg, at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0 and 24h blood collection. A standard curve with a suitable range was established according to the sample concentration. Using AB SCIEX API4000 LC-MS/MS, the concentration of the test sample in the plasma sample was determined in the MRM mode, and the quantitative analysis was carried out. According to the drug concentration-time curve, the non-compartmental model method of WinNonLin 6.3 software was used to calculate the pharmacokinetic parameters. The experimental results are shown in Table 1.

Table 1 Pharmacokinetic experimental data

Test sample	Cmax (ng/ml)	T 1/2 (h)	Tmax (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

Experimental results:

As can be seen from Table 1, (1) relative to the compound crystal form I represented by formula (I), the diethylamine salt crystal form I of the present invention has a comparable blood concentration and half-life in Beagle dogs. The plasma concentration of butanetrioxide crystal form I in beagle dogs is slightly higher, and the half-life is longer; (2) Compared with the ethylenediamine of the compound represented by the formula (I), the crystal form I and the compound represented by the formula (I) Salt crystal form I, diethanolamine salt crystal form I, diethylamine salt crystal form I or tromethamine salt crystal form I, the triethanolamine salt crystal form I of the present invention has higher blood levels in beagle dogs. drug concentration and longer half-life. 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.

Example 7 Stability test of the salt of the present invention or its crystal form

High temperature experiment : Take a batch of test samples and put an appropriate amount into a flat weighing bottle, spread it into a thin layer of ≤5mm thick, and place it at 40°C and RH 75% for 32 days, and the sampling is stable on the 5th, 11th, and 32nd days. Sexual key inspection projects are tested.

High- humidity experiment: Take a batch of the test sample and put it into a flat weighing bottle, spread it into a thin layer of ≤5mm thick, and place it for 32 days at 25°C and RH 90%±5%. Daily sampling stability key inspection items for testing.

The experimental results are shown in Table 2.

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

Experimental results:

It can be seen from the results in Table 2 that under high temperature and high humidity conditions, the triethanolamine salt crystal form I of the compound represented by formula (I) of the present invention has no obvious change in appearance and purity, and has good stability effect, which is suitable for pharmaceutical use.

Example 8 Hygroscopicity test of the salt of the present invention or its crystalline form

An appropriate amount of the test sample was taken, and its hygroscopicity was tested by a dynamic moisture adsorption instrument. Experiments show that the salt of the present invention or its crystal form is not easily affected by high humidity and deliquescence.

Example 9 Solubility test of the salt of the present invention or its crystalline form

Take the test sample and put it in water at 37°C to prepare a supersaturated turbid solution, shake it for 24 hours, filter it, take the filtrate, and detect the solubility of the target sample in water by HPLC. Experiments show that the salt or its crystal form of the present invention has high solubility in water, so it has good druggability and is suitable for formulation development.

The above content is only a basic description under the concept of the present invention, and any equivalent transformation made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (11)

1. The salt of the compound represented by formula (I),

   

   Wherein, the salt is an organic alkali salt.
2. The salt according to claim 1, wherein the salt is a triethanolamine salt, the triethanolamine salt is a triethanolamine salt crystal form I, and the X-ray powder diffraction pattern of the triethanolamine salt crystal form I is in Diffraction peaks were observed 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°.
3. The salt according to claim 1 or 2, wherein the salt is a triethanolamine salt, the triethanolamine salt is a triethanolamine salt crystal form I, and the X-ray powder diffraction of the triethanolamine salt crystal form I The pattern 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°.
4. The salt according to any one of claims 1-3, wherein the salt is a triethanolamine salt, the triethanolamine salt is a triethanolamine salt crystal form I, and X of the triethanolamine salt crystal form I The X-ray powder diffraction pattern 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°.
5. The salt according to any one of claims 1-4, wherein the salt is a triethanolamine salt, the triethanolamine salt is a triethanolamine salt crystal form I, and the triethanolamine salt crystal form I has a basic The X-ray powder diffraction pattern shown in Figure 1 above.
6. The salt according to any one of claims 1-5, wherein the salt is a triethanolamine salt, the triethanolamine salt is a triethanolamine salt crystal form I, and the difference between the triethanolamine salt crystal form I The scanning calorimetry shown contains an endothermic peak at 178.24°C ± 3°C.
7. The salt according to any one of claims 1-6, wherein the salt is a triethanolamine salt, the triethanolamine salt is a triethanolamine salt crystal form I, and the triethanolamine salt crystal form I has a basic The differential scanning calorimetry map shown in Figure 2 above.
8. A pharmaceutical composition comprising the salt of any one of claims 1-7, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
9. Use of the salt according to any one of claims 1-7 or the pharmaceutical composition according to claim 8 in the preparation of a medicament for preventing, treating or reducing the mediated by PGD ₂ on the CRTH2 receptor in a patient disease.
10. The use according to claim 9, wherein the disease mediated by PGD ₂ on the CRTH2 receptor is asthma, chronic obstructive pulmonary disease, allergic asthma, perennial allergic rhinitis, seasonal allergy 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.
11. The use according to claim 10, wherein the autoimmune disorder is psoriasis, multiple sclerosis, allograft rejection, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus or osteoarthritis inflammation.

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