Solid forms of N-substituted phenyl sulfonamides

Abstract

The invention relates to a solid form of an N-substituted phenyl sulfonamide compound. In particular to a free-state crystal form, a fumarate crystal form, a hydrochloride crystal form, a sulfate crystal form, a succinate crystal form, a malate crystal form, a phosphate crystal form, a tartrate crystal form, a pyroglutamate crystal form, a benzenesulfonic acid-salt crystal form, a malonate crystal form and a hemifumaric acid crystal form of an N-substituted phenyl sulfonamide compound. The solid form has excellent stability and solubility, has an excellent inhibition effect on transient receptor potential channel protein TRPA1, and has a good treatment effect on diseases related to the TRPA1.

Description

Solid form of N-substituted phenylsulfonamide compounds Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and in particular to a solid form of an N-substituted phenylsulfonamide compound. Background Art

[0002] TRPA1 is a member of the TRP ion channel superfamily and the only member of the TRPA subfamily. It is a non-selective cation channel that is permeable to Na + , K + , Ca 2+ and Mg 2+ . TRPA1 is mainly distributed in the primary sensory neurons of the dorsal root ganglion (DRG), trigeminal nerve (TG) and vagus nerve (VG). From the perspective of the human body system distribution, TRPA1 is highly expressed in the peripheral nervous system, respiratory system, gastrointestinal system and urinary system. When these organs and tissues have functional abnormalities, the expression and function of TRPA1 channels are usually also abnormal. TRPA1 can convert cold stimulation, chemical stimulation and mechanical stimulation into inward currents, triggering a series of physiological functions and participating in the formation of various pain sensations. Inflammatory pain is a common problem of certain chronic diseases, and there is still a lack of very effective treatment methods in clinical practice. Animal experimental studies have shown that TRPA1 is involved in inflammatory reactions and plays an important role in inflammatory pain. The use of TRPA1-specific blockers can significantly reduce the inflammatory pain response of rats. From current research, TRPA1 plays an important role in the occurrence of asthma and cough. Compounds that induce asthma and cough, whether endogenous factors or exogenous factors, can activate TRPA1. TRPA1 antagonists can alleviate asthma symptoms and block airway hyperresponsiveness. Using various animal models of visceral hypersensitivity, such as colitis, rectal distension, or stress, it has been confirmed that TRPA1 is involved in the regulation of 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, characterized by hyperalgesia, abnormal pain sensitivity, and spontaneous pain. In recent years, an increasing number of studies have shown that the TRPA1 channel plays an important role in various neuropathic pain conditions, such as diabetic neuropathy and chemotherapy-induced neuropathy. Recent studies have also shown that TRPA1 plays a mediating role in pain such as toothache and migraine, and that administering TRPA1 antagonists can significantly alleviate pain symptoms.

[0003] TRPA1 is widely distributed and expressed in the human body. In addition to the physiological functions mentioned above, TRPA1 inhibitors have been reported for indications in development including inflammatory bowel disease, chronic obstructive pulmonary disease, cough suppression, antipruritic effects, allergic rhinitis, ear diseases, anti-diabetes, and urinary incontinence. TRPA1 is a proven new target for the treatment of multiple diseases.

[0004] N-substituted phenylsulfonamide compounds exhibit potent therapeutic and analgesic effects for inflammatory bowel disease by inhibiting transient receptor potential ankyrin 1 (TRPA1), while also having excellent safety characteristics.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a solid form of N-substituted phenylsulfonamide compounds with excellent stability and solubility.

[0007] In a first aspect of the present invention, a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is provided.

[0008] In another preferred embodiment, the structure of the N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is shown in Formula I:

[0009] In a preferred embodiment, the solid form includes a free crystalline form or a salt crystalline form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide.

[0010] In another preferred embodiment, the salt crystal form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is a salt crystal form formed by reacting the compound with a pharmaceutically acceptable acid, and the pharmaceutically acceptable acid is selected from the following group: 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.

[0011] In another preferred embodiment, the fumarate salt crystal form is a mono-fumarate salt crystal form.

[0012] In another preferred embodiment, the fumarate salt crystal form is a hemi-fumarate salt crystal form.

[0013] In another preferred embodiment, the hydrochloride salt crystal form is a monohydrochloride salt crystal form.

[0014] In another preferred embodiment, the sulfate crystal form is a monosulfate crystal form.

[0015] In another preferred embodiment, the succinate salt crystal form is a monosuccinate salt crystal form.

[0016] In another preferred embodiment, the malate crystal form is a monomalate crystal form.

[0017] In another preferred embodiment, the phosphate crystal form is a monophosphate crystal form.

[0018] In another preferred embodiment, the tartrate crystal form is a monotartrate crystal form.

[0019] In another preferred embodiment, the pyroglutamate crystal form is a monopyroglutamate crystal form.

[0020] In another preferred embodiment, the benzenesulfonate crystalline form is a monobenzenesulfonate crystalline form.

[0021] In another preferred embodiment, the malonate crystal form is a monomalonate crystal form.

[0022] In another preferred embodiment, the solid form is free crystalline form A, and the X-ray powder diffraction pattern of the free crystalline form A has characteristic peaks at the following 2θ values: 16.24±0.2°, 19.23±0.2°, 23.17±0.2°, 24.45±0.2°, and 32.76±0.2°.

[0023] In another preferred embodiment, the X-ray powder diffraction pattern of the free crystalline form A has characteristic peaks at the following 2θ values: 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°.

[0024] In another preferred embodiment, the X-ray powder diffraction pattern of the free crystalline form A has the following characteristic peaks and peak intensities at 2θ values:

[0025] In another preferred embodiment, the free crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG1 .

[0026] In another preferred embodiment, the free crystalline form A comprises one or more characteristics selected from the following group:

[0027] The differential scanning calorimetry (DSC) diagram 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), and 182.3±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0028] The differential scanning calorimetry (DSC) diagram of the free crystalline Form A is substantially as shown in FIG13 ;

[0029] The thermogravimetric analysis (TGA) graph of the free crystalline Form A shows a weight loss of about 0.9±0.5% (preferably ±0.4%, ±0.3%, ±0.2% or ±0.1%) when heated to 150° C.;

[0030] The thermogravimetric analysis (TGA) diagram of the free crystalline form A is basically shown in Figure 13.

[0031] In another preferred embodiment, the salt crystal forms include fumarate crystal form, hydrochloride crystal form, sulfate crystal form, succinate crystal form, malate crystal form, phosphate crystal form, tartrate crystal form, pyroglutamate crystal form, benzenesulfonate crystal form, malonate crystal form and hemifumarate crystal form.

[0032] In another preferred embodiment, the solid form is fumarate crystalline form B, and the X-ray powder diffraction pattern of the fumarate crystalline form B has characteristic peaks at the following 2θ values: 11.34±0.2°, 14.40±0.2°, 19.71±0.2°, and 19.86±0.2°.

[0033] In another preferred embodiment, the solid form is fumarate crystalline form B, and the X-ray powder diffraction pattern of the fumarate crystalline form B has characteristic peaks at the following 2θ values: 11.34±0.2°, 14.40±0.2°, 19.23±0.2°, and 19.71±0.2°.

[0034] In another preferred embodiment, the X-ray powder diffraction pattern of the fumarate salt form B has characteristic peaks at the following 2θ values: 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°.

[0035] In another preferred embodiment, the X-ray powder diffraction pattern of the fumarate salt form B has characteristic peaks at the following 2θ values: 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°. 2°, 23.18±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°.

[0036] In another preferred embodiment, the X-ray powder diffraction pattern of the fumarate salt form B has the following characteristic peaks and peak intensities at 2θ values:

[0037] In another preferred embodiment, the fumarate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG2 .

[0038] In another preferred embodiment, the fumarate salt crystalline form B includes one or more characteristics selected from the following group:

[0039] The differential scanning calorimetry (DSC) diagram of the fumarate salt form B begins to show an endothermic peak when heated to 189.4±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0040] The differential scanning calorimetry (DSC) diagram of the fumarate salt form B is substantially as shown in FIG14 ;

[0041] The thermogravimetric analysis (TGA) graph of the fumarate salt Form B shows a weight loss of about 0.8±0.2% (preferably ±0.15%, ±0.1%, ±0.05% or ±0.02%) when heated to 150° C.;

[0042] The thermogravimetric analysis (TGA) diagram of the fumarate salt form B is basically shown in Figure 14.

[0043] In another preferred embodiment, in the fumarate salt 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.

[0044] In another preferred embodiment, the solid form is hydrochloride crystal form C, and the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic peaks at the following 2θ values: 17.20±0.2°, 20.34±0.2°, 24.74±0.2°, and 25.25±0.2°.

[0045] In another preferred embodiment, the X-ray powder diffraction pattern of the hydrochloride salt form C has characteristic peaks at the following 2θ values: 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°.

[0046] In another preferred embodiment, the X-ray powder diffraction pattern of the hydrochloride salt form C has characteristic peaks at the following 2θ values: 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°.

[0047] In another preferred embodiment, the X-ray powder diffraction pattern of the hydrochloride salt form C has the following characteristic peaks and peak intensities at 2θ values:

[0048] In another preferred embodiment, the hydrochloride salt form C has an X-ray powder diffraction pattern substantially as shown in FIG3 .

[0049] In another preferred embodiment, the hydrochloride salt form C includes one or more characteristics selected from the following group:

[0050] The differential scanning calorimetry (DSC) diagram of the hydrochloride salt form C begins to show endothermic peaks when heated 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);

[0051] The differential scanning calorimetry (DSC) diagram of the hydrochloride salt form C is substantially as shown in FIG15 ;

[0052] The thermogravimetric analysis (TGA) of the hydrochloride salt form C shows a weight loss of about 4.2±0.5% (preferably ±0.4%, ±0.3%, ±0.2% or ±0.1%) when heated to 100° C.;

[0053] The thermogravimetric analysis (TGA) diagram of the hydrochloride salt form C is basically shown in Figure 15.

[0054] In another preferred embodiment, in the hydrochloride salt 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.

[0055] In another preferred embodiment, the solid form is sulfate crystal form D, and the X-ray powder diffraction pattern of the sulfate crystal form D has characteristic peaks at the following 2θ values: 16.84±0.2°, 23.08±0.2°, and 24.38±0.2°.

[0056] In another preferred embodiment, the X-ray powder diffraction pattern of the sulfate salt crystal form D has characteristic peaks at the following 2θ values: 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°.

[0057] In another preferred embodiment, the X-ray powder diffraction pattern of the sulfate salt form D has characteristic peaks at the following 2θ values: 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°.

[0058] In another preferred embodiment, the X-ray powder diffraction pattern of the sulfate crystal form D has the following characteristic peaks and peak intensities at 2θ values:

[0059] In another preferred embodiment, the sulfate salt crystal form D has an X-ray powder diffraction pattern substantially as shown in FIG4 .

[0060] In another preferred embodiment, the sulfate crystal form D includes one or more characteristics selected from the following group:

[0061] The differential scanning calorimetry (DSC) diagram of the sulfate salt crystal form D begins to show an endothermic peak when heated to 175.8±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0062] The differential scanning calorimetry (DSC) diagram of the sulfate salt crystal form D is substantially as shown in FIG16 ;

[0063] The thermogravimetric analysis (TGA) of the sulfate salt form D shows a weight loss of about 0.6±0.1% (preferably ±0.08%, ±0.05%, ±0.02% or ±0.01%) when heated to 150°C;

[0064] The thermogravimetric analysis (TGA) diagram of the sulfate crystal form D is basically shown in Figure 16.

[0065] In another preferred embodiment, in the sulfate crystal 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.

[0066] In another preferred embodiment, the solid form is succinate crystal form E, and the X-ray powder diffraction pattern of the succinate crystal form E has characteristic peaks at the following 2θ values: 12.57±0.2°, 19.18±0.2°, 19.89±0.2°, and 22.68±0.2°.

[0067] In another preferred example, the X-ray powder diffraction pattern of the succinate salt form E has characteristic peaks at the following 2θ values: 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°.

[0068] In another preferred embodiment, the X-ray powder diffraction pattern of the succinate salt form E has characteristic peaks at the following 2θ values: 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°.

[0069] In another preferred embodiment, the X-ray powder diffraction pattern of the succinate salt crystal form E has the following characteristic peaks and peak intensities at 2θ values:

[0070] In another preferred embodiment, the succinate salt crystal form E has an X-ray powder diffraction pattern substantially as shown in FIG5 .

[0071] In another preferred embodiment, the succinate salt crystal form E includes one or more characteristics selected from the following group:

[0072] The differential scanning calorimetry (DSC) diagram of the succinate salt form E shows an endothermic peak when heated to 172.9±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0073] The differential scanning calorimetry (DSC) diagram of the succinate salt form E is substantially as shown in FIG17 ;

[0074] The thermogravimetric analysis (TGA) of the succinate salt 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;

[0075] The thermogravimetric analysis (TGA) diagram of the succinate salt form E is basically shown in Figure 17.

[0076] In another preferred embodiment, in the succinate salt crystal 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.

[0077] In another preferred embodiment, the solid form is malate crystal form F, and the X-ray powder diffraction pattern of the malate crystal form F has characteristic peaks at the following 2θ values: 12.70±0.2°, 14.57±0.2°, 19.13±0.2°, and 19.47±0.2°.

[0078] In another preferred example, the X-ray powder diffraction pattern of the malate salt form F has characteristic peaks at the following 2θ values: 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°.

[0079] In another preferred embodiment, the X-ray powder diffraction pattern of the malate salt form F has characteristic peaks at the following 2θ values: 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°.

[0080] In another preferred embodiment, the X-ray powder diffraction pattern of the malate crystalline form F has the following characteristic peaks and peak intensities at 2θ values:

[0081] In another preferred embodiment, the malate salt form F has an X-ray powder diffraction pattern substantially as shown in FIG6 .

[0082] In another preferred embodiment, the malate crystalline form F comprises one or more characteristics selected from the following group:

[0083] The differential scanning calorimetry (DSC) diagram of the malate salt form F begins to show endothermic peaks when heated 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);

[0084] The differential scanning calorimetry (DSC) diagram of the malate salt form F is substantially as shown in FIG18 ;

[0085] The thermogravimetric analysis (TGA) of the malate salt Form F shows a weight loss of about 2.0±0.3% (preferably ±0.2%, ±0.15%, ±0.1% or ±0.05%) when heated to 100° C.;

[0086] The thermogravimetric analysis (TGA) diagram of the malate crystal form F is basically as shown in Figure 18.

[0087] In another preferred embodiment, in the malate salt 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.

[0088] In another preferred embodiment, the solid form is phosphate crystal form G, and the X-ray powder diffraction pattern of the phosphate crystal form G has characteristic peaks at the following 2θ values: 11.20±0.2°, 19.70±0.2°, 21.24±0.2°, and 22.49±0.2°.

[0089] In another preferred example, the X-ray powder diffraction pattern of the phosphate crystal form G has characteristic peaks at the following 2θ values: 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°.

[0090] In another preferred embodiment, the X-ray powder diffraction pattern of the phosphate crystal form G has characteristic peaks at the following 2θ values: 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°.

[0091] In another preferred embodiment, the X-ray powder diffraction pattern of the phosphate crystal form G has the following characteristic peaks and peak intensities at 2θ values:

[0092] In another preferred embodiment, the phosphate crystal form G has an X-ray powder diffraction pattern substantially as shown in FIG7 .

[0093] In another preferred embodiment, the phosphate crystal form G includes one or more characteristics selected from the following group:

[0094] The differential scanning calorimetry (DSC) diagram of the phosphate crystal form G begins to show an endothermic peak when heated to 164.1±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0095] The differential scanning calorimetry (DSC) diagram of the phosphate crystal form G is substantially as shown in FIG19 ;

[0096] The thermogravimetric analysis (TGA) graph of the phosphate crystal 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.;

[0097] The thermogravimetric analysis (TGA) diagram of the phosphate crystal form G is basically shown in Figure 19.

[0098] In another preferred example, in the phosphate crystal 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, and more preferably 1:1.

[0099] In another preferred embodiment, the solid form is tartrate crystal form H, and the X-ray powder diffraction pattern of the tartrate crystal form H has characteristic peaks at the following 2θ values: 14.19±0.2°, 18.64±0.2°, 18.95±0.2°, and 23.70±0.2°.

[0100] In another preferred embodiment, the X-ray powder diffraction pattern of the tartrate salt form H has characteristic peaks at the following 2θ values: 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°.

[0101] In another preferred embodiment, the X-ray powder diffraction pattern of the tartrate salt form H has characteristic peaks at the following 2θ values: 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°.

[0102] In another preferred embodiment, the X-ray powder diffraction pattern of the tartrate salt form H has the following characteristic peaks and peak intensities at 2θ values:

[0103] In another preferred embodiment, the tartrate salt form H has an X-ray powder diffraction pattern substantially as shown in FIG8 .

[0104] In another preferred embodiment, the tartrate salt form H comprises one or more characteristics selected from the following group:

[0105] The differential scanning calorimetry (DSC) diagram of the tartrate salt form H begins to show an endothermic peak when heated to 164.7±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0106] The differential scanning calorimetry (DSC) diagram of the tartrate salt form H is substantially as shown in FIG20 ;

[0107] The thermogravimetric analysis (TGA) of the tartrate salt Form H shows a weight loss of about 0.72% (preferably ±0.1%, ±0.05%, ±0.02% or ±0.01%) when heated to 150° C.;

[0108] The thermogravimetric analysis (TGA) diagram of the tartrate salt form H is basically shown in Figure 20.

[0109] In another preferred embodiment, in the tartrate salt 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.

[0110] In another preferred embodiment, the solid form is pyroglutamate crystal form I, and the X-ray powder diffraction pattern of the pyroglutamate crystal form I has characteristic peaks at the following 2θ values: 9.29±0.2°, 10.76±0.2°, 17.98±0.2°, and 23.72±0.2°.

[0111] In another preferred embodiment, the X-ray powder diffraction pattern of the pyroglutamate salt form I has characteristic peaks at the following 2θ values: 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°.

[0112] In another preferred embodiment, the X-ray powder diffraction pattern of the pyroglutamate salt form I has characteristic peaks at the following 2θ values: 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°.

[0113] In another preferred embodiment, the X-ray powder diffraction pattern of the pyroglutamate salt crystal form I has the following characteristic peaks and peak intensities at 2θ values:

[0114] In another preferred embodiment, the pyroglutamate salt crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG9 .

[0115] In another preferred embodiment, the pyroglutamate salt crystal form I includes one or more characteristics selected from the following group:

[0116] The differential scanning calorimetry (DSC) diagram of the pyroglutamate salt 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);

[0117] The differential scanning calorimetry (DSC) diagram of the pyroglutamate salt form I is substantially as shown in FIG21 ;

[0118] The thermogravimetric analysis (TGA) of the pyroglutamate salt 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.;

[0119] The thermogravimetric analysis (TGA) diagram of the pyroglutamate salt form I is basically shown in Figure 21.

[0120] In another preferred embodiment, in the pyroglutamate salt crystal 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, and more preferably 1:1.

[0121] In another preferred embodiment, the solid form is benzenesulfonate salt form J, and the X-ray powder diffraction pattern of the benzenesulfonate salt form J has characteristic peaks at the following 2θ values: 13.69±0.2°, 19.48±0.2°, 21.07±0.2°, and 22.15±0.2°.

[0122] In another preferred embodiment, the X-ray powder diffraction pattern of the benzenesulfonate salt form J has characteristic peaks at the following 2θ values: 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°.

[0123] In another preferred embodiment, the X-ray powder diffraction pattern of the benzenesulfonate salt form J has characteristic peaks at the following 2θ values: 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°.

[0124] In another preferred embodiment, the X-ray powder diffraction pattern of the benzenesulfonate salt form J has the following characteristic peaks and peak intensities at 2θ values:

[0125] In another preferred embodiment, the benzenesulfonate salt form J has an X-ray powder diffraction pattern substantially as shown in FIG10 .

[0126] In another preferred embodiment, the benzenesulfonate salt form J includes one or more characteristics selected from the following group:

[0127] The differential scanning calorimetry (DSC) analysis of the benzenesulfonate salt form J shows an endothermic peak when heated to 164.9±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0128] The differential scanning calorimetry (DSC) diagram of the benzenesulfonate salt form J is substantially as shown in FIG22 ;

[0129] The thermogravimetric analysis (TGA) of the benzenesulfonate salt 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.

[0130] The thermogravimetric analysis (TGA) diagram of the benzenesulfonate salt form J is basically as shown in Figure 22.

[0131] In another preferred embodiment, in the benzenesulfonate salt 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.

[0132] In another preferred embodiment, the solid form is malonate crystal form K, and the X-ray powder diffraction pattern of the malonate crystal form K has characteristic peaks at the following 2θ values: 15.28±0.2°, 19.66±0.2°, and 20.42±0.2°.

[0133] In another preferred embodiment, the X-ray powder diffraction pattern of the malonate salt form K has characteristic peaks at the following 2θ values: 15.28±0.2°, 19.43±0.2°, 19.66±0.2°, 20.42±0.2°, and 23.66±0.2°.

[0134] In another preferred embodiment, the X-ray powder diffraction pattern of the malonate salt form K has characteristic peaks at the following 2θ values: 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°.

[0135] In another preferred embodiment, the X-ray powder diffraction pattern of the malonate salt crystal form K has the following characteristic peaks and peak intensities at 2θ values:

[0136] In another preferred embodiment, the malonate salt form K has an X-ray powder diffraction pattern substantially as shown in FIG11 .

[0137] In another preferred embodiment, the malonate salt crystal form K includes one or more characteristics selected from the following group:

[0138] The differential scanning calorimetry (DSC) diagram of the malonate salt form K begins to show an endothermic peak when heated to 139.8±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0139] The differential scanning calorimetry (DSC) diagram of the malonate salt form K is substantially as shown in FIG23 ;

[0140] The thermogravimetric analysis (TGA) of the malonate salt form K shows a weight loss of about 1.58% (preferably ±0.2%, ±0.15%, ±0.1% or ±0.05%) when heated to 130° C.;

[0141] The thermogravimetric analysis (TGA) diagram of the malonate salt form K is basically as shown in Figure 23.

[0142] In another preferred embodiment, in the malonate salt crystal 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.

[0143] In another preferred embodiment, the solid form is hemi-fumarate crystal form L, and the X-ray powder diffraction pattern of the hemi-fumarate crystal form L has characteristic peaks at the following 2θ values: 11.57±0.2°, 17.25±0.2°, 23.08±0.2°, and 24.33±0.2°.

[0144] In another preferred embodiment, the X-ray powder diffraction pattern of the hemi-fumarate salt form L has characteristic peaks at the following 2θ values: 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°.

[0145] In another preferred embodiment, the X-ray powder diffraction pattern of the hemi-fumarate salt form L has characteristic peaks at the following 2θ values: 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°.

[0146] In another preferred embodiment, the X-ray powder diffraction pattern of the hemi-fumarate salt form L has the following characteristic peaks and peak intensities at 2θ values:

[0147] In another preferred embodiment, the hemi-fumarate salt form L has an X-ray powder diffraction pattern substantially as shown in FIG12 .

[0148] In another preferred embodiment, the hemi-fumarate salt form L includes one or more characteristics selected from the following group:

[0149] The differential scanning calorimetry (DSC) analysis of the hemi-fumarate salt form L shows an endothermic peak when heated to 171.5±5°C (preferably ±4°C, ±3°C, ±2°C or ±1°C);

[0150] The differential scanning calorimetry (DSC) diagram of the hemi-fumarate salt form L is substantially as shown in FIG24 ;

[0151] The thermogravimetric analysis (TGA) of the hemi-fumarate salt Form L shows a weight loss of about 0.3% (preferably ±0.1% or ±0.05%) when heated to 150±2°C;

[0152] The thermogravimetric analysis (TGA) diagram of the hemi-fumarate salt form L is basically as shown in Figure 24.

[0153] In another preferred embodiment, in the hemi-fumarate salt 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.

[0154] In a second aspect of the present invention, there is provided a method for preparing a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide as described in the first aspect of the present invention, wherein the method comprises any one of methods 1 to 8:

[0155] The method 1 comprises:

[0156] (a1) dissolving the prepared crude compound in a first solvent, heating, and mixing until the system becomes clear;

[0157] (a2) adding a second solvent, followed by cooling and crystallization to obtain free crystalline Form A.

[0158] In another preferred example, in method one, the crude compound is the crude product obtained by filtering, washing, and drying under reduced pressure according to the method with application number 202110666168.6.

[0159] In another preferred embodiment, in step (a1), the first solvent is selected from the group consisting of dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, dimethyl sulfoxide, or a combination thereof, preferably dimethyl sulfoxide.

[0160] In another preferred embodiment, in step (a1), the volume ratio of the first solvent to the crude product is 1.5-3:1, preferably 2:1.

[0161] In another preferred embodiment, in step (a1), the heating refers to heating to 50-70°C, preferably 60-70°C.

[0162] In another preferred embodiment, in step (a1), the mixing time is 0.3-1 h, preferably 0.5 h.

[0163] In another preferred embodiment, in step (a2), the second solvent is selected from the group consisting of methanol, anhydrous ethanol, 95% ethanol, ethanol / water, acetone / water, acetonitrile / water, or a combination thereof, preferably methanol, anhydrous ethanol, 95% ethanol, and more preferably anhydrous ethanol.

[0164] In another preferred embodiment, in step (a2), the volume ratio of the second solvent to the crude product is 1.5-5:1, for example, 2:1, 3:1.

[0165] In another preferred embodiment, in step (a2), the second solvent is added at 50-70°C, preferably 60-70°C.

[0166] In another preferred embodiment, in step (a2), the cooling and crystallization includes staged cooling and crystallization.

[0167] In another preferred embodiment, in step (a2), the cooling crystallization comprises: stirring for 0.5 hours, turning off the heating, slowly cooling to 0-10°C, and keeping at 0-10°C and stirring for 4 hours.

[0168] The second method comprises: dissolving the compound raw material and fumaric acid in a third solvent, mixing and crystallizing at low temperature to obtain the fumarate salt crystal form B.

[0169] In another preferred embodiment, the third solvent is selected from the group consisting of methanol, anhydrous ethanol, 95% ethanol, ethanol / water, acetone / water, acetonitrile / water, ethyl acetate, acetone, or a combination thereof, preferably methanol or 95% ethanol, and more preferably methanol.

[0170] In another preferred embodiment, in method 2, the molar ratio of the compound raw material to fumaric acid is 1:1-1.5, preferably 1:1-1.2, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, 1:1.2.

[0171] In another preferred example, in method 2, the mass volume ratio of the compound raw material and the third solvent is 1g:1-20ml, preferably 1g:1-10ml, such as 1g:3ml, 1g:6ml, 1g:9ml.

[0172] In another preferred embodiment, in method 2, the mixing is carried out at 0-15°C, preferably 3-10°C, more preferably 4-6°C.

[0173] In another preferred embodiment, in method 2, the mixing time is 0.5-2 days, preferably 1 day.

[0174] In another preferred embodiment, the second method comprises: dissolving the compound raw material and fumaric acid in a third solvent, and stirring at 5° C. for 1 day.

[0175] In another preferred embodiment, the method 2 further includes post-processing steps of filtration and vacuum drying.

[0176] The third method comprises:

[0177] (b1) dissolving the compound starting material in a fourth solvent;

[0178] (b2) dissolving concentrated hydrochloric acid in the fourth solvent;

[0179] (b3) adding dropwise the solution of hydrochloric acid obtained in step (b2) in the fourth solvent to the mixture obtained in step (b1), mixing and crystallizing to obtain the hydrochloride crystal form C.

[0180] In another preferred embodiment, in step (b1), the fourth solvent is selected from the group consisting of dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran.

[0181] In another preferred embodiment, the concentrated hydrochloric acid is an aqueous solution of HCl with a mass fraction of 35-40%.

[0182] In another preferred example, in method three, the molar ratio of the compound raw material to the concentrated hydrochloric acid is 1:1-1.5, preferably 1:1-1.4, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, 1:1.2, 1:1.4.

[0183] In another preferred embodiment, the volume ratio of the fourth solvent used in step (b1) to that used in step (b2) is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0184] In another preferred embodiment, in step (b3), the mixing is performed at 10-35°C.

[0185] In another preferred embodiment, in step (b3), the mixing time is 0.5-2 h, preferably 1 h.

[0186] In another preferred embodiment, the step (b3) comprises: slowly dripping a solution of hydrochloric acid in a fourth solvent into the suspension of the compound raw material under stirring conditions, and stirring at room temperature for 1 hour.

[0187] In another preferred embodiment, the method three further includes post-processing steps of filtration and vacuum drying.

[0188] The fourth method comprises:

[0189] (c1) dissolving the compound starting material in a fifth solvent;

[0190] (c2) dissolving concentrated sulfuric acid in a fifth solvent;

[0191] (c3) adding dropwise the solution of sulfuric acid in the fifth solvent obtained in step (c2) to the mixture obtained in step (c1) to dissolve;

[0192] (c4) adding a sixth solvent dropwise to the mixture obtained in step (c3), mixing and crystallizing to obtain the sulfate crystal form D.

[0193] 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 acetonitrile / water.

[0194] In another preferred embodiment, in step (c1), the mixing volume ratio of the organic solvent and water in the fifth solvent is 10-30:1, for example, 15:1, 19:1, 20:1, 25:1, 30:1.

[0195] In another preferred embodiment, the concentrated sulfuric acid is an H2SO4 aqueous solution with a mass fraction of 95-98%.

[0196] In another preferred embodiment, in method 4, the molar ratio of the compound raw material to the concentrated sulfuric acid is 1:1-1.5, for example, 1:1.1, 1:1.15, 1:1.2, 1:3, 1:4.

[0197] In another preferred example, the volume ratio of the compound raw material to the total amount of the fifth solvent used in the fourth method is 1g:10-40ml, preferably 1g:10-30ml, for example 1g:15ml, 1g:20ml, 1g:25ml, 1g:30ml.

[0198] In another preferred embodiment, the volume ratio of the fifth solvent used in step (c1) to that used in step (c2) is 1-1.5:1-1.5, preferably 1-1.2:1-1.2, and more preferably 1:1.

[0199] 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, so that the sample is dissolved.

[0200] In another preferred embodiment, in step (c4), the sixth solvent is selected from the group consisting of dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably methyl tert-butyl ether.

[0201] In another preferred example, the volume ratio of the total amount of the fifth solvent used in the method 4 to the sixth solvent is 1:1.5-3, for example, 1:1.7, 1:2, 1:2.5, 1:3.

[0202] In another preferred embodiment, in step (c4), the mixing is performed at 10-35°C.

[0203] In another preferred embodiment, in step (c4), the mixing time is 0.5-2 h, preferably 1 h.

[0204] In another preferred embodiment, the step (c4) comprises: slowly adding the sixth solvent dropwise to the system under stirring, and then stirring at room temperature for 1 hour to crystallize.

[0205] In another preferred embodiment, the method four further includes post-processing steps of filtration and vacuum drying.

[0206] The fifth method comprises:

[0207] The compound raw material and succinic acid are dissolved in a seventh solvent, mixed and crystallized to obtain the succinate salt crystal form E.

[0208] In another preferred embodiment, the seventh solvent is selected from the group consisting of methanol, anhydrous ethanol, 95% ethanol, ethanol / water, acetone / water, acetonitrile / water, ethyl acetate, acetone, or a combination thereof, preferably methanol and 95% ethanol, and more preferably methanol.

[0209] In another preferred embodiment, in method five, the molar ratio of the compound raw material to succinic acid is 1:1-1.5, preferably 1:1-1.2, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, 1:1.2.

[0210] In another preferred example, in method five, the mass volume ratio of the compound raw material and the seventh solvent is 1g:1-20ml, preferably 1g:1-10ml, for example 1g:3ml, 1g:6ml, 1g:9ml.

[0211] In another preferred embodiment, in method five, the mixing is carried out at 10-35°C.

[0212] In another preferred embodiment, in method five, the mixing time is 0.5-2 days, preferably 1 day.

[0213] In another preferred embodiment, the method five comprises: dissolving the compound raw material and succinic acid in a seventh solvent, and stirring at room temperature for 1 day.

[0214] In another preferred embodiment, the method five further includes post-processing steps of filtration and vacuum drying.

[0215] The sixth method comprises:

[0216] The compound raw material and malic acid are dissolved in an eighth solvent, mixed and crystallized to obtain the malate crystal form F.

[0217] In another preferred embodiment, the eighth solvent is selected from the group consisting of dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran.

[0218] In another preferred embodiment, in method six, the molar ratio of the compound raw material to malic acid is 1:1-1.5, preferably 1:1-1.2, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, 1:1.2.

[0219] In another preferred example, in method six, the mass volume ratio of the compound raw material and the eighth solvent is 1g:1-20ml, preferably 1g:1-15ml, for example 1g:5ml, 1g:9ml, 1g:10ml, 1g:12ml.

[0220] In another preferred embodiment, in method six, the mixing is carried out at 10-35°C.

[0221] In another preferred embodiment, in method six, the mixing time is 0.5-2 days, preferably 1 day.

[0222] In another preferred embodiment, the method six comprises: dissolving the compound raw material and malic acid in an eighth solvent, and stirring at room temperature for 1 day.

[0223] In another preferred embodiment, the method six further includes post-processing steps of filtration and vacuum drying.

[0224] The seventh method comprises:

[0225] The compound raw material and the acid are dissolved in a ninth solvent, and mixed and crystallized to obtain the phosphate crystal form G, tartrate crystal form H, pyroglutamate crystal form I, benzenesulfonate crystal form J or malonate crystal form K corresponding to the acid; wherein the acid is selected from the following group: phosphoric acid, tartaric acid, pyroglutamic acid, benzenesulfonic acid or malonic acid.

[0226] In another preferred embodiment, the ninth solvent is selected from the group consisting of dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran.

[0227] In another preferred embodiment, in method seven, the molar ratio of the compound raw material to the acid is 1:1-1.5, preferably 1:1-1.2, for example, 1:1.02, 1:1.04, 1:1.06, 1:1.1, 1:1.12, 1:1.15, 1:1.2.

[0228] In another preferred embodiment, in method seven, the concentration of the compound raw material in the ninth solvent is 0.05-0.5 mol / L, preferably 0.05-0.3 mol / L, for example 0.08 mol / L, 0.1 mol / L, 0.12 mol / L, 0.15 mol / L.

[0229] In another preferred embodiment, in method seven, the mixing is carried out at 10-35°C.

[0230] In another preferred embodiment, the method seven further includes post-processing steps of filtration and vacuum drying.

[0231] The eighth method comprises:

[0232] The compound raw material and fumaric acid are dissolved in a third solvent, mixed and crystallized to obtain the hemi-fumarate crystal form L.

[0233] In another preferred embodiment, the third solvent is selected from the group consisting of methanol, anhydrous ethanol, 95% ethanol, ethanol / water, acetone / water, acetonitrile / water, ethyl acetate, acetone, or a combination thereof, preferably methanol or 95% ethanol, and more preferably methanol.

[0234] In another preferred embodiment, in method eight, the molar ratio of the compound raw material to fumaric acid is 1:0.5-0.75, preferably 1:0.5-0.6, for example 1:0.5, 1:0.55, 1:0.58, 1:0.6.

[0235] In another preferred embodiment, in method eight, the mass volume ratio of the compound raw material and the third solvent is 1g:1-10ml, preferably 1g:1-5ml, for example 1g:2ml, 1g:3ml, 1g:4ml.

[0236] In another preferred embodiment, in method eight, the mixing is carried out at room temperature, preferably 10-35°C, more preferably 15-25°C.

[0237] In another preferred embodiment, in method eight, the mixing time is 1-7 days, preferably 4 days.

[0238] In another preferred embodiment, the method eight comprises: dissolving the compound raw material and fumaric acid in a third solvent, and suspending and stirring at room temperature for 4 days.

[0239] In another preferred embodiment, the method eight further includes post-processing steps of filtration and vacuum drying.

[0240] In another preferred embodiment, in the method, the compound raw material includes an amorphous or crystalline form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide, preferably free crystalline form A.

[0241] In a third aspect of the present invention, a pharmaceutical composition is provided, comprising:

[0242] (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

[0243] (b) pharmaceutically acceptable excipients, carriers, vehicles, and diluents.

[0244] In the fourth aspect of the present invention, there is provided a use of a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide as described in the first aspect of the present invention for (a) preparing a transient receptor potential channel protein TRPA1 inhibitor; and / or (b) preparing a medicament for preventing and / or treating diseases associated with the transient receptor potential channel protein TRPA1.

[0245] In another preferred embodiment, the disease associated with transient receptor potential channel protein TRPA1 is selected from the following group: inflammatory bowel disease, irritable bowel syndrome, pain, inflammation, cough, or a combination thereof.

[0246] In another preferred embodiment, the inflammatory bowel disease includes Crohn's disease and / or ulcerative colitis.

[0247] In another preferred embodiment, the pain includes visceral pain, acute inflammatory pain, chronic inflammatory pain, neurogenic pain, fibromyalgia, headache, neuralgia or pain caused by cancer.

[0248] In the fifth aspect of the present invention, a method is provided for (a) inhibiting transient receptor potential channel protein TRPA1; and / or (b) preventing and / or treating diseases associated with transient receptor potential channel protein TRPA1, the method comprising: administering the solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide described in the first aspect of the present invention to a subject in need thereof.

[0249] In another preferred embodiment, the subject is a human or non-human mammal.

[0250] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0251] FIG1 is a characteristic XPRD pattern of free-state crystalline form A.

[0252] FIG2 is a characteristic XPRD pattern of the fumarate salt form B.

[0253] FIG3 is a characteristic XPRD pattern of hydrochloride form C.

[0254] FIG4 is a characteristic XPRD pattern of sulfate salt form D.

[0255] FIG5 is a characteristic XPRD pattern of succinate salt Form E.

[0256] FIG6 is a characteristic XPRD pattern of malate Form F.

[0257] FIG7 is a characteristic XPRD pattern of phosphate crystal form G.

[0258] FIG8 is a characteristic XPRD pattern of tartrate salt Form H.

[0259] FIG9 is a characteristic XPRD pattern of pyroglutamate crystal form I.

[0260] FIG10 is a characteristic XPRD pattern of Form J of benzenesulfonate.

[0261] FIG11 is a characteristic XPRD pattern of malonate salt Form K.

[0262] FIG12 is a characteristic XPRD pattern of the hemi-fumarate salt Form L.

[0263] FIG13 is an overlay of DSC and TGA of free crystalline Form A.

[0264] FIG14 is an overlay of DSC and TGA of fumarate salt Form B.

[0265] FIG15 is an overlay of DSC and TGA of hydrochloride salt form C.

[0266] FIG16 is an overlay of DSC and TGA of sulfate salt form D.

[0267] FIG17 is an overlay of DSC and TGA of Form E of the succinate salt.

[0268] FIG18 is an overlay of DSC and TGA of malate Form F.

[0269] FIG19 is an overlay of DSC and TGA of phosphate crystal form G.

[0270] FIG20 is an overlay of DSC and TGA of tartrate salt Form H.

[0271] FIG21 is an overlay of DSC and TGA of pyroglutamate salt Form I.

[0272] FIG22 is an overlay of DSC and TGA of benzenesulfonate Form J.

[0273] FIG23 is an overlay of DSC and TGA of malonate salt Form K.

[0274] FIG24 is an overlay of DSC and TGA of hemi-fumarate Form L.

[0275] FIG25 is a DVS diagram of free-state crystalline form A.

[0276] FIG26 is a DVS diagram of the fumarate salt Form B.

[0277] FIG27 is a DVS diagram of hydrochloride form C.

[0278] FIG28 is a DVS diagram of sulfate salt form D.

[0279] FIG29 is a DVS diagram of succinate salt Form E.

[0280] FIG30 is a DVS diagram of malate Form F.

[0281] Figure 31 is a diagram of the dynamic dissolution of different salt crystal forms. DETAILED DESCRIPTION

[0282] Through extensive and intensive research, the present inventors unexpectedly developed, for the first time, an N-substituted phenylsulfonamide compound or a pharmaceutically acceptable salt thereof, and a solid form thereof. The salt crystal form of the present invention significantly increases the compound's solubility, thereby improving the compound's physicochemical properties and pharmacokinetic characteristics. This led to the completion of the present invention.

[0283] the term

[0284] Unless defined otherwise, 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.

[0285] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0286] As used herein, when used in reference to a specific recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0287] As used herein, room temperature refers to 25±5°C.

[0288] Pharmaceutical compositions and administration

[0289] The various solid forms of the present invention, and pharmaceutical compositions containing the solid forms of the present invention as a main active ingredient can be used to treat, prevent and alleviate TRPA1-related diseases.

[0290] The pharmaceutical composition of the present invention comprises a safe and effective amount of a solid form of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.1-1000 mg of the solid form of the present invention per dose, more preferably 0.5-500 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0291] One or more pharmaceutically acceptable carriers may also be added to the pharmaceutical composition of the present invention. The carriers include conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field. Pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0292] There is no particular limitation on the administration of the pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular), and topical administration. The preferred administration method is oral administration.

[0293] The dosage form of the pharmaceutical composition of the present invention is an oral preparation, an external preparation or an injection preparation. Representatively, solid dosage forms for oral administration or administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0294] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents.

[0295] 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, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures thereof.

[0296] Besides such inert diluents, the pharmaceutical composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and flavorings.

[0297] In addition to the active ingredients, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0298] Pharmaceutical compositions for parenteral injection may comprise 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 carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0299] The solid form of the present invention can be administered or administrated alone or in combination with other drugs for preventing and / or treating diseases associated with TRPAl.

[0300] When administering the pharmaceutical composition, a safe and effective amount of the acellular fat extract of the present invention is applied to a human or non-human animal (such as rats, mice, dogs, cats, cattle, sheep, chickens, ducks, etc.) in need of treatment, wherein the dosage during administration is a pharmaceutically acceptable effective dosage. Those of ordinary skill in the art will appreciate that a "safe and effective amount" may vary depending on the form of the pharmaceutical composition, the route of administration, the adjuvants of the drug used, the severity of the disease, and other drug combinations. For example, for a person weighing 60 kg, the daily dosage is typically 0.1 to 1000 mg, preferably 1 to 600 mg, and more preferably 2 to 300 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill range of skilled physicians.

[0301] The main advantages of the present invention include:

[0302] The salt crystal form of the compound of the present invention has excellent solubility and stability, which is beneficial to improving the physicochemical properties and pharmacokinetic characteristics of the compound.

[0303] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The implementation methods in the following examples where specific conditions are not indicated are generally carried out under conventional conditions or under conditions recommended by the manufacturer.

[0304] Test Method

[0305] XRPD: X-ray powder diffraction; DSC: differential scanning calorimetry; TGA: thermogravimetric analysis; DVS: dynamic water sorption.

[0306] The X-ray powder diffraction analysis method used in the present invention is: a PANalytical X-ray powder diffraction analyzer, an operating voltage of 45 kV, an operating current of 40 mA, and a Cu target to obtain an X-ray powder diffraction pattern.

[0307] The differential scanning calorimetry (DSC) analysis method used in the present invention is as follows: the instrument is TA Q2000 / Discovery DSC2500; the scanning speed is 10° C. / min; and the protective gas is nitrogen.

[0308] Thermogravimetric analysis (TGA) analysis method used in the present invention: the instrument is TA Q5000 / Discovery TGA5500; the scanning speed is 10° C. / min; the protective gas is nitrogen.

[0309] The dynamic moisture sorption (DVS) analysis method used in the present invention uses a DVS Intrinsic instrument manufactured by SMS (Surface Measurement Systems); temperature: 25° C.; carrier gas flow rate: nitrogen, 200 ml / min; mass change per unit time: 0.002% / min; relative humidity range: 0% RH to 95% RH.

[0310] The liquid nuclear magnetic resonance analysis method used in the present invention is: the instrument is a Bruker 400M nuclear magnetic resonance instrument.

[0311] The high performance liquid chromatography (HPLC) purity of the present invention was collected on an Agilent 1260 high performance liquid chromatograph.

[0312] The ion chromatography (IC) test of the present invention to determine the molar ratio of the counter ions was collected by Thermo ICS1100.

[0313] Example 1: N-(2-(Furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide (I) Free Form A

[0314] N-(2-(Furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide was prepared according to the method of application number 202110666168.6. After the reaction is completed, the temperature is adjusted to 0-10°C and purified water and sodium hydroxide aqueous solution are added dropwise, filtered, and the filter cake is first soaked twice with purified water, and then soaked twice with anhydrous methanol to obtain a filter cake, which is dried under reduced pressure to obtain a yellow crude compound. The crude product is poured into a reactor, 2 times the volume of dimethyl sulfoxide is added, the temperature is raised to 60-70°C, stirred for 0.5 hours, the system is clarified, and 3 times the volume of anhydrous methanol is added dropwise at 60-65°C. After stirring for 0.5 hours, the heating is turned off, the temperature is slowly lowered to 0-10°C, and after stirring at 0-10°C for 4 hours, it is filtered to obtain a yellow free crystalline form A with a yield of 79.8%.

[0315] Example 2: Characterization of Free Form A of N-(2-(Furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide (I)

[0316] N-(2-(Furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is in a crystalline state and is designated as free form Form A. X-ray powder diffraction data are shown in Table 1 and Figure 1 , and the TGA / DSC overlay is shown in Figure 13 . When the sample is heated to 150°C, it loses 0.9% of its weight, and exhibits endothermic peaks at 181.0°C, 181.8°C (peak temperature), and 182.3°C.

[0317] Table 1

[0318] Example 3: Screening of salt and crystal forms of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide

[0319] The present inventors screened a variety of salt forms of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide by a suspension stirring method. 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. Among them, most of the acid ligands formed a good salt solid with N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide. The obtained salt samples were characterized by thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), and were analyzed by high performance liquid chromatography (HPLC) coupled with ion chromatography (IC) or liquid nuclear magnetic hydrogen spectroscopy ( 1 The stoichiometric ratio of the samples was determined by H NMR.

[0320] Preparation method of fumarate crystal form B:

[0321] 300.0 mg (0.86 mmol) of the compound (the free crystalline form A obtained in Preferred Example 1) and 101.0 mg of fumaric acid (0.87 mmol) were weighed, 1 mL of MeOH was added, and magnetic stirring was performed at room temperature. The mixture was then stirred at low temperature for 1 day, filtered, and the filter cake was vacuum dried to constant weight to obtain 305.2 mg of a solid, with a yield of 76.1%.

[0322] The X-ray powder diffraction data of the fumarate salt form B are shown in Table 2, the XRPD pattern is shown in Figure 2, and the TGA / DSC overlay is shown in Figure 14.

[0323] Table 2

[0324] As can be seen in Figure 14, DSC shows that the fumarate hydrochloride Form B begins to exhibit an endothermic peak near 189.4°C (peak temperature), and TGA shows that the fumarate salt Form B experiences a weight loss of approximately 0.8% when heated to 150°C. Further HPLC / IC results show that the molar ratio of the free form to the acid is 1:1.

[0325] Preparation method of hydrochloride crystal form C:

[0326] 500.10 mg (1.43 mmol) of the compound was weighed and dissolved in 6.25 mL of tetrahydrofuran solution. The sample was vortexed and sonicated to dissolve. 167.8 μL (2.00 mmol) of concentrated hydrochloric acid with a mass fraction of 36-38% was pipetted and diluted in 6.25 mL of tetrahydrofuran solution. The hydrochloric acid solution in tetrahydrofuran was slowly added dropwise to the suspension of the free sample under stirring. The mixture was stirred at room temperature for 1 hour, filtered, and the filter cake was vacuum dried to constant weight to obtain 466.95 mg of solid with a yield of 84.54%.

[0327] The X-ray powder diffraction data of hydrochloride form C are shown in Table 3, the XRPD pattern is shown in Figure 3, and the TGA / DSC overlay is shown in Figure 15.

[0328] Table 3

[0329] As can be seen from Figure 15, the sample begins to exhibit endothermic peaks around 93.1°C and 150.7°C (peak temperature) when heated to 100°C, and has a weight loss of approximately 4.2% when heated to 100°C. Further HPLC / IC results show that the molar ratio of free form / acid is 1:1.

[0330] Preparation method of sulfate crystal form D:

[0331] 499.63 mg (1.43 mmol) of the compound was weighed and dissolved in 6.25 mL of an acetonitrile / water (v / v = 19:1) mixture. The sample was vortexed and sonicated to dissolve. 91.8 μL (1.72 mmol) of 95-98% concentrated sulfuric acid was diluted in 6.25 mL of an acetonitrile / water (v / v = 19:1) mixture. The sulfuric acid solution was then added dropwise to the free sample suspension under stirring, causing the sample to dissolve. 25 mL of MTBE was slowly added to the mixture under stirring, causing a solid to precipitate. After stirring at room temperature for approximately one hour, the mixture was filtered and the filter cake was vacuum dried to constant weight. A total of 557.98 mg of solid was obtained, with a yield of 87.08%.

[0332] The X-ray powder diffraction data of sulfate crystal form D are shown in Table 4, the XRPD pattern is shown in Figure 4, and the TGA / DSC overlay is shown in Figure 16.

[0333] Table 4

[0334] As can be seen from Figure 16, the sample begins to exhibit an endothermic peak when heated to around 175.8°C (peak temperature), and has a weight loss of approximately 0.6% when heated to 150°C. Further HPLC / IC results show that the molar ratio of free form to acid is 1:1.

[0335] Preparation method of succinate salt crystal form E:

[0336] 300.3 mg (0.86 mmol) of the compound and 102.7 mg (0.87 mmol) of succinic acid were dissolved in 2 mL of methanol solution, stirred at room temperature for 1 day, filtered, and the filter cake was vacuum dried to constant weight to obtain 370.0 mg of solid with a yield of 91.8%.

[0337] The X-ray powder diffraction data of the succinate salt form E are shown in Table 5, the XRPD pattern is shown in Figure 5, and the TGA / DSC overlay is shown in Figure 17.

[0338] Table 5

[0339] As can be seen from Figure 17, the sample begins to exhibit an endothermic peak when heated to around 172.9°C (peak temperature), and has a weight loss of approximately 1.2% when heated to 150°C. Further HPLC / IC results show that the molar ratio of free form to acid is 1:1.

[0340] Preparation method of malate crystal form F:

[0341] 300.1 mg (0.86 mmol) of the compound and 117.0 mg (0.87 mmol) of malic acid were dissolved in 3 mL of tetrahydrofuran solution, stirred at room temperature for 1 day, filtered, and the filter cake was vacuum dried to constant weight to obtain 315.4 mg of solid with a yield of 75.6%.

[0342] The X-ray powder diffraction data of malate Form F are shown in Table 6, the XRPD pattern is shown in Figure 6, and the TGA / DSC overlay is shown in Figure 18.

[0343] Table 6

[0344] As can be seen from Figure 18, the sample begins to exhibit endothermic peaks around 144.7°C and 160.6°C (peak temperature) when heated to 100°C, and has a weight loss of approximately 2.0% when heated to 100°C. Further HPLC / IC results show that the molar ratio of free form / acid is 1:1.

[0345] Preparation method of phosphate crystal form G:

[0346] 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. The mixture was stirred at room temperature and filtered. The filter cake was vacuum dried to constant weight to obtain 18.5 mg of solid with a yield of 69.1%.

[0347] The X-ray powder diffraction data of phosphate crystal form G are shown in Table 7, the XRPD pattern is shown in Figure 7, and the TGA / DSC overlay is shown in Figure 19.

[0348] Table 7

[0349] As can be seen from Figure 19, the sample begins to exhibit an endothermic peak when heated to around 164.1°C (peak temperature), and has a weight loss of approximately 1.8% when heated to 150°C. Further HPLC / IC results show that the molar ratio of free form to acid is 1:1.

[0350] Preparation method of tartrate crystal form H:

[0351] 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. The mixture was stirred at room temperature and filtered. The filter cake was vacuum dried to constant weight to obtain 24.4 mg of solid with a yield of 81.6%.

[0352] The X-ray powder diffraction data of the tartrate salt form H are shown in Table 8, the XRPD pattern is shown in Figure 8, and the TGA / DSC overlay is shown in Figure 20.

[0353] Table 8

[0354] As can be seen from Figure 20, the sample begins to exhibit an endothermic peak around 164.7°C (peak temperature) and has a weight loss of approximately 0.7% when heated to 150°C. Further HPLC / IC results show that the molar ratio of free form to acid is 1:1.

[0355] Preparation method of pyroglutamate crystal form I:

[0356] 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. The mixture was stirred at room temperature and filtered. The filter cake was vacuum dried to constant weight to obtain 25.1 mg of solid with a yield of 87.6%.

[0357] The X-ray powder diffraction data of pyroglutamate salt form I are shown in Table 9, the XRPD pattern is shown in Figure 9, and the TGA / DSC overlay is shown in Figure 21.

[0358] Table 9

[0359] As can be seen from Figure 21, the sample begins to exhibit an endothermic peak when heated to around 155.4°C (peak temperature), and has a weight loss of approximately 1.3% when heated to 120°C. Further HPLC / IC results show that the molar ratio of free form / acid is 1:1.

[0360] Preparation method of benzenesulfonate salt form J:

[0361] 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. The mixture was stirred at room temperature and filtered. The filter cake was vacuum dried to constant weight to obtain 28.3 mg of solid with a yield of 93.1%.

[0362] The X-ray powder diffraction data of benzenesulfonate salt Form J are shown in Table 10, the XRPD pattern is shown in Figure 10, and the TGA / DSC overlay is shown in Figure 22.

[0363] Table 10

[0364] As can be seen from Figure 22, the sample begins to exhibit an endothermic peak when heated to around 164.9°C (peak temperature), and has a weight loss of approximately 1.3% when heated to 150°C. Further HPLC / IC results show that the molar ratio of free form to acid is 1:1.

[0365] Preparation method of malonate crystal form K:

[0366] 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. The mixture was stirred at room temperature and filtered. The filter cake was vacuum dried to constant weight to obtain 21.7 mg of solid with a yield of 80.1%.

[0367] The X-ray powder diffraction data of malonate salt form K are shown in Table 11, the XRPD pattern is shown in Figure 11, and the TGA / DSC overlay is shown in Figure 23.

[0368] Table 11

[0369] As can be seen from Figure 23, the sample begins to exhibit an endothermic peak when heated to around 139.8°C (peak temperature), and has a weight loss of approximately 1.6% when heated to 130°C. Further HPLC / IC results show that the molar ratio of free form to acid is 1:1.

[0370] Preparation method of hemi-fumarate crystal form L:

[0371] 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 suspended and stirred at room temperature for 4 days. The mixture was filtered and the filter cake was vacuum dried to constant weight to obtain 489.2 mg of solid with a yield of 83.7%.

[0372] The X-ray powder diffraction data of the hemi-fumarate salt form L are shown in Table 12, the XRPD pattern is shown in FIG12, and the TGA / DSC overlay is shown in FIG24.

[0373] Table 12

[0374] As can be seen from Figure 24, the sample begins to exhibit an endothermic peak when heated to around 173.8°C (peak temperature), and has a weight loss of approximately 0.3% when heated to 150°C. Further HPLC / IC results show that the molar ratio of free form / acid is 1:0.5.

[0375] Example 4: Evaluation of the properties of some salt crystal forms prepared in Example

[0376] Hygroscopicity

[0377] The hygroscopicity was tested using a dynamic moisture sorption (DVS) instrument. The results are shown in Figures 25-30. On the adsorption curve of 0% RH to 95% RH, at 25°C / 80RH, the moisture adsorption capacity of the free crystalline form A was 1.6%, which was slightly hygroscopic; the moisture adsorption capacity of the fumarate crystalline form B was 0.2%, which was slightly hygroscopic; the moisture adsorption capacity of the hydrochloride crystalline form C was 5.5%, and the sample was hygroscopic; the moisture adsorption capacity of the sulfate crystalline form D was 1.3%, and the sample was slightly hygroscopic; the moisture adsorption capacity of the succinate crystalline form E was 0.6%, and the sample was slightly hygroscopic; and the moisture adsorption capacity of the malate crystalline form F was 1.4%, and the sample was slightly hygroscopic (refer to the Chinese Pharmacopoeia 2015 edition (Guidelines for Drug Hygroscopicity Test)).

[0378] Dynamic solubility

[0379] The dynamic solubility of fumaric acid form B, hydrochloride form C, sulfate form D, succinic acid form E, malic acid form F, and free form A in the biological solvents SGF, FaSSIF, and water at 37°C was tested. In the experiment, the solid dosage of all samples in the three solvents was 10 mg / mL. The samples were sealed and fixed on a rotating disk with a rotation speed of 25 rpm, and the rotating disk was placed in a 37°C constant temperature box. Samples were taken at 1, 2, 4, and 24 hours of equilibrium, and the filtrate was separated and tested for HPLC concentration and pH. The obtained solid was tested by XRPD. The results are shown in Figure 31. It can be seen that the solubility of each salt form in the biological solvents SGF, FaSSIF, and water was significantly improved compared to the free form. The starting sample was almost insoluble in water and FaSSIF, while the solubility of the salt form could be increased to 6-10 mg / mL.

[0380] Solid-state stability

[0381] Approximately 10 mg of the solid was weighed and added to an HPLC vial. The vial was sealed with parafilm and 10 small holes were punctured in the film. The vial was placed in a 25°C / 60% RH and 40°C / 75% RH environment for 4 weeks. Samples were collected at 1, 2, and 4 weeks for HPLC purity and XRPD analysis. HPLC results showed no significant change in purity for the free form and various salt forms after storage under the corresponding conditions. XRPD results showed no significant change in the crystalline form of the free form and various salt forms before and after stability testing. The solid stability results are summarized in Table 13.

[0382] Table 13

[0383] Rough solubility

[0384] Add the corresponding crystalline form sample to a 3-mL glass vial. Add pure water in increments of 50, 50, 200, and 700 μL. Vortex and sonicate to aid dissolution, and observe for complete dissolution of the solid sample. Stop adding solvent when the solid is completely dissolved or the total volume of pure water reaches 1 mL. Calculate the approximate solubility based on the volume of solvent added.

[0385] The results of the rough solubility test are shown in Table 14. Compared with the free crystalline form A, the solubility of each salt form in pure water is significantly improved.

[0386] Table 14

[0387] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide, The solid form includes a free crystal form or a salt crystal form; The salt crystal form is a salt crystal form formed by reacting the compound with a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid is selected from the following group: 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 of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is free crystalline form A, and the X-ray powder diffraction pattern of the free crystalline form A has characteristic peaks at the following 2θ values: 16.24±0.2°, 19.23±0.2°, 23.17±0.2°, 24.45±0.2°, and 32.76±0.2°.

3. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is fumarate crystal form B, and the X-ray powder diffraction pattern of the fumarate crystal form B has characteristic peaks at the following 2θ values: 11.34±0.2°, 14.40±0.2°, 19.71±0.2°, and 19.86±0.2°.

4. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is hydrochloride crystal form C, and the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic peaks at the following 2θ values: 17.20±0.2°, 20.34±0.2°, 24.74±0.2°, and 25.25±0.2°.

5. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is sulfate crystal form D, and the X-ray powder diffraction pattern of the sulfate crystal form D has characteristic peaks at the following 2θ values: 16.84±0.2°, 23.08±0.2°, and 24.38±0.2°.

6. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is succinate crystal form E, and the X-ray powder diffraction pattern of the succinate crystal form E has characteristic peaks at the following 2θ values: 12.57±0.2°, 19.18±0.2°, 19.89±0.2°, and 22.68±0.2°.

7. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is malate crystal form F, and the X-ray powder diffraction pattern of the malate crystal form F has characteristic peaks at the following 2θ values: 12.70±0.2°, 14.57±0.2°, 19.13±0.2°, and 19.47±0.2°.

8. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is phosphate crystal form G, and the X-ray powder diffraction pattern of the phosphate crystal form G has characteristic peaks at the following 2θ values: 11.20±0.2°, 19.70±0.2°, 21.24±0.2°, and 22.49±0.2°.

9. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is tartrate crystal form H, and the X-ray powder diffraction pattern of the tartrate crystal form H has characteristic peaks at the following 2θ values: 14.19±0.2°, 18.64±0.2°, 18.95±0.2°, and 23.70±0.2°.

10. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is pyroglutamate crystal form I, and the X-ray powder diffraction pattern of the pyroglutamate crystal form I has characteristic peaks at the following 2θ values: 9.29±0.2°, 10.76±0.2°, 17.98±0.2°, and 23.72±0.2°.

11. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, wherein The solid form is benzenesulfonate crystal form J, and the X-ray powder diffraction pattern of the benzenesulfonate crystal form J has characteristic peaks at the following 2θ values: 13.69±0.2°, 19.48±0.2°, 21.07±0.2°, and 22.15±0.2°.

12. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide of claim 1, wherein The solid form is malonate crystal form K, and the X-ray powder diffraction pattern of the malonate crystal form K has characteristic peaks at the following 2θ values: 15.28±0.2°, 19.66±0.2°, and 20.42±0.2°.

13. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide of claim 1, wherein The solid form is hemi-fumarate crystal form L, and the X-ray powder diffraction pattern of the hemi-fumarate crystal form L has characteristic peaks at the following 2θ values: 11.57±0.2°, 17.25±0.2°, 23.08±0.2°, and 24.33±0.2°.

14. The solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide of claim 1, wherein The solid form is fumarate crystal form B, and the X-ray powder diffraction pattern of the fumarate crystal form B has characteristic peaks at the following 2θ values: 11.34±0.2°, 14.40±0.2°, 19.23±0.2°, and 19.71±0.2°.

15. A method for preparing the solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to claim 1, characterized in that: The method includes any one of methods 1 to 8: The method 1 comprises: (a1) dissolving the prepared crude compound in a first solvent, heating, and mixing until the solution becomes clear; (a2) adding a second solvent, cooling and crystallizing to obtain free crystalline Form A; The second method includes: Dissolving the compound raw material and fumaric acid in a third solvent, mixing, cooling and crystallizing to obtain the fumarate salt crystal form B; The third method comprises: (b1) dissolving the compound starting material in a fourth solvent; (b2) dissolving concentrated hydrochloric acid in the fourth solvent; (b3) adding dropwise the solution of hydrochloric acid obtained in step (b2) in a fourth solvent to the mixture obtained in step (b1), mixing and crystallizing to obtain the hydrochloride crystalline form C; The fourth method comprises: (c1) dissolving the compound starting material in a fifth solvent; (c2) dissolving concentrated sulfuric acid in a fifth solvent; (c3) adding dropwise the solution of sulfuric acid in the fifth solvent obtained in step (c2) to the mixture obtained in step (c1) to dissolve; (c4) adding a sixth solvent dropwise to the mixture obtained in step (c3), mixing and crystallizing to obtain the sulfate salt crystal form D; The fifth method comprises: Dissolving the compound raw material and succinic acid in a seventh solvent, mixing and crystallizing to obtain the succinate salt crystal form E; The sixth method comprises: Dissolving the compound raw material and malic acid in an eighth solvent, mixing and crystallizing to obtain the malate crystal form F; The seventh method comprises: Dissolving the compound raw material and an acid in a ninth solvent, mixing and crystallizing to obtain a phosphate crystal form G, a tartrate crystal form H, a pyroglutamate crystal form I, a benzenesulfonate crystal form J, and a malonate crystal 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; The eighth method comprises: dissolving the compound raw material and fumaric acid in a third solvent, mixing and crystallizing to obtain the hemi-fumarate crystal form L; The compound raw material includes an amorphous or crystalline form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide.

16. A pharmaceutical composition comprising a 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 a solid form of N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide according to any one of claims 1 to 14, characterized in that Used for (a) preparing inhibitors of transient receptor potential channel protein TRPA1; and / or (b) preparing drugs for preventing and / or treating diseases related to transient receptor potential channel protein TRPA1.

18. The use according to claim 17, characterized in that The disease associated with transient receptor potential channel protein TRPA1 is selected from the following group: inflammatory bowel disease, irritable bowel syndrome, pain, inflammation, or a combination thereof.

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