Solid forms of N-substituted phenylsulfonamide compounds

Abstract

The present invention relates to solid forms of N-substituted phenylsulfonamide compounds, specifically free crystalline forms, fumarate crystalline forms, hydrochloride crystalline forms, sulfate crystalline forms, succinate crystalline forms, malate crystalline forms, phosphate crystalline forms, tartrate crystalline forms, pyroglutamate crystalline forms, benzenesulfonate crystalline forms, malonate crystalline forms, and hemifumarate crystalline forms of N-substituted phenylsulfonamide compounds. The solid forms have excellent stability and solubility, excellent inhibitory effects on the transient receptor potential channel protein TRPA1, and good therapeutic effects on TRPA1-related diseases.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to solid forms of N-substituted phenylsulfonamide compounds. [Background technology]

[0002] TRPA1 belongs to the TRP ion channel superfamily and is the only member of the TRPA subfamily, which mediates Na+ + , K. + , Ca 2+ and Mg 2+TRPA1 is a nonselective cation channel that can permeate ions. It is primarily distributed in primary sensory neurons of the dorsal root nerve (DRG), trigeminal nerve (TG), and vagus nerve (VG). In terms of the human body systems in which it is distributed, TRPA1 is highly expressed in the peripheral nervous system, respiratory system, digestive system, and urinary system. Functional abnormalities in these organ tissues usually result in abnormalities in the expression and function of TRPA1 channels. TRPA1 converts cold, chemical, and mechanical stimuli into inward currents, triggering a range of physiological functions and contributing to the formation of various pain sensations. Inflammatory pain is a common problem in some chronic diseases, and clinically, effective treatments remain lacking. Animal experimental studies have shown that TRPA1 is involved in inflammatory responses and plays an important role in inflammatory pain. The use of a TRPA1-specific blocker significantly reduced inflammatory pain responses in rats. Current research has revealed that TRPA1 plays an important role in the development of asthma and cough, and that compounds that cause asthma and cough, whether endogenous or exogenous, can activate TRPA1. TRPA1 antagonists can alleviate asthma symptoms and block airway hyperresponsiveness. Various animal models of visceral hypersensitivity, such as colitis, rectal distension, and stress, have confirmed that TRPA1 is involved in regulating visceral hypersensitivity and plays an important role in visceral pain. Neuropathic pain is a pain syndrome caused by damage or disease of the central or peripheral nervous system, and is primarily manifested as hyperalgesia, abnormal pain sensitivity, and spontaneous pain. In recent years, an increasing number of studies have demonstrated that the TRPA1 channel plays an important role in various neuropathic pain conditions, such as diabetic neuropathy and chemotherapeutic drug-induced neuropathy. Recent studies have also shown that TRPA1 is involved in pain such as toothache and migraine, and that administration of TRPA1 antagonists can significantly reduce pain symptoms.

[0003] TRPA1 is widely distributed and expressed throughout the human body. In addition to the physiological functions associated with TRPA1, the development of TRPA1 inhibitors has been reported for a variety of indications, including inflammatory bowel disease, chronic obstructive pulmonary disease, antitussive and antipruritic effects, allergic rhinitis, ear diseases, antidiabetic effects, and urinary incontinence. TRPA1 has been identified as a novel target point for the treatment of various diseases.

[0004] N-substituted phenylsulfonamide compounds exhibit potent therapeutic effects for inflammatory bowel disease and analgesia by inhibiting transient receptor potential ankyrin 1 (TRPA1), while at the same time possessing an excellent safety profile. Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a solid form of an N-substituted phenylsulfonamide compound having excellent stability and solubility. [Means for solving the problem]

[0006] A first aspect of the present invention provides a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide. In another preferred example, the structure of the N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is as shown in Formula I. [ka]

[0007] In a preferred example, the solid form comprises a free or salt crystalline form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide. In another preferred example, the crystalline salt form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is a crystalline salt form formed by reacting the compound with a pharmaceutically acceptable acid, and the pharmaceutically acceptable acid is selected from the group consisting of hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, fumaric acid, L-tartaric acid, citric acid, D-glucuronic acid, L-malic acid, succinic acid, pyroglutamic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, malonic acid, benzoic acid, and hippuric acid.

[0008] In another preferred embodiment, the fumarate crystalline form is a fumarate salt crystalline form. In another preferred embodiment, the fumarate crystalline form is a hemifumarate crystalline form. In another preferred embodiment, the hydrochloride salt crystalline form is a hydrochloride salt crystalline form. In another preferred embodiment, the sulfate crystalline form is a sulfate crystalline form. In another preferred embodiment, the succinate crystalline form is a succinate crystalline form. In another preferred embodiment, the malate crystalline form is a malate crystalline form. In another preferred embodiment, the phosphate crystalline form is a phosphate crystalline form. In another preferred embodiment, the tartrate salt crystalline form is a tartrate salt crystalline form. In another preferred embodiment, the pyroglutamate crystalline form is a pyroglutamate crystalline form. In another preferred embodiment, the benzenesulfonate crystalline form is a benzenesulfonate crystalline form. In another preferred embodiment, the malonate crystalline form is a malonate crystalline form.

[0009] In another preferred example, the solid form is free crystalline form A, the X-ray powder diffraction spectrum of which has characteristic peaks at 2θ values ​​of 16.24±0.2°, 19.23±0.2°, 23.17±0.2°, 24.45±0.2°, and 32.76±0.2°. In another preferred example, the X-ray powder diffraction spectrum of said free crystalline form A has characteristic peaks at 2θ values ​​of 12.27±0.2°, 13.55±0.2°, 16.24±0.2°, 18.71±0.2°, 19.23±0.2°, 21.37±0.2°, 22.78±0.2°, 23.17±0.2°, 24.45±0.2°, 25.60±0.2° and 32.76±0.2°.

[0010] In another preferred example, the X-ray powder diffraction spectrum of the free crystalline form A has characteristic peaks and peak intensities at the following 2θ values: [Table 1]

[0011] In another preferred embodiment, the free crystalline form A has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred embodiment, the free crystalline form A comprises one or more characteristics selected from the group consisting of: The differential scanning calorimetry (DSC) graph of the free crystalline form A begins to show endothermic peaks when heated to 181.0±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C), 181.8±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C), 182.3±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C), The differential scanning calorimetry (DSC) graph of the free crystalline form A is essentially as shown in Figure 13;

[0012] a thermogravimetric analysis (TGA) graph of the free crystalline form A showing a weight loss of about 0.9±0.5% (preferably ±0.4%, ±0.3%, ±0.2% or ±0.1%) when heated to 150° C.; The thermogravimetric analysis (TGA) graph of the free crystalline form A is essentially as shown in FIG.

[0013] In another preferred embodiment, the salt crystalline form includes a fumarate crystalline form, a hydrochloride crystalline form, a sulfate crystalline form, a succinate crystalline form, a malate crystalline form, a phosphate crystalline form, a tartrate crystalline form, a pyroglutamate crystalline form, a benzenesulfonate crystalline form, a malonate crystalline form, and a hemifumarate crystalline form.

[0014] In another preferred example, the solid form is fumarate crystalline form B, and the X-ray powder diffraction spectrum of fumarate crystalline form B has characteristic peaks at 2θ values ​​of 11.34±0.2°, 14.40±0.2°, 19.71±0.2°, and 19.86±0.2°. In another preferred example, the solid form is fumarate crystalline form B, and the X-ray powder diffraction spectrum of fumarate crystalline form B has characteristic peaks at 2θ values ​​of 11.34±0.2°, 14.40±0.2°, 19.23±0.2°, and 19.71±0.2°.

[0015] In another preferred example, the X-ray powder diffraction spectrum of the fumarate salt crystalline form B has characteristic peaks at 2θ values ​​of 11.34±0.2°, 14.40±0.2°, 16.75±0.2°, 19.23±0.2°, 19.71±0.2°, 19.86±0.2°, and 24.03±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the fumarate salt crystalline form B is 4.79±0.2°, 11.34±0.2°, 12.14±0.2°, 12.64±0.2°, 13.05±0.2°, 13.45±0.2°, 14.40±0.2°, 15.54±0.2°, 16.14±0.2°, 16.75±0.2°, 18.08±0.2°, 19.23±0.2°, 19.71±0.2°, 19.86±0.2°, 22.30±0.2°, 22.47±0.2°, 22.78±0.2°, 23.18±0.2° Characteristic peaks were observed at 2θ values ​​of 0.2°, 24.03±0.2°, 24.41±0.2°, 24.85±0.2°, 25.28±0.2°, 25.44±0.2°, 25.75±0.2°, 25.91±0.2°, 26.28±0.2°, 26.86±0.2°, 27.28±0.2°, 28.45±0.2°, 28.76±0.2°, 29.02±0.2°, 31.54±0.2°, 32.60±0.2°, 34.30±0.2°, 35.11±0.2°, 36.61±0.2°, and 38.17±0.2°.

[0016] In another preferred example, the X-ray powder diffraction spectrum of the fumarate salt crystalline form B has characteristic peaks and peak intensities at the following 2θ values: [Table 2]

[0017] In another preferred example, the fumarate salt crystalline form B has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred embodiment, the fumarate salt crystalline form B comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the fumarate salt crystalline form B exhibits an endothermic peak upon heating to 189.4±5°C (preferably ±4°C, ±3°C, ±2°C, or ±1°C); The differential scanning calorimetry (DSC) graph of the fumarate salt crystalline form B is essentially as shown in Figure 14;

[0018] a thermogravimetric analysis (TGA) graph of the fumarate salt crystalline form B showing a weight loss of about 0.8±0.2% (preferably ±0.15%, ±0.1%, ±0.05% or ±0.02%) when heated to 150° C.; The thermogravimetric analysis (TGA) graph of the fumarate salt crystalline form B is essentially as shown in FIG.

[0019] In another preferred example, in the fumarate salt crystalline form B, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to fumaric acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0020] In another preferred example, the solid form is hydrochloride crystalline form C, the X-ray powder diffraction spectrum of which has characteristic peaks at 2θ values ​​of 17.20±0.2°, 20.34±0.2°, 24.74±0.2°, and 25.25±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the hydrochloride salt crystalline form C has characteristic peaks at 2θ values ​​of 11.56±0.2°, 17.20±0.2°, 20.34±0.2°, 23.27±0.2°, 23.52±0.2°, 24.74±0.2°, and 25.25±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the hydrochloride salt crystalline form C has characteristic peaks at 2θ values ​​of 11.56±0.2°, 13.49±0.2°, 17.20±0.2°, 19.63±0.2°, 20.34±0.2°, 23.27±0.2°, 23.52±0.2°, 24.74±0.2°, and 25.25±0.2°.

[0021] In another preferred example, the X-ray powder diffraction spectrum of the hydrochloride salt crystalline form C has the following characteristic peaks and peak intensities at the following 2θ values: [Table 3]

[0022] In another preferred example, the hydrochloride salt crystalline form C has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred embodiment, the hydrochloride salt crystalline form C comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the hydrochloride salt crystalline form C begins to show endothermic peaks upon heating to 93.1±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C) and 150.7±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C); The differential scanning calorimetry (DSC) graph of the hydrochloride salt crystalline form C is essentially as shown in Figure 15;

[0023] a thermogravimetric analysis (TGA) graph of the hydrochloride salt crystalline form C showing a weight loss of about 4.2±0.5% (preferably ±0.4%, ±0.3%, ±0.2% or ±0.1%) when heated to 100° C.; The thermogravimetric analysis (TGA) graph of the hydrochloride salt crystalline form C is essentially as shown in FIG.

[0024] In another preferred example, in the hydrochloride salt crystalline form C, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to hydrochloric acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0025] In another preferred example, the solid form is Sulfate Crystalline Form D, and the X-ray powder diffraction spectrum of Sulfate Crystalline Form D has characteristic peaks at 2θ values ​​of 16.84±0.2°, 23.08±0.2°, and 24.38±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the Sulfate Salt Crystalline Form D has characteristic peaks at 2θ values ​​of 11.51±0.2°, 12.13±0.2°, 16.84±0.2°, 23.08±0.2°, 23.49±0.2°, and 24.38±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the Sulfate Salt Crystalline Form D has characteristic peaks at 2θ values ​​of 11.51±0.2°, 12.13±0.2°, 16.84±0.2°, 19.14±0.2°, 20.42±0.2°, 23.08±0.2°, 23.49±0.2°, and 24.38±0.2°.

[0026] In another preferred example, the X-ray powder diffraction spectrum of the sulfate salt crystalline form D has the following characteristic peaks and peak intensities at the following 2θ values: [Table 4]

[0027] In another preferred example, the Sulfate Salt Crystalline Form D has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred embodiment, the Sulfate Salt Crystalline Form D comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the Sulfate Salt crystalline form D exhibits an endothermic peak upon heating to 175.8±5°C (preferably ±4°C, ±3°C, ±2°C, or ±1°C); The differential scanning calorimetry (DSC) graph of the Sulfate Salt Crystalline Form D is essentially as shown in FIG. 16.

[0028] a thermogravimetric analysis (TGA) graph of the Sulfate Salt crystalline form D showing a weight loss of about 0.6±0.1% (preferably ±0.08%, ±0.05%, ±0.02% or ±0.01%) when heated to 150° C.; The thermogravimetric analysis (TGA) graph of the Sulfate Salt Crystalline Form D is essentially as shown in FIG.

[0029] In another preferred example, in the Sulfate Crystalline Form D, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to sulfuric acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0030] In another preferred example, the solid form is succinate crystalline form E, and the X-ray powder diffraction spectrum of succinate crystalline form E has characteristic peaks at 2θ values ​​of 12.57±0.2°, 19.18±0.2°, 19.89±0.2°, and 22.68±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the succinate salt crystalline form E has characteristic peaks at 2θ values ​​of 12.57±0.2°, 14.89±0.2°, 19.18±0.2°, 19.89±0.2°, 22.68±0.2°, 23.48±0.2°, and 24.31±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the succinate salt crystalline form E has characteristic peaks at 2θ values ​​of 12.57±0.2°, 12.83±0.2°, 14.63±0.2°, 14.89±0.2°, 15.43±0.2°, 18.04±0.2°, 18.35±0.2°, 18.97±0.2°, 19.18±0.2°, 19.89±0.2°, 21.98±0.2°, 22.68±0.2°, 22.97±0.2°, 23.48±0.2°, 24.31±0.2°, 25.15±0.2°, 25.51±0.2°, 26.57±0.2°, and 27.33±0.2°.

[0031] In another preferred example, the X-ray powder diffraction spectrum of the succinate crystalline form E has characteristic peaks and peak intensities at the following 2θ values: [Table 5]

[0032] In another preferred example, the succinate salt crystalline form E has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred example, the succinate crystalline form E comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the succinate salt crystalline form E begins to exhibit an endothermic peak upon heating to 172.9±5°C (preferably ±4°C, ±3°C, ±2°C, or ±1°C); The differential scanning calorimetry (DSC) graph of the succinate salt crystalline form E is essentially as shown in FIG. 17;

[0033] a thermogravimetric analysis (TGA) graph of the succinate salt crystalline form E shows a weight loss of about 1.2±0.2% (preferably ±0.15%, ±0.1%, ±0.05% or ±0.02%) when heated to 150° C.; The thermogravimetric analysis (TGA) graph of the succinate salt crystalline form E is essentially as shown in FIG.

[0034] In another preferred example, in the succinate crystalline form E, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to succinic acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0035] In another preferred example, the solid form is malate crystalline form F, and the X-ray powder diffraction spectrum of malate crystalline form F has characteristic peaks at 2θ values ​​of 12.70±0.2°, 14.57±0.2°, 19.13±0.2°, and 19.47±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the malate crystalline form F has characteristic peaks at 2θ values ​​of 12.70±0.2°, 14.57±0.2°, 18.39±0.2°, 19.13±0.2°, 19.47±0.2°, 22.94±0.2°, 23.77±0.2°, and 24.35±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the malate crystalline form F has characteristic peaks at 2θ values ​​of 11.41±0.2°, 12.11±0.2°, 12.70±0.2°, 14.57±0.2°, 17.73±0.2°, 18.39±0.2°, 19.13±0.2°, 19.47±0.2°, 22.17±0.2°, 22.49±0.2°, 22.94±0.2°, 23.77±0.2°, 24.35±0.2°, 25.56±0.2°, 26.44±0.2°, 27.48±0.2°, and 28.08±0.2°.

[0036] In another preferred example, the X-ray powder diffraction spectrum of the malate crystalline form F has characteristic peaks and peak intensities at the following 2θ values: [Table 6]

[0037] In another preferred example, the malate crystalline form F has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred example, the Malate Crystalline Form F comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the malate crystalline form F exhibits endothermic peaks upon heating to 144.7±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C) and 160.6±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C); The differential scanning calorimetry (DSC) graph of the malate crystalline form F is essentially as shown in Figure 18;

[0038] a thermogravimetric analysis (TGA) graph of the malate crystalline form F exhibits a weight loss of about 2.0±0.3% (preferably ±0.2%, ±0.15%, ±0.1% or ±0.05%) upon heating to 100° C.; The thermogravimetric analysis (TGA) graph of the malate crystalline form F is essentially as shown in FIG.

[0039] In another preferred example, in the malate crystalline form F, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to malic acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0040] In another preferred example, the solid form is phosphate crystalline form G, and the X-ray powder diffraction spectrum of phosphate crystalline form G has characteristic peaks at 2θ values ​​of 11.20±0.2°, 19.70±0.2°, 21.24±0.2°, and 22.49±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the phosphate crystalline form G has characteristic peaks at 2θ values ​​of 11.20±0.2°, 12.79±0.2°, 19.70±0.2°, 21.24±0.2°, 22.49±0.2°, and 23.32±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the phosphate crystalline form G has characteristic peaks at 2θ values ​​of 11.20±0.2°, 12.79±0.2°, 19.70±0.2°, 20.37±0.2°, 21.24±0.2°, 22.49±0.2°, 23.32±0.2°, 24.64±0.2°, and 30.11±0.2°.

[0041] In another preferred example, the X-ray powder diffraction spectrum of the phosphate crystalline form G has the following characteristic peaks and peak intensities at the following 2θ values: [Table 7]

[0042] In another preferred embodiment, the phosphate salt crystalline form G has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred embodiment, the phosphate crystalline form G comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the phosphate crystalline form G begins to exhibit an endothermic peak upon heating to 164.1±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C); The differential scanning calorimetry (DSC) graph of the phosphate crystalline form G is essentially as shown in FIG. 19;

[0043] a thermogravimetric analysis (TGA) graph of the phosphate crystalline form G shows a weight loss of about 1.8% (preferably ±0.2%, ±0.15%, ±0.1% or ±0.05%) when heated to 150°C; The thermogravimetric analysis (TGA) graph of the phosphate salt crystalline form G is essentially as shown in FIG.

[0044] In another preferred example, in the phosphate crystalline form G, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to phosphoric acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, more preferably 1:1.

[0045] In another preferred example, the solid form is tartrate salt crystalline form H, the X-ray powder diffraction spectrum of which has characteristic peaks at 2θ values ​​of 14.19±0.2°, 18.64±0.2°, 18.95±0.2°, and 23.70±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the tartrate salt crystalline form H has characteristic peaks at 2θ values ​​of 14.19±0.2°, 18.17±0.2°, 18.64±0.2°, 18.95±0.2°, 22.11±0.2°, 23.70±0.2°, and 24.54±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the tartrate salt crystalline form H has characteristic peaks at 2θ values ​​of 11.45±0.2°, 12.57±0.2°, 12.92±0.2°, 14.19±0.2°, 14.62±0.2°, 18.17±0.2°, 18.64±0.2°, 18.95±0.2°, 22.11±0.2°, 23.30±0.2°, 23.70±0.2°, 24.54±0.2°, and 25.68±0.2°.

[0046] In another preferred example, the X-ray powder diffraction spectrum of the tartrate salt crystalline form H has characteristic peaks and peak intensities at the following 2θ values: [Table 8]

[0047] In another preferred example, the tartrate salt crystalline form H has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred embodiment, the Tartrate Salt Crystalline Form H comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the tartrate salt crystalline form H exhibits an endothermic peak upon heating to 164.7±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C); The differential scanning calorimetry (DSC) graph of the tartrate salt crystalline form H is essentially as shown in Figure 20;

[0048] a thermogravimetric analysis (TGA) graph of the tartrate salt crystalline form H showing a weight loss of about 0.72% (preferably ±0.1%, ±0.05%, ±0.02% or ±0.01%) when heated to 150°C; The thermogravimetric analysis (TGA) graph of the tartrate salt crystalline form H is essentially as shown in FIG.

[0049] In another preferred example, in the tartrate salt crystalline form H, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to tartaric acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0050] In another preferred example, the solid form is pyroglutamate crystalline form I, and the X-ray powder diffraction spectrum of pyroglutamate crystalline form I has characteristic peaks at 2θ values ​​of 9.29±0.2°, 10.76±0.2°, 17.98±0.2°, and 23.72±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the pyroglutamate crystalline form I has characteristic peaks at 2θ values ​​of 9.29±0.2°, 10.76±0.2°, 17.81±0.2°, 17.98±0.2°, 19.93±0.2°, 21.60±0.2°, 21.86±0.2°, and 23.72±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the pyroglutamate crystalline Form I has characteristic peaks at 2θ values ​​of 9.29±0.2°, 10.76±0.2°, 14.33±0.2°, 16.91±0.2°, 17.81±0.2°, 17.98±0.2°, 18.83±0.2°, 19.93±0.2°, 21.60±0.2°, 21.86±0.2°, 22.98±0.2°, 23.72±0.2°, and 30.86±0.2°.

[0051] In another preferred example, the X-ray powder diffraction spectrum of the pyroglutamate crystalline form I has characteristic peaks and peak intensities at the following 2θ values: [Table 9]

[0052] In another preferred embodiment, the pyroglutamate crystalline form I has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred embodiment, the pyroglutamate crystalline form I comprises one or more characteristics selected from the group consisting of: The differential scanning calorimetry (DSC) graph of the pyroglutamate crystalline form I begins to show an endothermic peak when heated to 155.4±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C); The differential scanning calorimetry (DSC) graph of the pyroglutamate crystalline form I is essentially as shown in FIG. 21.

[0053] a thermogravimetric analysis (TGA) graph of the pyroglutamate crystalline form I shows a weight loss of about 1.3% (preferably ±0.2%, ±0.15%, ±0.1% or ±0.05%) when heated to 120°C; The thermogravimetric analysis (TGA) graph of the pyroglutamate crystalline form I is essentially as shown in FIG.

[0054] In another preferred example, in the pyroglutamate crystalline form I, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to pyroglutamic acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, more preferably 1:1.

[0055] In another preferred example, the solid form is benzenesulfonate crystalline form J, and the X-ray powder diffraction spectrum of the benzenesulfonate crystalline form J has characteristic peaks at 2θ values ​​of 13.69±0.2°, 19.48±0.2°, 21.07±0.2°, and 22.15±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the benzenesulfonate salt crystalline form J has characteristic peaks at 2θ values ​​of 11.53±0.2°, 13.69±0.2°, 17.96±0.2°, 19.48±0.2°, 21.07±0.2°, 22.15±0.2°, and 23.06±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the benzenesulfonate salt crystalline form J has characteristic peaks at 2θ values ​​of 9.70±0.2°, 11.53±0.2°, 13.69±0.2°, 15.72±0.2°, 17.96±0.2°, 19.48±0.2°, 19.96±0.2°, 21.07±0.2°, 22.15±0.2°, 23.06±0.2°, 27.64±0.2°, and 29.58±0.2°.

[0056] In another preferred example, the X-ray powder diffraction spectrum of the benzenesulfonate salt crystalline form J has the following characteristic peaks and peak intensities at the following 2θ values: [Table 10]

[0057] In another preferred example, the benzenesulfonate salt crystalline form J has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred example, the benzenesulfonate salt crystalline form J comprises one or more characteristics selected from the group consisting of: The differential scanning calorimetry (DSC) graph of the benzenesulfonate salt crystalline form J begins to show an endothermic peak when heated to 164.9±5°C (preferably ±4°C, ±3°C, ±2°C, or ±1°C); The differential scanning calorimetry (DSC) graph of the benzenesulfonate salt crystalline form J is essentially as shown in FIG. 22.

[0058] a thermogravimetric analysis (TGA) graph of the benzenesulfonate salt crystalline form J shows a weight loss of about 1.3% (preferably ±0.2%, ±0.15%, ±0.1%, or ±0.05%) when heated to 150°C; The thermogravimetric analysis (TGA) graph of the benzenesulfonate salt crystalline form J is essentially as shown in FIG.

[0059] In another preferred example, in the benzenesulfonate Crystal Form J, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to benzenesulfonic acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0060] In another preferred example, the solid form is malonate crystalline form K, and the X-ray powder diffraction spectrum of the malonate crystalline form K has characteristic peaks at 2θ values ​​of 15.28±0.2°, 19.66±0.2°, and 20.42±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the malonate crystalline form K has characteristic peaks at 2θ values ​​of 15.28±0.2°, 19.43±0.2°, 19.66±0.2°, 20.42±0.2°, and 23.66±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the malonate crystalline form K has characteristic peaks at 2θ values ​​of 13.71±0.2°, 15.28±0.2°, 19.43±0.2°, 19.66±0.2°, 20.42±0.2°, 22.66±0.2°, 23.66±0.2°, 25.46±0.2°, 26.42±0.2°, and 27.82±0.2°.

[0061] In another preferred example, the X-ray powder diffraction spectrum of the malonate crystalline form K has characteristic peaks and peak intensities at the following 2θ values: [Table 11]

[0062] In another preferred example, the malonate crystalline form K has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred embodiment, the malonate crystalline form K comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the malonate salt crystalline form K begins to exhibit an endothermic peak upon heating to 139.8±5°C (preferably ±4°C, ±3°C, ±2°C, or ±1°C); The differential scanning calorimetry (DSC) graph of the malonate crystalline form K is essentially as shown in Figure 23;

[0063] a thermogravimetric analysis (TGA) graph of the malonate salt crystalline form K showing a weight loss of about 1.58% (preferably ±0.2%, ±0.15%, ±0.1% or ±0.05%) when heated to 130°C; The thermogravimetric analysis (TGA) graph of the malonate crystalline form K is essentially as shown in FIG.

[0064] In another preferred example, in the malonate crystalline form K, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to malonic acid is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0065] In another preferred example, the solid form is hemifumarate crystalline form L, and the X-ray powder diffraction spectrum of the hemifumarate crystalline form L has characteristic peaks at 2θ values ​​of 11.57±0.2°, 17.25±0.2°, 23.08±0.2°, and 24.33±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the hemifumarate salt crystalline form L has characteristic peaks at 2θ values ​​of 11.57±0.2°, 12.12±0.2°, 17.25±0.2°, 23.08±0.2°, 24.33±0.2°, and 25.68±0.2°. In another preferred example, the X-ray powder diffraction spectrum of the hemifumarate salt crystalline form L has characteristic peaks at 2θ values ​​of 5.75±0.2°, 11.57±0.2°, 12.12±0.2°, 16.91±0.2°, 17.25±0.2°, 17.50±0.2°, 19.31±0.2°, 20.67±0.2°, 23.08±0.2°, 24.33±0.2°, and 25.68±0.2°.

[0066] In another preferred example, the X-ray powder diffraction spectrum of the hemifumarate salt crystalline form L has characteristic peaks and peak intensities at the following 2θ values: [Table 12]

[0067] In another preferred example, the hemifumarate salt crystalline form L has an X-ray powder diffraction spectrum essentially as shown in FIG. In another preferred example, the hemifumarate crystalline form L comprises one or more characteristics selected from the group consisting of: the differential scanning calorimetry (DSC) graph of the hemifumarate salt crystalline form L begins to exhibit an endothermic peak upon heating to 171.5±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C); The differential scanning calorimetry (DSC) graph of the hemifumarate salt crystalline form L is essentially as shown in Figure 24;

[0068] a thermogravimetric analysis (TGA) graph of the hemifumarate salt crystalline form L showing a weight loss of about 0.3% (preferably ±0.1% or ±0.05%) when heated to 150±2°C; The thermogravimetric analysis (TGA) graph of the hemifumarate salt crystalline form L is essentially as shown in FIG.

[0069] In another preferred example, in the hemifumarate crystalline form L, the molar ratio of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide to fumaric acid is 1-1.5:0.5-0.75, preferably 1-1.2:0.5-0.6, and more preferably 1:0.5.

[0070] A second aspect of the present invention provides a method for preparing a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to the first aspect of the present invention, the method comprising any one of Methods 1 to 8.

[0071] The method 1 is (a1) dissolving the crude product of the compound prepared in a first solvent, heating the solution, and mixing the solution until the solution becomes clear; (a2) adding a second solvent followed by cooling and crystallization to obtain free crystalline form A. In another preferred embodiment, in Method 1, the crude product of the compound is a crude product obtained by filtering, washing, and drying under reduced pressure according to the method of Application No. 202110666168.6.

[0072] In another preferred embodiment, in step (a1), the first solvent is selected from the group consisting of dichloromethane, methyl t-butyl ether, toluene, tetrahydrofuran, dimethyl sulfoxide, or a combination thereof. Preferably, dimethyl sulfoxide. In another preferred example, in step (a1), the volume ratio of the first solvent to the crude product is 1.5-3:1, preferably 2:1. In another preferred example, in step (a1), the temperature increase refers to increasing the temperature to 50 to 70°C, preferably 60 to 70°C. In another preferred embodiment, in step (a1), the mixing time is 0.3 to 1 hour, preferably 0.5 hour.

[0073] In another preferred embodiment, in step (a2), the second solvent is selected from the group consisting of methanol, absolute ethanol, 95% ethanol, ethanol / water, acetone / water, acetonitrile / water, or a combination thereof, preferably methanol, absolute ethanol, or 95% ethanol, more preferably absolute ethanol. In another preferred example, in step (a2), the volume ratio of the second solvent to the crude product is 1.5 to 5:1, for example, 2:1, 3:1. In another preferred embodiment, in step (a2), the second solvent is added at 50 to 70°C, preferably 60 to 70°C. In another preferred embodiment, in step (a2), the cooling crystallization comprises split cooling crystallization. In another preferred example, in step (a2), the cooling crystallization includes a step of stirring for 0.5 hours, then stopping the heating, gradually cooling to 0 to 10°C, maintaining the temperature at 0 to 10°C, and stirring for 4 hours.

[0074] Method 2 includes dissolving the starting compound and fumaric acid in a third solvent, mixing them at a low temperature, and crystallizing them to obtain the fumarate salt crystalline form B. In another preferred embodiment, the third solvent is selected from the group consisting of methanol, absolute ethanol, 95% ethanol, ethanol / water, acetone / water, acetonitrile / water, ethyl acetate, acetone, or a combination thereof, preferably methanol or 95% ethanol, more preferably methanol.

[0075] In another preferred example, in Method 2, the molar ratio of the compound starting material to fumaric acid is 1:1 to 1.5, preferably 1:1 to 1.2, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, or 1:1.2. In another preferred example, in Method 2, the mass / volume ratio of the compound raw material to the third solvent is 1 g:1 to 20 ml, preferably 1 g:1 to 10 ml, for example, 1 g:3 ml, 1 g:6 ml, or 1 g:9 ml. In another preferred example, in Method 2, the mixing is carried out at 0 to 15°C, preferably 3 to 10°C, and more preferably 4 to 6°C. In another preferred example, in Method 2, the mixing time is 0.5 to 2 days, preferably 1 day. In another preferred example, the method 2 includes dissolving the compound raw material and fumaric acid in a third solvent and stirring the mixture at 5° C. for 1 day. In another preferred embodiment, the method 2 further comprises post-treatment steps of suction filtration and vacuum drying.

[0076] The method 3 is (b1) dissolving a compound raw material in a fourth solvent; (b2) dissolving concentrated hydrochloric acid in a fourth solvent; (b3) adding the fourth solvent solution of hydrochloric acid obtained in step (b2) dropwise to the mixture obtained in step (b1), mixing, and crystallizing to obtain said hydrochloride salt crystalline form C.

[0077] In another preferred embodiment, in step (b1), the fourth solvent is selected from the group consisting of dichloromethane, methyl t-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran. In another preferred example, the concentrated hydrochloric acid is an aqueous HCl solution with a mass fraction of 35 to 40%. In another preferred example, in Method 3, the molar ratio of the compound raw material to the concentrated hydrochloric acid is 1:1 to 1.5, preferably 1:1 to 1.4, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, 1:1.2, or 1:1.4.

[0078] In another preferred example, the volume ratio of the fourth solvent used in step (b1) to the fourth solvent used in step (b2) is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, more preferably 1:1. In another preferred example, in step (b3), the mixing is carried out at 10 to 35°C. In another preferred embodiment, in step (b3), the mixing time is 0.5 to 2 hours, preferably 1 hour. In another preferred example, the step (b3) comprises slowly dropping a solution of hydrochloric acid in the fourth solvent into the suspension of the compound raw material under stirring conditions, and stirring at room temperature for 1 hour. In another preferred embodiment, the method 3 further comprises post-treatment steps of suction filtration and vacuum drying.

[0079] The method 4 is (c1) dissolving a compound raw material in a fifth solvent; (c2) dissolving concentrated sulfuric acid in a fifth solvent; (c3) adding the fifth solvent solution of sulfuric acid obtained in step (c2) dropwise to the mixture obtained in step (c1) until the solution becomes clear; (c4) adding a sixth solvent dropwise to the mixture obtained in step (c3), mixing, and crystallizing to obtain Form D of the Sulfate Salt.

[0080] In another preferred embodiment, in step (c1), the fifth solvent is a mixed solvent of an organic solvent and water. The fifth solvent is selected from the group consisting of ethanol / water, acetone / water, acetonitrile / water, or a combination thereof. Preferably, it is acetonitrile / water. In another preferred example, in step (c1), the volume ratio of the organic solvent to water in the fifth solvent is 10 to 30:1, for example, 15:1, 19:1, 20:1, 25:1, or 30:1. In another preferred example, the concentrated sulfuric acid is an aqueous solution of H2SO4 with a mass fraction of 95 to 98%.

[0081] In another preferred example, in Method 4, the molar ratio of the compound raw material to the concentrated sulfuric acid is 1:1 to 1.5, for example, 1:1.1, 1:1.15, 1:1.2, 1:3, or 1:4. In another preferred example, the volume ratio of the compound raw material to the total amount of the fifth solvent used in Method 4 is 1 g:10 to 40 ml, preferably 1 g:10 to 30 ml, for example, 1 g:15 ml, 1 g:20 ml, 1 g:25 ml, or 1 g:30 ml. In another preferred example, the volume ratio of the fifth solvent used in step (c1) to the fifth solvent used in step (c2) is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, more preferably 1:1.

[0082] In another preferred embodiment, the step (c3) comprises slowly dropping the fifth solvent solution of sulfuric acid into the suspension of the free sample under stirring conditions until the solution of the sample becomes clear. In another preferred embodiment, in step (c4), the sixth solvent is selected from the group consisting of dichloromethane, methyl t-butyl ether, toluene, tetrahydrofuran, or a combination thereof, and preferably methyl t-butyl ether.

[0083] In another preferred example, the volume ratio of the total amount of the fifth solvent to the sixth solvent used in the method 4 is 1:1.5 to 3, for example, 1:1.7, 1:2, 1:2.5, or 1:3. In another preferred example, in step (c4), the mixing is carried out at 10 to 35°C. In another preferred embodiment, in step (c4), the mixing time is 0.5 to 2 hours, preferably 1 hour. In another preferred embodiment, the step (c4) includes slowly dropping the sixth solvent into the system under stirring, followed by stirring at room temperature for 1 hour to allow crystallization. In another preferred embodiment, the method 4 further comprises post-treatment steps of suction filtration and vacuum drying.

[0084] The method 5 is The method includes dissolving the starting compound and succinic acid in a seventh solvent, mixing, and crystallizing the compound to obtain the succinate crystalline form E. In another preferred embodiment, the seventh solvent is selected from the group consisting of methanol, absolute ethanol, 95% ethanol, ethanol / water, acetone / water, acetonitrile / water, ethyl acetate, acetone, or a combination thereof, preferably methanol or 95% ethanol, more preferably methanol. In another preferred example, in Method 5, the molar ratio of the compound starting material to succinic acid is 1:1 to 1.5, preferably 1:1 to 1.2, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, or 1:1.2.

[0085] In another preferred example, in Method 5, the mass volume ratio of the compound raw material to the seventh solvent is 1 g:1 to 20 ml, preferably 1 g:1 to 10 ml, for example, 1 g:3 ml, 1 g:6 ml, or 1 g:9 ml. In another preferred example, in Method 5, the mixing is carried out at 10 to 35°C. In another preferred example, in Method 5, the mixing time is 0.5 to 2 days, preferably 1 day. In another preferred example, the method 5 includes dissolving the compound raw material and succinic acid in the seventh solvent and stirring the mixture at room temperature for 1 day. In another preferred embodiment, the method 5 further comprises post-treatment steps of suction filtration and vacuum drying.

[0086] The method 6 is The method includes dissolving the compound raw material and malic acid in an eighth solvent, mixing, and crystallizing to obtain the malate crystalline form F. In another preferred embodiment, the eighth solvent is selected from the group consisting of dichloromethane, methyl t-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran. In another preferred example, in Method 6, the molar ratio of the compound raw material to malic acid is 1:1 to 1.5, preferably 1:1 to 1.2, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, or 1:1.2.

[0087] In another preferred example, in Method 6, the mass / volume ratio of the compound raw material to the eighth solvent is 1 g:1 to 20 ml, preferably 1 g:1 to 15 ml, for example, 1 g:5 ml, 1 g:9 ml, 1 g:10 ml, or 1 g:12 ml. In another preferred example, in Method 6, the mixing is carried out at 10 to 35°C. In another preferred example, in Method 6, the mixing time is 0.5 to 2 days, preferably 1 day. In another preferred example, the method 6 includes dissolving the compound raw material and malic acid in the eighth solvent, and stirring the mixture at room temperature for 1 day. In another preferred embodiment, the method 6 further comprises post-treatment steps of suction filtration and vacuum drying.

[0088] The method 7 is The method includes dissolving, mixing, and crystallizing a raw compound and an acid in a ninth solvent to obtain phosphate crystalline form G, tartrate crystalline form H, pyroglutamate crystalline form I, benzenesulfonate crystalline form J, or malonate crystalline form K corresponding to the acid, wherein the acid is selected from the group consisting of phosphoric acid, tartaric acid, pyroglutamic acid, benzenesulfonic acid, or malonic acid. In another preferred embodiment, the ninth solvent is selected from the group consisting of dichloromethane, methyl t-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran.

[0089] In another preferred example, in Method 7, the molar ratio of the compound raw material to the acid is 1:1 to 1.5, preferably 1:1 to 1.2, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, or 1:1.2. In another preferred example, in the method 7, the concentration of the ninth solvent in the compound raw material is 0.05 to 0.5 mol / L, preferably 0.05 to 0.3 mol / L, for example, 0.08 mol / L, 0.1 mol / L, 0.12 mol / L, or 0.15 mol / L. In another preferred embodiment, in Method 7, the mixing is carried out at 10 to 35°C. In another preferred embodiment, the method 7 further comprises post-treatment steps of suction filtration and vacuum drying.

[0090] The method 8 is The method includes dissolving the starting compound and fumaric acid in a third solvent, mixing, and crystallizing the compound to obtain the hemifumarate crystalline form L. In another preferred embodiment, the third solvent is selected from the group consisting of methanol, absolute ethanol, 95% ethanol, ethanol / water, acetone / water, acetonitrile / water, ethyl acetate, acetone, or a combination thereof, preferably methanol or 95% ethanol, more preferably methanol.

[0091] In another preferred example, in Method 8, the molar ratio of the compound starting material to fumaric acid is 1:0.5 to 0.75, preferably 1:0.5 to 0.6, for example, 1:0.5, 1:0.55, 1:0.58, or 1:0.6. In another preferred example, in Method 8, the mass / volume ratio of the compound raw material to the third solvent is 1 g:1-10 ml, preferably 1 g:1-5 ml, for example, 1 g:2 ml, 1 g:3 ml, or 1 g:4 ml. In another preferred example, in Method 8, the mixing is carried out at room temperature, preferably 10 to 35°C, more preferably 15 to 25°C. In another preferred embodiment, in Method 8, the mixing time is 1 to 7 days, preferably 4 days. In another preferred example, the method 8 includes dissolving the compound raw material and fumaric acid in a third solvent, and suspending and stirring the mixture at room temperature for 4 days. In another preferred embodiment, the method 8 further comprises post-treatment steps of suction filtration and vacuum drying. In another preferred embodiment, in the method, the compound starting material comprises an amorphous or crystalline form, preferably free crystalline form A, of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide.

[0092] A third aspect of the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising: (a) one or more solid forms of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to the first aspect of the present invention; and (b) Pharmaceutically acceptable auxiliary materials, carriers, excipients, and diluents.

[0093] A fourth aspect of the present invention provides use of a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to the first aspect of the present invention for use in (a) the preparation of a transient receptor potential channel protein TRPA1 inhibitor, and / or (b) the preparation of a medicament for preventing and / or treating a transient receptor potential channel protein TRPA1-associated disease. In another preferred embodiment, the transient receptor potential channel protein TRPA1-associated disease is selected from the group consisting of inflammatory bowel disease, irritable bowel syndrome, pain, inflammation, cough, or a combination thereof. In another preferred embodiment, the inflammatory bowel disease comprises Crohn's disease and / or ulcerative colitis. In another preferred embodiment, the pain includes visceral pain, acute inflammatory pain, chronic inflammatory pain, neuropathic pain, fibromyalgia, headache, neuralgia, or pain caused by cancer.

[0094] A fifth aspect of the present invention provides (a) a method for inhibiting the transient receptor potential channel protein TRPA1, and / or (b) a method for preventing and / or treating a transient receptor potential channel protein TRPA1-associated disease, said method comprising administering to a subject in need thereof a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to the first aspect of the present invention. In another preferred embodiment, the subject is a human or non-human mammal. [Effects of the Invention]

[0095] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief explanation of the drawings]

[0096] [Figure 1] 1 is a characteristic XPRD graph of free crystalline form A. [Figure 2] 1 is a characteristic XPRD graph of fumarate salt crystalline form B. [Figure 3] 1 is a characteristic XPRD graph of the hydrochloride salt crystalline form C. [Figure 4] 1 is a characteristic XPRD graph of crystalline form D of the sulfate salt. [Figure 5] 1 is a characteristic XPRD graph of succinate crystalline form E. [Figure 6] 1 is a characteristic XPRD graph of malate crystalline form F. [Figure 7] 1 is a characteristic XPRD graph of phosphate crystalline form G. [Figure 8]1 is a characteristic XPRD graph of crystalline form H of the tartrate salt. [Figure 9] 1 is a characteristic XPRD graph of pyroglutamate crystalline form I. [Figure 10] 1 is a characteristic XPRD graph of benzenesulfonate salt crystalline form J.

[0097] [Figure 11] 1 is a characteristic XPRD graph of malonate crystalline form K. [Figure 12] 1 is a characteristic XPRD graph of hemifumarate crystalline form L. [Figure 13] 1 is a stacked graph of DSC and TGA of free crystalline form A. [Figure 14] 1 is a stacked graph of DSC and TGA of fumarate salt crystalline form B. [Figure 15] 1 is a stacked DSC and TGA graph of the hydrochloride salt crystalline form C. [Figure 16] 1 is a stacked graph of DSC and TGA of the sulfate salt crystalline form D. [Figure 17] 1 is a stacked graph of DSC and TGA of succinate crystalline form E. [Figure 18] 1 is a stacked DSC and TGA graph of malate crystalline form F. [Figure 19] 1 is a stacked graph of DSC and TGA of crystalline form G of the phosphate salt. [Figure 20] 1 is a stacked DSC and TGA graph of crystalline form H of the tartrate salt.

[0098] [Figure 21] 1 is a stacked graph of DSC and TGA of pyroglutamate crystalline form I. [Figure 22] 1 is a stacked graph of DSC and TGA of benzenesulfonate salt crystalline form J. [Figure 23] 1 is a stacked graph of DSC and TGA of malonate crystalline form K. [Figure 24] 1 is a stacked DSC and TGA graph of hemifumarate salt crystalline form L. [Figure 25] 1 is a DVS graph of free crystalline form A. [Figure 26] 1 is a DVS graph of fumarate salt crystalline form B. [Figure 27] 1 is a DVS graph of the hydrochloride salt crystalline form C. [Figure 28] 1 is a DVS graph of the sulfate salt crystalline form D. [Figure 29] 1 is a DVS graph of succinate crystalline form E. [Figure 30] 1 is a DVS graph of malate crystalline form F. [Figure 31] FIG. 1 shows kinetic dissolution diagrams of different salt crystal forms. DETAILED DESCRIPTION OF THE INVENTION

[0099] As a result of extensive and thorough research, the present inventors have unexpectedly developed for the first time an N-substituted phenylsulfonamide compound or a pharmaceutically acceptable salt thereof, as well as a solid form thereof. The crystalline salt form of the present invention significantly improves the solubility of the compound, which is beneficial for improving the physicochemical properties and pharmacokinetic characteristics of the compound. Based on this, the present invention has been completed.

[0100] term 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. As used herein, the terms "comprise," "comprising," and "containing" can be used interchangeably and further include semi-closed and open definitions as well as closed definitions. In other words, the terms include "consisting of" and "consisting essentially of." As used herein, when used in reference to a specifically recited numerical value, the term "about" means that the value can vary by no more than 1% from the recited value. For example, as used herein, the term "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.). As used herein, room temperature refers to 25±5°C.

[0101] Pharmaceutical Compositions and Administration The various solid forms of the present invention, as well as pharmaceutical compositions comprising the solid forms of the present invention as the primary active ingredient, can be used to treat, prevent, and alleviate TRPA1-related disorders. The pharmaceutical composition of the present invention contains a safe and effective amount of the solid form of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. Here, "safe and effective amount" refers to an amount of the compound sufficient to clearly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.1 to 1000 mg of the solid form / agent of the present invention, more preferably 0.5 to 500 mg of the solid form / agent of the present invention. Preferably, the "single agent" is one capsule or tablet.

[0102] One or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition of the present invention. These carriers include conventional diluents, excipients, fillers, adhesives, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field. Pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween®), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0103] The method of administration of the pharmaceutical composition of the present invention is not particularly limited, and typical administration methods include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular), and topical administration, with oral administration being the preferred administration method.

[0104] The dosage form of the pharmaceutical composition of the present invention is an oral preparation, an external preparation, or an injectable preparation. Typically, solid dosage forms for oral administration or administration include capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or vector), such as sodium citrate or dicalcium phosphate, or with (a) a filler or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) a binder, such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) a humectant, such as glycerin; (d) agar, calcium carbonate, potato starch, etc. The formulation may be mixed with ingredients such as disintegrating agents such as potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, retarders such as paraffin, absorption accelerators such as quaternary amine compounds, wetting agents such as cetyl alcohol and glyceryl monostearate, adsorbents such as kaolin, and lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also contain a buffering agent.

[0105] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others known in the art. They can contain opacifying agents. Liquid dosage forms for oral administration or administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor seed oil, and sesame oil, or mixtures of these substances.

[0106] Besides these inert diluents, pharmaceutical compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and perfuming agents. In addition to the active ingredient, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar, or mixtures of these substances. Pharmaceutical compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0107] The solid forms of the present invention can be administered or medicated alone or in combination with drugs for preventing and / or treating TRPA1-related disorders. When administering the pharmaceutical composition, a safe and effective amount of the cell-free fat extract of the present invention is administered to a human or non-human animal (e.g., rat, mouse, dog, cat, cow, sheep, chicken, duck, etc.) in need of treatment, and the administered amount is a pharmaceutically acceptable effective amount. Those skilled in the art will understand that the "safe and effective amount" varies depending on the form of the pharmaceutical composition, the route of administration, the adjuvant used, the severity of the disease, and the concomitant use of other drugs. For example, for a person weighing 60 kg, the daily dose is typically 0.1 to 1000 mg, preferably 1 to 600 mg, and more preferably 2 to 300 mg. Of course, the specific dosage must take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0108] The main advantages of the present invention are: The salt crystalline forms of the compounds of the present invention have excellent solubility and stability properties, which are beneficial for improving the physicochemical and pharmacokinetic properties of the compounds.

[0109] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are used only to illustrate the present invention and do not limit the scope of the present invention. The following examples, in which no specific conditions are specified, are generally carried out according to conventional conditions or conditions recommended by manufacturers.

[0110] Test Method XRPD: X-ray powder diffraction, DSC: differential scanning calorimetry, TGA: thermogravimetric analysis, DVS: dynamic moisture sorption. The powder X-ray diffraction analysis method used in the present invention obtains a powder X-ray diffraction pattern using a powder X-ray diffraction analyzer manufactured by PANalytical, operating voltage: 45 kV, operating current: 40 mA, and a Cu target. The differential scanning calorimetry (DSC) analysis method used in the present invention is: TA Q2000 / Discovery DSC2500 instrument, scanning rate: 10°C / min, protective gas: nitrogen gas. The thermogravimetric analysis (TGA) method used in the present invention is: instrument TA Q5000 / Discovery TGA5500, scanning rate: 10°C / min, protective gas: nitrogen gas. The dynamic moisture sorption (DVS) analysis method used in the present invention: DVS Intrinsic manufactured by SMS (Surface Measurement Systems), temperature 25°C, carrier gas, flow rate: nitrogen gas, 200 mL / min; mass conversion per unit time: 0.002% / min, relative humidity range: 0%RH to 95%RH. Liquid nuclear magnetic resonance spectroscopy used in the present invention: The instrument is a Bruker 400M nuclear magnetic resonance spectrometer. High performance liquid chromatography purity (HPLC) data as described in this invention are collected on an Agilent 1260 high performance liquid chromatograph. Ion chromatography (IC) experiments to determine the molar ratio of counterions according to the present invention are collected on a Thermo ICS1100.

[0111] Example 1: Free crystalline form A of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide (I) N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide) was prepared according to the method of Application No. 202110666168.6. After the reaction was completed, the temperature was adjusted to 0-10°C, purified water and aqueous sodium hydroxide solution were added dropwise, and the mixture was filtered. The filter cake was first immersed twice in purified water and then twice in anhydrous methanol to obtain a filter cake, which was then dried under reduced pressure to obtain a yellow crude product compound. The crude product was poured into a reactor, and two volumes of dimethyl sulfoxide were added. The temperature was raised to 60-70°C and stirred for 0.5 hours until the system became clear. Three volumes of anhydrous methanol were added dropwise at 60-65°C. After stirring for 0.5 hours, the heating was stopped, and the mixture was gradually cooled to 0-10°C. The temperature was maintained at 0-10°C, and the mixture was stirred for 4 hours. After filtering, a yellow free crystalline form A was obtained in a yield of 79.8%.

[0112] Example 2: Characterization of the free crystalline form A of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide (I) N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is crystalline and designated as free crystalline form A. Its powder X-ray diffraction data are shown in Table 1 and FIG. 1, and its TGA / DSC stacked graph is shown in FIG. 13. When the sample is heated to 150°C, there is a weight loss of 0.9%, and there are endothermic peaks at 181.0°C, 181.8°C (peak temperature), and 182.3°C.

[0113] Table 1 [Table 13]

[0114] Example 3: Screening of salt and crystalline forms of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide The present inventors used a suspension stirring method to screen various salt forms of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide. The acids selected for screening included hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, fumaric acid, L-tartaric acid, citric acid, D-glucuronic acid, L-malic acid, succinic acid, pyroglutamic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, malonic acid, benzoic acid, and hippuric acid. Most of the acidic ligands formed good solid salt forms with N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide. The resulting salt samples were characterized by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and analyzed by ion chromatography (IC) or liquid nuclear magnetic hydrogen spectroscopy (LMS). 1 The stoichiometry of the samples is determined by high performance liquid chromatography (HPLC) coupled with 1 H NMR.

[0115] Preparation of fumarate crystalline form B: 300.0 mg (0.86 mmol) of the compound (preferably the free crystalline form A obtained in Example 1) and 101.0 mg of fumaric acid (0.87 mmol) were weighed, 1 mL of MeOH was added, and the mixture was stirred magnetically at room temperature, then cooled and stirred for 1 day, suction filtered, and the filter cake was dried under vacuum to a constant weight to obtain 305.2 mg of a solid, with a yield of 76.1%.

[0116] The powder X-ray diffraction data of the fumarate salt crystalline form B is as shown in Table 2, the XRPD pattern is as shown in FIG. 2, and the TGA / DSC stack graph is as shown in FIG. Table 2 [Table 14]

[0117] As can be seen from Figure 14, DSC shows that Form B of the fumarate salt begins to exhibit an endothermic peak when heated to 189.4°C (peak temperature), and TGA shows that Form B of the fumarate salt exhibits a weight loss of about 0.8% when heated to 150°C. Furthermore, HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0118] Preparation of Hydrochloride Crystalline Form C: Weigh out 500.10 mg (1.43 mmol) of the compound and dissolve it in 6.25 mL of tetrahydrofuran solution. Dissolve the sample using a vortex and ultrasonic wave. Weigh out 167.8 μL (2.00 mmol) of concentrated hydrochloric acid with a mass fraction of 36-38% and dilute it in 6.25 mL of tetrahydrofuran solution. Under stirring conditions, add the hydrochloric acid tetrahydrofuran solution slowly dropwise to the suspension of the free sample. Stir at room temperature for 1 hour, suction filter, and vacuum dry the filter cake to a constant weight to obtain 466.95 mg of solid, a yield of 84.54%.

[0119] The powder X-ray diffraction data of the hydrochloride salt crystalline form C is as shown in Table 3, the XRPD pattern is as shown in Figure 3, and the TGA / DSC stack graph is as shown in Figure 15.

[0120] Table 3 [Table 15]

[0121] As can be seen from Figure 15, the sample begins to show endothermic peaks when heated to 93.1°C and 150.7°C (peak temperature), and shows a weight loss of about 4.2% when heated to 100°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0122] Preparation of sulfate crystalline form D: Weigh out 499.63 mg (1.43 mmol) of the compound and dissolve it in 6.25 mL of a 19:1 acetonitrile / water mixture. Dissolve the sample using a vortex and ultrasonic wave. Weigh out 91.8 μL (1.72 mmol) of concentrated sulfuric acid (95-98%) and dilute it in 6.25 mL of a 19:1 acetonitrile / water mixture. Add the sulfuric acid solution dropwise to the free sample suspension while stirring until the solution becomes clear. Add 25 mL of MTBE slowly to the mixture while stirring. After stirring at room temperature for approximately 1 hour, the mixture was filtered under suction and the filter cake was dried under vacuum to a constant weight, yielding 557.98 mg of solids in total, a yield of 87.08%.

[0123] The powder X-ray diffraction data for the sulfate salt crystalline form D is shown in Table 4, the XRPD pattern is shown in FIG. 4, and the TGA / DSC stack graph is shown in FIG. 16. Table 4 [Table 16]

[0124] As can be seen from Figure 16, the sample begins to show an endothermic peak when heated to 175.8°C (peak temperature) and shows a weight loss of about 0.6% when heated to 150°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0125] Preparation of succinate crystalline form E: 300.3 mg (0.86 mmol) of the compound and 102.7 mg (0.87 mmol) of succinic acid were weighed and dissolved in 2 mL of methanol solution, stirred at room temperature for 1 day, suction filtered, and the filter cake was vacuum dried to a constant weight to obtain 370.0 mg of solid, the yield being 91.8%.

[0126] The powder X-ray diffraction data of succinate salt crystalline form E is as shown in Table 5, the XRPD pattern is as shown in FIG. 5, and the TGA / DSC stack graph is as shown in FIG. 17. Table 5 [Table 17]

[0127] As can be seen from Figure 17, the sample begins to show an endothermic peak when heated to 172.9°C (peak temperature) and shows a weight loss of about 1.2% when heated to 150°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0128] Preparation of Malate Crystalline Form F: 300.1 mg (0.86 mmol) of the compound and 117.0 mg (0.87 mmol) of malic acid were weighed and dissolved in 3 mL of tetrahydrofuran solution, stirred at room temperature for 1 day, suction filtered, and the filter cake was vacuum dried to a constant weight to obtain 315.4 mg of solid, the yield being 75.6%.

[0129] The powder X-ray diffraction data for malate crystalline form F is shown in Table 6, the XRPD pattern is shown in Figure 6, and the TGA / DSC stack graph is shown in Figure 18. Table 6 [Table 18]

[0130] As can be seen from Figure 18, the sample begins to show endothermic peaks when heated to 144.7°C and 160.6°C (peak temperature), and shows a weight loss of about 2.0% when heated to 100°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0131] Preparation of phosphate crystalline form G: 20 mg (0.06 mmol) of the compound and 6.9 mg of phosphoric acid were weighed and dissolved in 0.5 mL of tetrahydrofuran solution, stirred at room temperature, suction filtered, and the filter cake was vacuum dried to a constant weight to obtain 18.5 mg of solid, the yield being 69.1%.

[0132] The powder X-ray diffraction data for phosphate salt crystalline form G is shown in Table 7, the XRPD pattern is shown in FIG. 7, and the TGA / DSC stack graph is shown in FIG. 19. Table 7 [Table 19]

[0133] As can be seen from Figure 19, the sample begins to show an endothermic peak when heated to 164.1°C (peak temperature) and shows a weight loss of about 1.8% when heated to 150°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0134] Preparation of tartrate salt crystalline form H: 20 mg (0.06 mmol) of the compound and 9 mg of tartaric acid were weighed and dissolved in 0.5 mL of tetrahydrofuran solution, stirred at room temperature, suction filtered, and the filter cake was vacuum dried to a constant weight to obtain 24.4 mg of solid, the yield being 81.6%.

[0135] The powder X-ray diffraction data for tartrate salt crystalline form H is shown in Table 8, the XRPD pattern is shown in FIG. 8, and the TGA / DSC stack graph is shown in FIG. 20. Table 8 [Table 20]

[0136] As can be seen from Figure 20, the sample begins to show an endothermic peak when heated to 164.7°C (peak temperature), and shows a weight loss of about 0.7% when heated to 150°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0137] Preparation of pyroglutamate crystalline form I: 20 mg (0.06 mmol) of the compound and 7.7 mg of pyroglutamic acid were weighed and dissolved in 0.5 mL of tetrahydrofuran solution, stirred at room temperature, suction filtered, and the filter cake was vacuum dried to a constant weight to obtain 25.1 mg of solid, the yield being 87.6%.

[0138] The powder X-ray diffraction data of pyroglutamate crystalline form I is shown in Table 9, the XRPD pattern is shown in Figure 9, and the TGA / DSC stack graph is shown in Figure 21. Table 9 [Table 21]

[0139] As can be seen from Figure 21, the sample begins to show an endothermic peak when heated to 155.4°C (peak temperature) and shows a weight loss of about 1.3% when heated to 120°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0140] Preparation of benzenesulfonate crystalline form J: 20 mg (0.06 mmol) of the compound and 9.5 mg of benzenesulfonic acid were weighed and dissolved in 0.5 mL of tetrahydrofuran solution, stirred at room temperature, suction filtered, and the filter cake was vacuum dried to a constant weight to obtain 28.3 mg of solid, the yield being 93.1%.

[0141] The powder X-ray diffraction data of the benzenesulfonate salt crystalline form J is shown in Table 10, the XRPD pattern is shown in FIG. 10, and the TGA / DSC stack graph is shown in FIG. 22. Table 10 [Table 22]

[0142] As can be seen from Figure 22, the sample begins to show an endothermic peak when heated to 164.9°C (peak temperature) and shows a weight loss of about 1.3% when heated to 150°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0143] Preparation of Malonate Crystalline Form K: 20 mg (0.06 mmol) of the compound and 6.2 mg of malonic acid were weighed and dissolved in 0.5 mL of tetrahydrofuran solution, stirred at room temperature, suction filtered, and the filter cake was vacuum dried to a constant weight to obtain 21.7 mg of solid, the yield being 80.1%.

[0144] The powder X-ray diffraction data for malonate crystalline form K is shown in Table 11, the XRPD pattern is shown in FIG. 11, and the TGA / DSC stack graph is shown in FIG. 23. Table 11 [Table 23]

[0145] As can be seen from Figure 23, the sample begins to show an endothermic peak when heated to 139.8°C (peak temperature) and shows a weight loss of about 1.6% when heated to 130°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:1.

[0146] Preparation of hemifumarate crystalline form L: 500.8 mg (1.44 mmol) of the compound and 83.6 mg of fumaric acid (0.72 mmol) were weighed, 2.0 mL of methanol solution was added, and the mixture was stirred at room temperature for 4 days, suction filtered, and the filter cake was vacuum dried to a constant weight to obtain 489.2 mg of a solid, the yield being 83.7%.

[0147] The powder X-ray diffraction data for hemifumarate salt crystalline form L is as shown in Table 12, the XRPD pattern is as shown in Figure 12, and the TGA / DSC stack graph is as shown in Figure 24. Table 12 [Table 24] As can be seen from Figure 24, the sample begins to show an endothermic peak when heated to 173.8°C (peak temperature) and shows a weight loss of about 0.3% when heated to 150°C. Furthermore, the HPLC / IC results indicate that the molar ratio of free form to acid is 1:0.5.

[0148] Example 4: Characterization of some salt crystalline forms prepared in the examples Hygroscopic The hygroscopicity was tested using a dynamic moisture sorption (DVS) apparatus, and the results are shown in Figures 25 to 30. In the adsorption curves from 0% RH to 95% RH, under 25°C / 80 RH conditions, the water adsorption amount of free crystalline form A was 1.6%, indicating slight hygroscopicity; the water adsorption amount of fumarate crystalline form B was 0.2%, indicating slight hygroscopicity; the water adsorption amount of hydrochloride crystalline form C was 5.5%, indicating hygroscopicity; the water adsorption amount of sulfate crystalline form D was 1.3%, indicating slight hygroscopicity; the water adsorption amount of succinate crystalline form E was 0.6%, indicating slight hygroscopicity; and the water adsorption amount of malate crystalline form F was 1.4%, indicating slight hygroscopicity (Chinese Pharmacopoeia 2015 Edition (Guideline for Drug Hygroscopicity Test)).

[0149] dynamic solubility The dynamic solubilities of fumaric acid crystalline form B, hydrochloride crystalline form C, sulfate crystalline form D, succinic acid crystalline form E, malic acid crystalline form F, and free crystalline form A in the biological solvents SGF, FaSSIF, and water at 37°C were tested. In the experiment, the solid content of all samples in the three solvents was 10 mg / mL. The samples were sealed and fixed on a rotating disk at a rotation speed of 25 rpm, and the rotating disk was placed in a thermostatic box at 37°C. Samples were taken at 1, 2, 4, and 24 hours after equilibration. The filtrates were separated and tested for HPLC concentration and pH. The resulting solids were then analyzed by XRPD. As can be seen from Figure 31, the solubility of each salt crystalline form in the biological solvents SGF, FaSSIF, and water was significantly improved compared to the free form. While the starting sample was practically insoluble in water and FaSSIF, the solubility of the salt crystalline forms increased to 6-10 mg / mL.

[0150] Solid-state stability Approximately 10 mg of solid was weighed into each HPLC vial, the bottle's mouth sealed with a sealing film, and 10 small holes were punched in the film. The vial was then placed in an environment of 25°C / 60%RH and 40°C / 75%RH for 4 weeks. Samples were taken at the first, second, and fourth weeks, respectively, and the samples were tested for HPLC purity and XRPD. The HPLC results indicated that the purity of the samples in the free state and each salt form did not change significantly after storage under the corresponding conditions, and the XRPD results indicated that the crystalline form of the samples in the free state and each salt form did not change significantly before and after the stability test. The solid stability results are summarized in Table 13.

[0151] Table 13 [Table 25-1] [Table 25-2] [Table 25-3]

[0152] Approximate solubility The corresponding crystalline sample was placed in a 3-mL glass bottle, and purified water (50, 50, 200, and 700 μL) was added stepwise. Dissolution was promoted by vortexing and ultrasonic vibration, and the solid sample was observed to see whether it was completely dissolved. The addition of solvent was stopped when the solid was completely dissolved or the total volume of added purified water reached 1 mL. The approximate solubility was calculated based on the volume of solvent added.

[0153] The results of the approximate solubility test are shown in Table 14. Compared with the free crystalline form A, the solubility of each salt crystalline form in pure water is significantly improved. Table 14 [Table 26]

[0154] All documents mentioned in this application are incorporated by reference in this application as if each document were incorporated by reference individually. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents will also fall within the scope defined by the appended claims of this application.

Claims

1. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide, The solid form includes a free crystalline form or a salt crystalline form; The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is characterized in that the crystalline salt form is formed by reacting the compound with a pharmaceutically acceptable acid, and the pharmaceutically acceptable acid is selected from the group consisting of hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, fumaric acid, L-tartaric acid, citric acid, D-glucuronic acid, L-malic acid, succinic acid, pyroglutamic acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, acetic acid, malonic acid, benzoic acid, and hippuric acid.

2. The solid form is free crystalline form A, and the X-ray powder diffraction spectrum of free crystalline form A is characterized by having characteristic peaks at 2θ values ​​of 16.24±0.2°, 19.23±0.2°, 23.17±0.2°, 24.45±0.2°, and 32.76±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

3. The solid form is fumarate crystalline form B, and the X-ray powder diffraction spectrum of the fumarate crystalline form B is characterized by having characteristic peaks at 2θ values ​​of 11.34±0.2°, 14.40±0.2°, 19.71±0.2°, and 19.86±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

4. The solid form is hydrochloride crystalline form C, and the X-ray powder diffraction spectrum of the hydrochloride crystalline form C is characterized by having characteristic peaks at 2θ values ​​of 17.20±0.2°, 20.34±0.2°, 24.74±0.2°, and 25.25±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

5. The solid form is sulfate crystalline form D, and the X-ray powder diffraction spectrum of sulfate crystalline form D is characterized by having characteristic peaks at 2θ values ​​of 16.84±0.2°, 23.08±0.2°, and 24.38±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

6. The solid form is succinate crystalline form E, and the X-ray powder diffraction spectrum of succinate crystalline form E is characterized by having characteristic peaks at 2θ values ​​of 12.57±0.2°, 19.18±0.2°, 19.89±0.2°, and 22.68±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

7. The solid form is malate crystalline form F, and the X-ray powder diffraction spectrum of malate crystalline form F is characterized by having characteristic peaks at 2θ values ​​of 12.70±0.2°, 14.57±0.2°, 19.13±0.2°, and 19.47±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

8. The solid form is phosphate crystalline form G, and the X-ray powder diffraction spectrum of phosphate crystalline form G is characterized by having characteristic peaks at 2θ values ​​of 11.20±0.2°, 19.70±0.2°, 21.24±0.2°, and 22.49±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

9. The solid form is tartrate salt crystalline form H, and the X-ray powder diffraction spectrum of the tartrate salt crystalline form H is characterized by having characteristic peaks at 2θ values ​​of 14.19±0.2°, 18.64±0.2°, 18.95±0.2°, and 23.70±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

10. The solid form is pyroglutamate crystalline form I, and the X-ray powder diffraction spectrum of pyroglutamate crystalline form I is characterized by having characteristic peaks at 2θ values ​​of 9.29±0.2°, 10.76±0.2°, 17.98±0.2°, and 23.72±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

11. The solid form is benzenesulfonate crystalline form J, and the X-ray powder diffraction spectrum of the benzenesulfonate crystalline form J is characterized by having characteristic peaks at 2θ values ​​of 13.69±0.2°, 19.48±0.2°, 21.07±0.2°, and 22.15±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

12. The solid form is malonate crystalline form K, and the X-ray powder diffraction spectrum of the malonate crystalline form K is characterized by having characteristic peaks at 2θ values ​​of 15.28±0.2°, 19.66±0.2°, and 20.42±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

13. The solid form is hemifumarate crystalline form L, and the X-ray powder diffraction spectrum of the hemifumarate crystalline form L is characterized by having characteristic peaks at 2θ values ​​of 11.57±0.2°, 17.25±0.2°, 23.08±0.2°, and 24.33±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

14. The solid form is fumarate crystalline form B, and the X-ray powder diffraction spectrum of the fumarate crystalline form B is characterized by having characteristic peaks at 2θ values ​​of 11.34±0.2°, 14.40±0.2°, 19.23±0.2°, and 19.71±0.2°.

2. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1.

15. 10. A process for preparing the solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide of claim 1, comprising: The method includes any one of methods 1 to 8, The method 1 is (a1) dissolving the crude product of the compound prepared in a first solvent, heating the solution, and mixing until the solution becomes clear; (a2) adding a second solvent, cooling and crystallizing to obtain free crystalline Form A; The method 2 is dissolving the starting compound and fumaric acid in a third solvent, mixing, cooling, and crystallizing to obtain the fumarate salt crystalline form B; The method 3 is (b1) dissolving a compound raw material in a fourth solvent; (b2) dissolving concentrated hydrochloric acid in a fourth solvent; (b3) adding the fourth solvent solution of hydrochloric acid obtained in step (b2) dropwise to the mixture obtained in step (b1), mixing and crystallizing to obtain said hydrochloride salt crystalline form C; The method 4 is (c1) dissolving a compound raw material in a fifth solvent; (c2) dissolving concentrated sulfuric acid in a fifth solvent; (c3) adding the fifth solvent solution of sulfuric acid obtained in step (c2) dropwise to the mixture obtained in step (c1) until the solution becomes clear; (c4) adding a sixth solvent dropwise to the mixture obtained in step (c3), mixing, and crystallizing to obtain the Sulfate Salt Crystalline Form D; The method 5 is dissolving the starting compound and succinic acid in a seventh solvent, mixing, and crystallizing to obtain the succinate crystalline form E; The method 6 is dissolving the compound raw material and malic acid in an eighth solvent, mixing, and crystallizing to obtain the malate crystalline form F; The method 7 is dissolving, mixing, and crystallizing a raw compound and an acid in a ninth solvent to obtain phosphate crystalline form G, tartrate crystalline form H, pyroglutamate crystalline form I, benzenesulfonate crystalline form J, and malonate crystalline form K corresponding to the acid, wherein the acid is selected from the group consisting of phosphoric acid, tartaric acid, pyroglutamic acid, benzenesulfonic acid, or malonic acid; Method 8 includes dissolving the starting compound and fumaric acid in a third solvent, mixing, and crystallizing to obtain the hemifumarate crystalline form L; The method for preparing a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein the compound raw material comprises an amorphous or crystalline form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide.

16. 1. A pharmaceutical composition comprising: A pharmaceutical composition comprising the solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to any one of claims 1 to 14, and a pharmaceutically acceptable excipient.

17. Use of the solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to any one of claims 1 to 14, The use, characterized in that it is used for (a) the preparation of an inhibitor of the transient receptor potential channel protein TRPA1, and / or (b) the preparation of a drug for preventing and / or treating a disease associated with the transient receptor potential channel protein TRPA1.

18. The transient receptor potential channel protein TRPA1-associated disease is selected from the group consisting of inflammatory bowel disease, irritable bowel syndrome, pain, inflammation, or a combination thereof.

18. The use according to claim 17.

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