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WO2024125361A1 - N-取代苯基磺酰胺类化合物的固体形式 - Google Patents

N-取代苯基磺酰胺类化合物的固体形式 Download PDF

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Publication number
WO2024125361A1
WO2024125361A1 PCT/CN2023/136809 CN2023136809W WO2024125361A1 WO 2024125361 A1 WO2024125361 A1 WO 2024125361A1 CN 2023136809 W CN2023136809 W CN 2023136809W WO 2024125361 A1 WO2024125361 A1 WO 2024125361A1
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acid
crystal form
solid form
methyl
furan
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French (fr)
Inventor
王友鑫
张玲玲
丁强
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Shanghai Leado Pharmatech Co Ltd
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Shanghai Leado Pharmatech Co Ltd
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Priority to CN202380082210.7A priority Critical patent/CN120379990A/zh
Priority to JP2025534939A priority patent/JP2025539918A/ja
Priority to EP23902558.8A priority patent/EP4635952A1/en
Publication of WO2024125361A1 publication Critical patent/WO2024125361A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a solid form of an N-substituted phenylsulfonamide compound.
  • 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 + , Ca2+ and Mg2 + .
  • 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 in which it is distributed, 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, trigger a series of physiological functions, and participate in the formation of multiple pain sensations. Inflammatory pain is a common problem of certain chronic diseases, and there is still a lack of effective treatment methods in clinical practice. Animal experimental studies have shown that TRPA1 participates in inflammatory reactions and plays an important role in inflammatory pain. By using TRPA1-specific blockers, the inflammatory pain response of rats can be significantly reduced. From the current research, TRPA1 plays an important role in the occurrence of asthma and cough. Compounds that induce asthma and cough, whether they are endogenous factors or exogenous factors, can activate TRPA1. TRPA1 antagonists can alleviate asthma symptoms and block airway hyperresponsiveness.
  • TRPA1 is involved in the regulation of visceral hypersensitivity and plays an important role in visceral pain.
  • Neurogenic pain is a pain syndrome caused by damage or disease of the central or peripheral nervous system, mainly manifested as hyperalgesia, abnormal pain sensitivity and spontaneous pain.
  • TRPA1 channels play an important role in different neurogenic pain, such as diabetic neuropathy and neuropathy caused by chemotherapy drugs.
  • TRPA1 also plays a mediating role in pain such as toothache and migraine.
  • the administration of TRPA1 antagonists can significantly relieve the occurrence of pain symptoms.
  • TRPA1 is widely distributed and expressed in the human body. In addition to the physiological functions involved in the above, the development of TRPA1 inhibitors has also been reported to involve inflammatory bowel disease, chronic obstructive pulmonary disease, antitussive, antipruritic, allergic rhinitis, ear diseases, anti-diabetes, urinary incontinence, etc. TRPA1 is a new target for the treatment of multiple diseases that has been confirmed.
  • N-substituted phenylsulfonamide compounds exhibit potent inflammatory bowel disease therapeutic and analgesic effects by inhibiting transient receptor potential ankyrin 1 (TRPA1), and also have excellent safety characteristics.
  • TRPA1 transient receptor potential ankyrin 1
  • the object of the present invention is to provide a solid form of N-substituted phenylsulfonamide compounds having excellent stability and excellent solubility.
  • N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is as shown in Formula I:
  • the solid form comprises N-(2-(furan-2-yl)-4-((methylamino)methyl)phenyl) Thiophene-3-sulfonamide in free form or salt form.
  • 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
  • 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.
  • the fumarate salt crystalline form is a fumarate salt crystalline form.
  • the fumarate salt crystal form is a hemi-fumarate salt crystal form.
  • the hydrochloride salt crystal form is a hydrochloride salt crystal form.
  • the sulfate crystal form is a monosulfate crystal form.
  • the succinate salt crystal form is a succinate salt crystal form.
  • the malate crystal form is a malate crystal form.
  • the phosphate crystal form is a monophosphate crystal form.
  • the tartrate salt crystal form is a monotartrate salt crystal form.
  • the pyroglutamate crystal form is a pyroglutamate crystal form.
  • the benzenesulfonate crystalline form is a benzenesulfonate crystalline form.
  • the malonate crystal form is a monomalonate crystal form.
  • the solid form is free crystalline form A
  • the X-ray powder diffraction pattern of the free crystalline form A has characteristic peaks at the following 2 ⁇ values: 16.24 ⁇ 0.2°, 19.23 ⁇ 0.2°, 23.17 ⁇ 0.2°, 24.45 ⁇ 0.2°, and 32.76 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the free crystalline form A has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the free crystalline form A has the following characteristic peaks and peak intensities of 2 ⁇ values:
  • the free crystalline form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the free crystalline form A comprises one or more characteristics selected from the following group:
  • 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);
  • the differential scanning calorimetry (DSC) diagram of the free-state crystalline form A is substantially as shown in FIG13 ;
  • thermogravimetric analysis (TGA) graph of the free crystalline form A has a weight loss of about 0.9 ⁇ 0.5% (preferably ⁇ 0.4%, ⁇ 0.3%, ⁇ 0.2% or ⁇ 0.1%) when heated to 150°C;
  • thermogravimetric analysis (TGA) graph of the free crystalline form A is substantially as shown in FIG13 .
  • 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.
  • the solid form is a fumarate salt form B
  • the X-ray powder diffraction pattern of the fumarate salt form B has characteristic peaks at the following 2 ⁇ values: 11.34 ⁇ 0.2°, 14.40 ⁇ 0.2°, 19.71 ⁇ 0.2°, and 19.86 ⁇ 0.2°.
  • the solid form is a fumarate salt form B
  • the X-ray powder diffraction pattern of the fumarate salt form B has characteristic peaks at the following 2 ⁇ values: 11.34 ⁇ 0.2°, 14.40 ⁇ 0.2°, 19.23 ⁇ 0.2°, and 19.71 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the fumarate salt form B has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the fumarate salt form B has characteristic peaks at the following 2 ⁇ 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.
  • the X-ray powder diffraction pattern of the fumarate salt form B has the following characteristic peaks and peak intensities at 2 ⁇ values:
  • the fumarate salt form B has an X-ray powder diffraction pattern substantially as shown in FIG. 2 .
  • the fumarate salt form B comprises one or more characteristics selected from the following group:
  • 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);
  • the differential scanning calorimetry (DSC) diagram of the fumarate salt form B is substantially as shown in FIG14 ;
  • thermogravimetric analysis (TGA) graph of the fumarate salt form B has a weight loss of about 0.8 ⁇ 0.2% (preferably ⁇ 0.15%, ⁇ 0.1%, ⁇ 0.05% or ⁇ 0.02%) when heated to 150°C;
  • thermogravimetric analysis (TGA) diagram of the fumarate salt form B is basically shown in Figure 14.
  • 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.
  • the solid form is hydrochloride crystal form C
  • the X-ray powder diffraction pattern of the hydrochloride crystal form C has characteristic peaks at the following 2 ⁇ values: 17.20 ⁇ 0.2°, 20.34 ⁇ 0.2°, 24.74 ⁇ 0.2°, and 25.25 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hydrochloride salt form C has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the hydrochloride salt form C has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the hydrochloride crystal form C has the following characteristic peaks and peak intensities of 2 ⁇ values:
  • the hydrochloride salt form C has an X-ray powder diffraction pattern substantially as shown in FIG. 3 .
  • hydrochloride salt form C comprises one or more characteristics selected from the following group:
  • 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);
  • the differential scanning calorimetry (DSC) diagram of the hydrochloride salt form C is substantially as shown in FIG15 ;
  • thermogravimetric analysis (TGA) of the hydrochloride crystal form C has a value of about 4.2 ⁇ 0.5% (preferably ⁇ 0.4%, ⁇ 0.3%, ⁇ 0.2% or ⁇ 0.1%) weight loss;
  • thermogravimetric analysis (TGA) diagram of the hydrochloride salt form C is basically as shown in Figure 15.
  • 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.
  • the solid form is sulfate crystal form D
  • the X-ray powder diffraction spectrum of the sulfate crystal form D has characteristic peaks at the following 2 ⁇ values: 16.84 ⁇ 0.2°, 23.08 ⁇ 0.2°, and 24.38 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the sulfate crystal form D has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the sulfate salt form D has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the sulfate crystal form D has the following characteristic peaks and peak intensities of 2 ⁇ values:
  • the sulfate crystal form D has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • the sulfate crystal form D includes one or more characteristics selected from the following group:
  • the differential scanning calorimetry (DSC) diagram of the sulfate 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);
  • the differential scanning calorimetry (DSC) diagram of the sulfate salt form D is substantially as shown in FIG16 ;
  • thermogravimetric analysis (TGA) graph of the sulfate salt form D has a weight loss of about 0.6 ⁇ 0.1% (preferably ⁇ 0.08%, ⁇ 0.05%, ⁇ 0.02% or ⁇ 0.01%) when heated to 150°C;
  • thermogravimetric analysis (TGA) graph of the sulfate crystal form D is basically as shown in Figure 16.
  • 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.
  • the solid form is succinate crystal form E
  • the X-ray powder diffraction pattern of the succinate crystal form E has characteristic peaks at the following 2 ⁇ values: 12.57 ⁇ 0.2°, 19.18 ⁇ 0.2°, 19.89 ⁇ 0.2°, and 22.68 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the succinate salt form E has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the succinate salt crystal form E has a characteristic 2 ⁇ value of Significant peaks: 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°, 27.33 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the succinate salt form E has the following characteristic peaks and peak intensities at 2 ⁇ values:
  • the succinate salt form E has an X-ray powder diffraction pattern substantially as shown in FIG. 5 .
  • the succinate crystalline form E comprises one or more characteristics selected from the following group:
  • the differential scanning calorimetry (DSC) diagram of the succinate salt form E begins to show an endothermic peak when heated to 172.9 ⁇ 5°C (preferably ⁇ 4°C, ⁇ 3°C, ⁇ 2°C or ⁇ 1°C);
  • the differential scanning calorimetry (DSC) diagram of the succinate salt form E is substantially as shown in FIG17 ;
  • thermogravimetric analysis (TGA) graph of the succinate salt form E has a weight loss of about 1.2 ⁇ 0.2% (preferably ⁇ 0.15%, ⁇ 0.1%, ⁇ 0.05% or ⁇ 0.02%) when heated to 150°C;
  • thermogravimetric analysis (TGA) diagram of the succinate salt form E is basically as shown in Figure 17.
  • 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.
  • the solid form is malate crystal form F
  • the X-ray powder diffraction spectrum of the malate crystal form F has characteristic peaks at the following 2 ⁇ values: 12.70 ⁇ 0.2°, 14.57 ⁇ 0.2°, 19.13 ⁇ 0.2°, 19.47 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the malate crystal form F has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the malate crystal form F has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the malate crystal form F has the following characteristic peaks and peak intensities at 2 ⁇ values:
  • the malate crystal form F has an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
  • the malate crystal form F comprises one or more characteristics selected from the following group:
  • the differential scanning calorimetry (DSC) diagram of the malate crystal 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);
  • the differential scanning calorimetry (DSC) diagram of the malate crystal form F is substantially as shown in FIG18 ;
  • thermogravimetric analysis (TGA) graph of the malate crystalline form F has a weight loss of about 2.0 ⁇ 0.3% (preferably ⁇ 0.2%, ⁇ 0.15%, ⁇ 0.1% or ⁇ 0.05%) when heated to 100°C;
  • thermogravimetric analysis (TGA) graph of the malate crystal form F is basically as shown in Figure 18.
  • 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.
  • the solid form is phosphate crystal form G
  • the X-ray powder diffraction spectrum of the phosphate crystal form G has characteristic peaks at the following 2 ⁇ values: 11.20 ⁇ 0.2°, 19.70 ⁇ 0.2°, 21.24 ⁇ 0.2°, and 22.49 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the phosphate crystal form G has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the phosphate crystal form G has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the phosphate crystal form G has the following characteristic peaks and peak intensities of 2 ⁇ values:
  • the phosphate crystal form G has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the phosphate crystal form G includes one or more characteristics selected from the following group:
  • 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);
  • the differential scanning calorimetry (DSC) diagram of the phosphate crystal form G is substantially as shown in FIG19 ;
  • thermogravimetric analysis (TGA) graph of the phosphate crystal form G has a weight loss of about 1.8% (preferably ⁇ 0.2%, ⁇ 0.15%, ⁇ 0.1% or ⁇ 0.05%) when heated to 150°C;
  • thermogravimetric analysis (TGA) graph of the phosphate crystal form G is basically as shown in Figure 19.
  • 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.
  • the solid form is tartrate crystal form H
  • the X-ray powder diffraction pattern of the tartrate crystal form H has characteristic peaks at the following 2 ⁇ values: 14.19 ⁇ 0.2°, 18.64 ⁇ 0.2°, 18.95 ⁇ 0.2°, and 23.70 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tartrate salt form H has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the tartrate salt form H has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the tartrate salt form H has the following characteristic peaks and peak intensities at 2 ⁇ values:
  • the tartrate salt form H has an X-ray powder diffraction pattern substantially as shown in FIG. 8 .
  • the tartrate salt form H comprises one or more characteristics selected from the following group:
  • 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);
  • the differential scanning calorimetry (DSC) diagram of the tartrate salt form H is substantially as shown in FIG20 ;
  • thermogravimetric analysis (TGA) graph of the tartrate salt form H has a weight loss of about 0.72% (preferably ⁇ 0.1%, ⁇ 0.05%, ⁇ 0.02% or ⁇ 0.01%) when heated to 150°C;
  • thermogravimetric analysis (TGA) diagram of the tartrate salt form H is basically as shown in Figure 20.
  • 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.
  • the solid form is pyroglutamate crystal form I
  • the X-ray powder diffraction pattern of the pyroglutamate crystal form I has characteristic peaks at the following 2 ⁇ values: 9.29 ⁇ 0.2°, 10.76 ⁇ 0.2°, 17.98 ⁇ 0.2°, and 23.72 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the pyroglutamate salt form I has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the pyroglutamate salt form I has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the pyroglutamate crystal form I has the following characteristic peaks and peak intensities of 2 ⁇ values:
  • the pyroglutamate salt form I has an X-ray powder diffraction pattern substantially as shown in FIG. 9 .
  • the pyroglutamate crystal form I includes one or more characteristics selected from the following group:
  • the differential scanning calorimetry (DSC) diagram of the pyroglutamate crystal 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) diagram of the pyroglutamate salt form I is substantially as shown in FIG21 ;
  • thermogravimetric analysis (TGA) graph of the pyroglutamate crystal form I has a weight loss of about 1.3% (preferably ⁇ 0.2%, ⁇ 0.15%, ⁇ 0.1% or ⁇ 0.05%) when heated to 120°C;
  • thermogravimetric analysis (TGA) diagram of the pyroglutamate crystal form I is basically shown in Figure 21.
  • 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.
  • the solid form is benzenesulfonate salt form J
  • the X-ray powder diffraction pattern of the benzenesulfonate salt form J has characteristic peaks at the following 2 ⁇ values: 13.69 ⁇ 0.2°, 19.48 ⁇ 0.2°, 21.07 ⁇ 0.2°, and 22.15 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the benzenesulfonate salt form J has the following 2 ⁇ values: Peaks: 11.53 ⁇ 0.2°, 13.69 ⁇ 0.2°, 17.96 ⁇ 0.2°, 19.48 ⁇ 0.2°, 21.07 ⁇ 0.2°, 22.15 ⁇ 0.2°, 23.06 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the benzenesulfonate salt form J has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the benzenesulfonate salt form J has the following characteristic peaks and peak intensities at 2 ⁇ values:
  • the benzenesulfonate salt form J has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .
  • the benzenesulfonate salt form J comprises one or more characteristics selected from the following group:
  • the differential scanning calorimetry (DSC) diagram of the benzenesulfonate salt 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) diagram of the benzenesulfonate salt form J is substantially as shown in FIG22 ;
  • thermogravimetric analysis (TGA) graph of the benzenesulfonate salt form J has a weight loss of about 1.3% (preferably ⁇ 0.2%, ⁇ 0.15%, ⁇ 0.1% or ⁇ 0.05%) when heated to 150°C;
  • thermogravimetric analysis (TGA) diagram of the benzenesulfonate salt form J is basically as shown in Figure 22.
  • 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.
  • the solid form is malonate crystal form K
  • the X-ray powder diffraction spectrum of the malonate crystal form K has characteristic peaks at the following 2 ⁇ values: 15.28 ⁇ 0.2°, 19.66 ⁇ 0.2°, 20.42 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the malonate salt form K has characteristic peaks at the following 2 ⁇ values: 15.28 ⁇ 0.2°, 19.43 ⁇ 0.2°, 19.66 ⁇ 0.2°, 20.42 ⁇ 0.2°, and 23.66 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the malonate salt form K has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the malonate crystal form K has the following characteristic peaks and peak intensities at 2 ⁇ values:
  • the malonate salt form K has an X-ray powder diffraction pattern substantially as shown in FIG. 11 .
  • the malonate salt form K comprises one or more characteristics selected from the following group:
  • 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);
  • the differential scanning calorimetry (DSC) diagram of the malonate salt form K is substantially as shown in FIG23 ;
  • thermogravimetric analysis (TGA) graph of the malonate salt form K has a weight loss of about 1.58% (preferably ⁇ 0.2%, ⁇ 0.15%, ⁇ 0.1% or ⁇ 0.05%) when heated to 130°C;
  • thermogravimetric analysis (TGA) diagram of the malonate crystal form K is basically as shown in Figure 23.
  • 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.
  • the solid form is hemi-fumarate crystal form L
  • the X-ray powder diffraction pattern of the hemi-fumarate crystal form L has characteristic peaks at the following 2 ⁇ values: 11.57 ⁇ 0.2°, 17.25 ⁇ 0.2°, 23.08 ⁇ 0.2°, and 24.33 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the hemi-fumarate salt form L has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the hemi-fumarate salt form L has characteristic peaks at the following 2 ⁇ 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°.
  • the X-ray powder diffraction pattern of the hemi-fumarate salt form L has the following characteristic peaks and peak intensities at 2 ⁇ values:
  • the hemi-fumarate salt form L has an X-ray powder diffraction pattern substantially as shown in FIG. 12 .
  • the hemi-fumarate salt form L comprises one or more characteristics selected from the following group:
  • the differential scanning calorimetry (DSC) diagram of the hemi-fumarate salt form L begins to show an endothermic peak when heated to 171.5 ⁇ 5°C (preferably ⁇ 4°C, ⁇ 3°C, ⁇ 2°C or ⁇ 1°C);
  • the differential scanning calorimetry (DSC) diagram of the hemi-fumarate salt form L is substantially as shown in FIG24 ;
  • thermogravimetric analysis (TGA) graph of the hemi-fumarate salt form L has a weight loss of about 0.3% (preferably ⁇ 0.1% or ⁇ 0.05%) when heated to 150 ⁇ 2°C;
  • thermogravimetric analysis (TGA) diagram of the hemi-fumarate salt form L is basically as shown in Figure 24.
  • 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.
  • 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:
  • the method 1 comprises:
  • the crude compound is a crude product obtained by filtering, washing, and drying under reduced pressure according to the method with application number 202110666168.6.
  • the first solvent is selected from the group consisting of dichloromethane, methyl Tert-butyl ether, toluene, tetrahydrofuran, dimethyl sulfoxide, or a combination thereof.
  • Dimethyl sulfoxide is preferred.
  • step (a1) the volume ratio of the first solvent to the crude product is 1.5-3:1, preferably 2:1.
  • the heating refers to heating to 50-70°C, preferably 60-70°C.
  • step (a1) the mixing time is 0.3-1 h, preferably 0.5 h.
  • 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.
  • step (a2) the volume ratio of the second solvent to the crude product is 1.5-5:1, such as 2:1, 3:1.
  • step (a2) the second solvent is added at 50-70°C, preferably 60-70°C.
  • the cooling crystallization includes staged cooling crystallization.
  • the cooling crystallization comprises: after stirring for 0.5 hours, turning off the heating, slowly cooling to 0-10°C, keeping the temperature at 0-10°C and stirring for 4 hours.
  • 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.
  • 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, 95% ethanol, and more preferably methanol.
  • 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.
  • 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.
  • the mixing is carried out at 0-15°C, preferably 3-10°C, more preferably 4-6°C.
  • the mixing time is 0.5-2 days, preferably 1 day.
  • the second method comprises: dissolving the compound raw material and fumaric acid in a third solvent, and stirring at 5° C. for 1 day.
  • the method 2 further comprises post-processing steps of filtration and vacuum drying.
  • the method three comprises:
  • step (b3) adding dropwise the solution of hydrochloric acid obtained in step (b2) in the fourth solvent into the mixture obtained in step (b1), mixing and crystallizing to obtain the hydrochloride crystal form C.
  • the fourth solvent is selected from the group consisting of dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran.
  • the concentrated hydrochloric acid is an aqueous solution of HCl with a mass fraction of 35-40%.
  • 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.
  • 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.
  • step (b3) the mixing is carried out at 10-35°C.
  • step (b3) the mixing time is 0.5-2 h, preferably 1 h.
  • the step (b3) comprises: mixing hydrochloric acid in a solution of the fourth solvent under stirring. The solution was slowly dripped into the suspension of the compound raw material and stirred at room temperature for 1 hour.
  • the method three also includes post-processing steps of filtration and vacuum drying.
  • the fourth method comprises:
  • step (c4) adding a sixth solvent dropwise to the mixture obtained in step (c3), mixing and crystallizing to obtain the sulfate crystal form D.
  • 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.
  • acetonitrile/water Preferably, acetonitrile/water.
  • 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.
  • the concentrated sulfuric acid is an aqueous solution of H 2 SO 4 with a mass fraction of 95-98%.
  • 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.
  • the volume ratio of the compound raw material to the total amount of the fifth solvent used in the method four is 1g:10-40ml, preferably 1g:10-30ml, for example 1g:15ml, 1g:20ml, 1g:25ml, 1g:30ml.
  • 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.
  • the step (c3) comprises: slowly dropping a fifth solvent solution of sulfuric acid into a suspension of the free sample under stirring conditions, so that the sample is dissolved.
  • 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.
  • the volume ratio of the total amount of the fifth solvent used in the method four to the sixth solvent is 1:1.5-3, for example, 1:1.7, 1:2, 1:2.5, 1:3.
  • step (c4) the mixing is carried out at 10-35°C.
  • step (c4) the mixing time is 0.5-2 h, preferably 1 h.
  • the step (c4) comprises: slowly dropping the sixth solvent into the system under stirring conditions, and stirring at room temperature for 1 hour for crystallization.
  • the method four also includes post-processing steps of filtration and vacuum drying.
  • the fifth method comprises:
  • the compound raw material and succinic acid are dissolved in a seventh solvent, mixed and crystallized to obtain the succinate salt crystal form E.
  • 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.
  • 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.
  • 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.
  • the mixing time is 0.5-2 days, preferably 1 day.
  • the method five comprises: dissolving the compound raw material and succinic acid in a seventh solvent, and stirring at room temperature for 1 day.
  • the method five also includes post-processing steps of filtration and vacuum drying.
  • the sixth method comprises:
  • the compound raw material and malic acid are dissolved in an eighth solvent, mixed and crystallized to obtain the malate crystal form F.
  • the eighth solvent is selected from the group consisting of dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran.
  • 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.
  • 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.
  • the mixing is carried out at 10-35°C.
  • the mixing time is 0.5-2 days, preferably 1 day.
  • the method six comprises: dissolving the compound raw material and malic acid in an eighth solvent, and stirring at room temperature for 1 day.
  • the method six also includes post-processing steps of filtration and vacuum drying.
  • the seventh method comprises:
  • 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.
  • the ninth solvent is selected from the group consisting of dichloromethane, methyl tert-butyl ether, toluene, tetrahydrofuran, or a combination thereof, preferably tetrahydrofuran.
  • 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.
  • 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.
  • the mixing is carried out at 10-35°C.
  • the method seven also includes post-processing steps of filtration and vacuum drying.
  • the method eight comprises:
  • the compound raw material and fumaric acid are dissolved in a third solvent, mixed and crystallized to obtain the hemi-fumarate crystal form L.
  • 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, 95% ethanol, and more preferably methanol.
  • 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.
  • 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.
  • the mixing is carried out at room temperature, preferably 10-35°C, more preferably 15-25°C.
  • the mixing time is 1-7 days, preferably 4 days.
  • 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.
  • the method eight also includes post-processing steps of filtration and vacuum drying.
  • the compound raw material includes N-(2-(furan-2-yl)-4-((methylamino
  • the amorphous or crystalline form of thiophene-3-sulfonamide is preferably the free crystalline form A.
  • a pharmaceutical composition comprising:
  • 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 an inhibitor of transient receptor potential channel protein TRPA1; and/or (b) preparing a drug for preventing and/or treating diseases associated with transient receptor potential channel protein TRPA1.
  • 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.
  • the inflammatory bowel disease includes Crohn's disease and/or ulcerative colitis.
  • the pain includes visceral pain, acute inflammatory pain, chronic inflammatory pain, neurogenic pain, fibromyalgia, headache, neuralgia or pain caused by cancer.
  • a method 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 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.
  • the subject is a human or non-human mammal.
  • FIG1 is a characteristic XPRD diagram of free form A.
  • FIG. 2 is a characteristic XPRD diagram of the fumarate salt Form B.
  • FIG3 is a characteristic XPRD diagram of hydrochloride form C.
  • FIG. 4 is a characteristic XPRD pattern of sulfate salt Form D.
  • FIG. 5 is a characteristic XPRD pattern of Form E of the succinate salt.
  • FIG. 6 is a characteristic XPRD pattern of malate Form F.
  • FIG. 7 is a characteristic XPRD pattern of phosphate crystal form G.
  • FIG. 8 is a characteristic XPRD pattern of tartrate salt Form H.
  • FIG. 9 is a characteristic XPRD diagram of pyroglutamate crystal form I.
  • FIG. 10 is a characteristic XPRD pattern of Form J of benzenesulfonate.
  • FIG. 11 is a characteristic XPRD pattern of malonate Form K.
  • FIG. 12 is a characteristic XPRD pattern of the hemi-fumarate Form L.
  • FIG. 13 is an overlay of DSC and TGA of free crystalline form A.
  • FIG. 14 is an overlay of DSC and TGA of fumarate form B.
  • FIG. 15 is an overlay of DSC and TGA of hydrochloride salt form C.
  • FIG. 16 is an overlay of DSC and TGA of sulfate salt form D.
  • FIG. 17 is an overlay of DSC and TGA of Form E of the succinate salt.
  • FIG. 18 is an overlay of DSC and TGA of malate Form F.
  • FIG. 19 is an overlay of DSC and TGA of phosphate form G.
  • FIG. 20 is an overlay of DSC and TGA of tartrate salt form H.
  • FIG. 21 is an overlay of DSC and TGA of pyroglutamate crystal form I.
  • FIG. 22 is an overlay of DSC and TGA of benzenesulfonate Form J.
  • FIG. 23 is an overlay of DSC and TGA of malonate Form K.
  • FIG. 24 is an overlay of DSC and TGA of hemi-fumarate Form L.
  • FIG. 25 is a DVS diagram of free-state crystalline form A.
  • FIG. 26 is a DVS diagram of the fumarate salt Form B.
  • FIG. 27 is a DVS diagram of hydrochloride form C.
  • FIG. 28 is a DVS diagram of sulfate crystal form D.
  • FIG. 29 is a DVS diagram of Form E of the succinate salt.
  • FIG. 30 is a DVS diagram of malate Form F.
  • Figure 31 is a diagram of the dynamic dissolution of different salt crystal forms.
  • the inventors have unexpectedly developed an N-substituted phenylsulfonamide compound or a pharmaceutically acceptable salt thereof, and a solid form for the first time through extensive and in-depth research.
  • the salt crystal form of the present invention significantly increases the solubility of the compound, which is beneficial to improving the physicochemical properties and pharmacokinetic characteristics of the compound. On this basis, the present invention was completed.
  • the terms “comprise”, “include”, and “contain” are used interchangeably and include not only closed definitions, but also semi-closed and open definitions. In other words, the terms include “consisting of”, “consisting essentially of”.
  • the term “about” means that the value may vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
  • room temperature refers to 25 ⁇ 5°C.
  • the various solid forms of the present invention, and the pharmaceutical compositions containing the solid forms of the present invention as the main active ingredient can be used to treat, prevent and alleviate TRPA1-related diseases.
  • the pharmaceutical composition of the present invention comprises a solid form of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 0.1-1000 mg of the solid form of the present invention/dose, and more preferably, contains 0.5-500 mg of the solid form of the present invention/dose.
  • the "one dose” is a capsule or tablet.
  • 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, adhesives, 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, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • compositions of the present invention 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.
  • the dosage form of the pharmaceutical composition of the present invention is an oral preparation, an external preparation or an injection preparation.
  • solid dosage forms for oral administration or administration include capsules, tablets, pills, powders and granules.
  • 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, starch, 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) disintegrators, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (
  • 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.
  • Liquid dosage forms for oral administration or administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • 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, isopropanol, 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 of these substances, etc.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils,
  • the pharmaceutical composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances.
  • compositions for parenteral injection may 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 carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • 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 TRPA1.
  • the acellular fat extract of the present invention in a safe and effective amount is applied to people or non-human animals (such as rats, mice, dogs, cats, cattle, sheep, chickens, ducks, etc.) that need treatment, wherein the dosage during application is a pharmaceutically acceptable effective dosage.
  • “safe and effective amount” may vary with the form of the pharmaceutical composition, the route of administration, the adjuvants of the drugs used, the severity of the disease, and the combination of drugs with other drugs.
  • the daily dosage is usually 0.1 to 1000 mg, preferably 1 to 600 mg, and more preferably 2 to 300 mg.
  • the specific dosage should also consider factors such as the route of administration and the health status of the patient, which are all within the skill range of skilled physicians.
  • the salt crystal form of the compound of the present invention has excellent solubility properties and stability, which is beneficial to improving the physicochemical properties and pharmacokinetic characteristics of the compound.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVS dynamic moisture sorption.
  • the X-ray powder diffraction analysis method used in the present invention is: PANalytical X-ray powder diffraction analyzer, working voltage: 45kV, working current: 40mA, and using Cu target to obtain X-ray powder diffraction pattern.
  • the differential scanning calorimetry (DSC) analysis method used in the present invention is: the instrument is TA Q2000/Discovery DSC2500; the scanning speed is 10°C/min; the protective gas is nitrogen.
  • Thermogravimetric analysis (TGA) analysis method used in the present invention instrument is TA Q5000/Discovery TGA5500; scanning speed: 10°C/min; protective gas, nitrogen.
  • the dynamic moisture adsorption (DVS) analysis method used in the present invention is DVS Intrinsic produced 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-95%RH.
  • the liquid nuclear magnetic resonance analysis method used in the present invention is a Bruker 400M nuclear magnetic resonance instrument.
  • HPLC high performance liquid chromatography purity
  • the ion chromatography (IC) test of the present invention to determine the molar ratio of the counter ions is collected by Thermo ICS1100.
  • 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, purified water and sodium hydroxide aqueous solution are added dropwise, filtered, and the filter cake is first rinsed twice with purified water, and then rinsed twice with anhydrous methanol to obtain a filter cake, which is dried under reduced pressure to obtain a yellow crude compound.
  • the crude product was poured into a reactor, 2 times the volume of dimethyl sulfoxide was added, the temperature was raised to 60-70°C, stirred for 0.5 hours, the system was clarified, 3 times the volume of anhydrous methanol was added dropwise at 60-65°C, stirred for 0.5 hours, the heating was turned off, the temperature was slowly lowered to 0-10°C, kept at 0-10°C and stirred for 4 hours, and filtered to obtain a yellow free crystalline form A with a yield of 79.8%.
  • N-(2-(Furan-2-yl)-4-((methylamino)methyl)phenyl)thiophene-3-sulfonamide is in a crystalline state and is named free form A.
  • the X-ray powder diffraction data are shown in Table 1 and Figure 1, and the TGA/DSC overlay is shown in Figure 13.
  • the sample is heated to 150°C, there is a 0.9% weight loss, and there are endothermic peaks at 181.0°C, 181.8°C (peak temperature) and 182.3°C.
  • the inventors screened various 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 include 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.
  • DSC shows that the fumaric acid hydrochloride crystal form B begins to have an endothermic peak when heated to about 189.4°C (peak temperature), and TGA shows that the fumarate crystal form B has a weight loss of about 0.8% when heated to 150°C.
  • HPLC/IC results show that the molar ratio of free state/acid is 1:1.
  • 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.
  • the sample begins to show endothermic peaks near 93.1°C and 150.7°C (peak temperature) when heated to 100°C, and has a weight loss of about 4.2% when heated to 100°C.
  • Further HPLC/IC results show that the molar ratio of free state/acid is 1:1.
  • the X-ray powder diffraction data of sulfate crystal form D are shown in Table 4, the XRPD graph is shown in Figure 4, and the TGA/DSC overlay graph is shown in Figure 16.
  • the sample begins to have an endothermic peak when heated to around 175.8° C. (peak temperature), and has a weight loss of about 0.6% when heated to 150° C.
  • peak temperature peak temperature
  • weight loss about 0.6% when heated to 150° C.
  • the sample begins to have an endothermic peak when heated to around 172.9°C (peak temperature), and has a weight loss of about 1.2% when heated to 150°C.
  • peak temperature peak temperature
  • weight loss about 1.2% when heated to 150°C.
  • 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.
  • the X-ray powder diffraction data of phosphate crystal form G are shown in Table 7, the XRPD graph is shown in Figure 7, and the TGA/DSC overlay graph is shown in Figure 19.
  • the sample begins to have an endothermic peak when heated to around 164.1° C. (peak temperature), and has a weight loss of about 1.8% when heated to 150° C. Further HPLC/IC results show that the molar ratio of free state/acid is 1:1.
  • 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.
  • the sample begins to have an endothermic peak when heated to around 164.7°C (peak temperature), and has a weight loss of about 0.7% when heated to 150°C.
  • peak temperature 164.7°C
  • weight loss 0.7% when heated to 150°C.
  • the X-ray powder diffraction data of pyroglutamate crystal form I are shown in Table 9, the XRPD diagram is shown in Figure 9, and the TGA/DSC overlay diagram is shown in Figure 21.
  • the sample begins to have an endothermic peak when heated to around 155.4°C (peak temperature), and has a weight loss of about 1.3% when heated to 120°C.
  • peak temperature peak temperature
  • weight loss about 1.3% when heated to 120°C.
  • 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 pattern is shown in Figure 22.
  • the sample begins to have an endothermic peak when heated to around 164.9°C (peak temperature), and has a weight loss of about 1.3% when heated to 150°C.
  • peak temperature peak temperature
  • weight loss about 1.3% when heated to 150°C.
  • 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 .
  • the sample begins to have an endothermic peak when heated to around 173.8° C. (peak temperature), and has a weight loss of about 0.3% when heated to 150° C. Further HPLC/IC results show that the molar ratio of free state/acid is 1:0.5.

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Abstract

一种N-取代苯基磺酰胺类化合物的固体形式，具体地涉及N-取代苯基磺酰胺类化合物的游离态晶型、富马酸盐晶型、盐酸盐晶型、硫酸盐晶型、琥珀酸盐晶型、苹果酸盐晶型、磷酸盐晶型、酒石酸盐晶型、焦谷氨酸盐晶型、苯磺酸-盐晶型、丙二酸盐晶型和半富马酸晶型。固体形式具有优异的稳定性、溶解性，对瞬时受体电位通道蛋白TRPA1具有优异的抑制作用，并对TRPA1相关的疾病具有良好的治疗作用。

Description

N-取代苯基磺酰胺类化合物的固体形式 技术领域
本发明涉及药物化学领域，具体地涉及一种N-取代苯基磺酰胺类化合物的固体形式。
背景技术
TRPA1是TRP离子通道超家族中的一员，TRPA亚家族的唯一成员，属于非选择性阳离子通道，可通透Na+，K+，Ca2+和Mg2+。TRPA1主要分布在背根神经(DRG)、三叉神经(TG)和迷走神经(VG)的初级感觉神经元上。从分布的人体系统来看，TRPA1高表达在外周神经系统、呼吸系统、胃肠系统和泌尿系统，当这些器官组织出现功能异常时，TRPA1通道的表达和功能通常也同步发生异常。TRPA1可以将冷刺激、化学刺激以及机械刺激转化为内向电流，引发一系列生理功能，并参与多种痛觉的形成。炎性痛是某些慢性疾病的共同困扰，临床上尚缺乏很有效的治疗手段。动物实验研究显示，TRPA1参与炎性反应，并在炎性疼痛中发挥重要作用，通过使用TRPA1特异性阻断剂，可以明显减轻大鼠炎性疼痛反应。从目前的研究来看，TRPA1在哮喘和咳嗽的发生中扮演重要的作用，诱导哮喘与咳嗽的化合物，无论是细胞内源因子，还是外源因子，都能激活TRPA1。TRPA1的拮抗剂能够减轻哮喘症状，能阻断气道高反应性。通过不同的内脏高敏感动物模型如结肠炎、直结肠扩张或应激，证实TRPA1参与内脏高敏感的调控，在内脏痛中发挥重要作用。神经源性疼痛是由中枢或外周神经系统损伤或者疾病引起的疼痛综合征，主要表现为痛觉过敏、异常痛敏和自发性疼痛等。近年来越来越多的研究显示，TRPA1通道在不同的神经源性疼痛中起到重要作用，例如糖尿病性神经病变和化疗药引起的神经病变等。最近研究还表明，TRPA1在牙痛、偏头痛等疼痛中也有介导作用，通过给予TRPA1的拮抗剂能明显缓解疼痛症状的产生。
TRPA1在人体系统中广泛分布和表达，除以上TRPA1参与的生理功能外，目前已报道的TRPA1抑制剂适应症的开发还涉及到炎症性肠病、慢性阻塞性肺疾病、镇咳、止痒、过敏性鼻炎、耳疾病、抗糖尿病、尿失禁等。TRPA1是已经被证实了的多种疾病治疗的新靶点。
N-取代苯基磺酰胺类化合物，通过抑制瞬时受体电位锚蛋白1(TRPA1)，表现出强效的炎症性肠病治疗药效和镇痛药效，同时具有非常优秀的安全特性。
发明内容
本发明的目的在于提供稳定性优异、溶解性能优异的N-取代苯基磺酰胺类化合物的固体形式。
在本发明的第一方面，提供了一种N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式。
在另一优选例中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的结构如式I所示：
在一优选例中，所述的固体形式包括N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基) 噻吩-3-磺酰胺的游离态晶型或盐晶型。
在另一优选例中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的盐晶型为该化合物与药学上可接受的酸反应形成的盐晶型，所述药学上可接受的酸选自下组：盐酸、硫酸、马来酸、磷酸、富马酸、L-酒石酸、柠檬酸、D-葡萄糖醛酸、L-苹果酸、琥珀酸、焦谷氨酸、对甲苯磺酸、甲磺酸、苯磺酸、乙酸、丙二酸、苯甲酸和马尿酸。
在另一优选例中，所述富马酸盐晶型为一富马酸盐晶型。
在另一优选例中，所述富马酸盐晶型为半富马酸盐晶型。
在另一优选例中，所述盐酸盐晶型为一盐酸盐晶型。
在另一优选例中，所述硫酸盐晶型为一硫酸盐晶型。
在另一优选例中，所述琥珀酸盐晶型为一琥珀酸盐晶型。
在另一优选例中，所述苹果酸盐晶型为一苹果酸盐晶型。
在另一优选例中，所述磷酸盐晶型为一磷酸盐晶型。
在另一优选例中，所述酒石酸盐晶型为一酒石酸盐晶型。
在另一优选例中，所述焦谷氨酸盐晶型为一焦谷氨酸盐晶型。
在另一优选例中，所述苯磺酸盐晶型为一苯磺酸盐晶型。
在另一优选例中，所述丙二酸盐晶型为一丙二酸盐晶型。
在另一优选例中，所述固体形式为游离态晶型A，所述的游离态晶型A的X-射线粉末衍射图谱在下述2θ值有特征峰：16.24±0.2°、19.23±0.2°、23.17±0.2°、24.45±0.2°、32.76±0.2°。
在另一优选例中，所述的游离态晶型A的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、32.76±0.2°。
在另一优选例中，所述的游离态晶型A的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：

在另一优选例中，所述的游离态晶型A具有基本如图1所示的X-射线粉末衍射图谱。
在另一优选例中，所述的游离态晶型A括选自下组的一个或多个特征：
所述的游离态晶型A的差示扫描量热分析(DSC)图在加热至181.0±5℃(较佳地±4℃，±3℃，±2℃或±1℃)、181.8±5℃(较佳地±4℃，±3℃，±2℃或±1℃)、182.3±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的游离态晶型A的差示扫描量热分析(DSC)图基本如图13所示；
所述的游离态晶型A的热重分析(TGA)图在加热至150℃时具有约0.9±0.5％(较佳地±0.4％，±0.3％，±0.2％或±0.1％)的重量损失；
所述的游离态晶型A的热重分析(TGA)图基本如图13所示。
在另一优选例中，所述盐晶型包括富马酸盐晶型、盐酸盐晶型、硫酸盐晶型、琥珀酸盐晶型、苹果酸盐晶型、磷酸盐晶型、酒石酸盐晶型、焦谷氨酸盐晶型、苯磺酸盐晶型、丙二酸盐晶型和半富马酸盐晶型。
在另一优选例中，所述固体形式为富马酸盐晶型B，所述的富马酸盐晶型B的X-射线粉末衍射图谱在下述2θ值有特征峰：11.34±0.2°、14.40±0.2°、19.71±0.2°、19.86±0.2°。
在另一优选例中，所述固体形式为富马酸盐晶型B，所述的富马酸盐晶型B的X-射线粉末衍射图谱在下述2θ值有特征峰：11.34±0.2°、14.40±0.2°、19.23±0.2°、19.71±0.2°。
在另一优选例中，所述的富马酸盐晶型B的X-射线粉末衍射图谱在下述2θ值有特征峰：11.34±0.2°、14.40±0.2°、16.75±0.2°、19.23±0.2°、19.71±0.2°、19.86±0.2°、24.03±0.2°。
在另一优选例中，所述的富马酸盐晶型B的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、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°、38.17±0.2°。
在另一优选例中，所述的富马酸盐晶型B的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：

在另一优选例中，所述的富马酸盐晶型B具有基本如图2所示的X-射线粉末衍射图谱。
在另一优选例中，所述的富马酸盐晶型B包括选自下组的一个或多个特征：
所述的富马酸盐晶型B的差示扫描量热分析(DSC)图在加热至189.4±5℃(较佳地±4℃，±3℃，±2℃或±1℃)开始出现吸热峰；
所述的富马酸盐晶型B的差示扫描量热分析(DSC)图基本如图14所示；
所述的富马酸盐晶型B的热重分析(TGA)图在加热至150℃时具有约0.8±0.2％(较佳地±0.15％，±0.1％，±0.05％或±0.02％)的重量损失；
所述的富马酸盐晶型B的热重分析(TGA)图基本如图14所示。
在另一优选例中，在所述富马酸盐晶型B中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与富马酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为盐酸盐晶型C，所述的盐酸盐晶型C的X-射线粉末衍射图谱在下述2θ值有特征峰：17.20±0.2°、20.34±0.2°、24.74±0.2°、25.25±0.2°。
在另一优选例中，所述的盐酸盐晶型C的X-射线粉末衍射图谱在下述2θ值有特征峰：11.56±0.2°、17.20±0.2°、20.34±0.2°、23.27±0.2°、23.52±0.2°、24.74±0.2°、25.25±0.2°。
在另一优选例中，所述的盐酸盐晶型C的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、25.25±0.2°。
在另一优选例中，所述的盐酸盐晶型C的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：
在另一优选例中，所述的盐酸盐晶型C具有基本如图3所示的X-射线粉末衍射图谱。
在另一优选例中，所述的盐酸盐晶型C包括选自下组的一个或多个特征：
所述的盐酸盐晶型C的差示扫描量热分析(DSC)图在加热至93.1±5℃(较佳地±4℃，±3℃，±2℃或±1℃)和150.7±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的盐酸盐晶型C的差示扫描量热分析(DSC)图基本如图15所示；
所述的盐酸盐晶型C的热重分析(TGA)图在加热至100℃时具有约4.2±0.5％(较佳 地±0.4％，±0.3％，±0.2％或±0.1％)的重量损失；
所述的盐酸盐晶型C的热重分析(TGA)图基本如图15所示。
在另一优选例中，在所述盐酸盐晶型C中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与盐酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为硫酸盐晶型D，所述的硫酸盐晶型D的X-射线粉末衍射图谱在下述2θ值有特征峰：16.84±0.2°、23.08±0.2°、24.38±0.2°。
在另一优选例中，所述的硫酸盐晶型D的X-射线粉末衍射图谱在下述2θ值有特征峰：11.51±0.2°、12.13±0.2°、16.84±0.2°、23.08±0.2°、23.49±0.2°、24.38±0.2°。
在另一优选例中，所述的硫酸盐晶型D的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、24.38±0.2°。
在另一优选例中，所述的硫酸盐晶型D的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：
在另一优选例中，所述的硫酸盐晶型D具有基本如图4所示的X-射线粉末衍射图谱。
在另一优选例中，所述的硫酸盐晶型D包括选自下组的一个或多个特征：
所述的硫酸盐晶型D的差示扫描量热分析(DSC)图在加热至175.8±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的硫酸盐晶型D的差示扫描量热分析(DSC)图基本如图16所示；
所述的硫酸盐晶型D的热重分析(TGA)图在加热至150℃时具有约0.6±0.1％(较佳地±0.08％，±0.05％，±0.02％或±0.01％)的重量损失；
所述的硫酸盐晶型D的热重分析(TGA)图基本如图16所示。
在另一优选例中，在所述硫酸盐晶型D中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与硫酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为琥珀酸盐晶型E，所述的琥珀酸盐晶型E的X-射线粉末衍射图谱在下述2θ值有特征峰：12.57±0.2°、19.18±0.2°、19.89±0.2°、22.68±0.2°。
在另一优选例中，所述的琥珀酸盐晶型E的X-射线粉末衍射图谱在下述2θ值有特征峰：12.57±0.2°、14.89±0.2°、19.18±0.2°、19.89±0.2°、22.68±0.2°、23.48±0.2°、24.31±0.2°。
在另一优选例中，所述的琥珀酸盐晶型E的X-射线粉末衍射图谱在下述2θ值有特 征峰：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°、27.33±0.2°。
在另一优选例中，所述的琥珀酸盐晶型E的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：
在另一优选例中，所述的琥珀酸盐晶型E具有基本如图5所示的X-射线粉末衍射图谱。
在另一优选例中，所述的琥珀酸盐晶型E包括选自下组的一个或多个特征：
所述的琥珀酸盐晶型E的差示扫描量热分析(DSC)图在加热至172.9±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的琥珀酸盐晶型E的差示扫描量热分析(DSC)图基本如图17所示；
所述的琥珀酸盐晶型E的热重分析(TGA)图在加热至150℃时具有约1.2±0.2％(较佳地±0.15％，±0.1％，±0.05％或±0.02％)的重量损失；
所述的琥珀酸盐晶型E的热重分析(TGA)图基本如图17所示。
在另一优选例中，在所述琥珀酸盐晶型E中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与琥珀酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为苹果酸盐晶型F，所述的苹果酸盐晶型F的X-射线粉末衍射图谱在下述2θ值有特征峰：12.70±0.2°、14.57±0.2°、19.13±0.2°、19.47±0.2°。
在另一优选例中，所述的苹果酸盐晶型F的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、24.35±0.2°。
在另一优选例中，所述的苹果酸盐晶型F的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、28.08±0.2°。
在另一优选例中，所述的苹果酸盐晶型F的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：

在另一优选例中，所述的苹果酸盐晶型F具有基本如图6所示的X-射线粉末衍射图谱。
在另一优选例中，所述的苹果酸盐晶型F包括选自下组的一个或多个特征：
所述的苹果酸盐晶型F的差示扫描量热分析(DSC)图在加热至144.7±5℃(较佳地±4℃，±3℃，±2℃或±1℃)和160.6±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的苹果酸盐晶型F的差示扫描量热分析(DSC)图基本如图18所示；
所述的苹果酸盐晶型F的热重分析(TGA)图在加热至100℃时具有约2.0±0.3％(较佳地±0.2％，±0.15％，±0.1％或±0.05％)的重量损失；
所述的苹果酸盐晶型F的热重分析(TGA)图基本如图18所示。
在另一优选例中，在所述苹果酸盐晶型F中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与苹果酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为磷酸盐晶型G，所述的磷酸盐晶型G的X-射线粉末衍射图谱在下述2θ值有特征峰：11.20±0.2°、19.70±0.2°、21.24±0.2°、22.49±0.2°。
在另一优选例中，所述的磷酸盐晶型G的X-射线粉末衍射图谱在下述2θ值有特征峰：11.20±0.2°、12.79±0.2°、19.70±0.2°、21.24±0.2°、22.49±0.2°、23.32±0.2°。
在另一优选例中，所述的磷酸盐晶型G的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、30.11±0.2°。
在另一优选例中，所述的磷酸盐晶型G的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：

在另一优选例中，所述的磷酸盐晶型G具有基本如图7所示的X-射线粉末衍射图谱。
在另一优选例中，所述的磷酸盐晶型G包括选自下组的一个或多个特征：
所述的磷酸盐晶型G的差示扫描量热分析(DSC)图在加热至164.1±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的磷酸盐晶型G的差示扫描量热分析(DSC)图基本如图19所示；
所述的磷酸盐晶型G的热重分析(TGA)图在加热至150℃时具有约1.8％(较佳地±0.2％，±0.15％，±0.1％或±0.05％)的重量损失；
所述的磷酸盐晶型G的热重分析(TGA)图基本如图19所示。
在另一优选例中，在所述磷酸盐晶型G中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与磷酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为酒石酸盐晶型H，所述的酒石酸盐晶型H的X-射线粉末衍射图谱在下述2θ值有特征峰：14.19±0.2°、18.64±0.2°、18.95±0.2°、23.70±0.2°。
在另一优选例中，所述的酒石酸盐晶型H的X-射线粉末衍射图谱在下述2θ值有特征峰：14.19±0.2°、18.17±0.2°、18.64±0.2°、18.95±0.2°、22.11±0.2°、23.70±0.2°、24.54±0.2°。
在另一优选例中，所述的酒石酸盐晶型H的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、25.68±0.2°。
在另一优选例中，所述的酒石酸盐晶型H的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：

在另一优选例中，所述的酒石酸盐晶型H具有基本如图8所示的X-射线粉末衍射图谱。
在另一优选例中，所述的酒石酸盐晶型H包括选自下组的一个或多个特征：
所述的酒石酸盐晶型H的差示扫描量热分析(DSC)图在加热至164.7±5℃(较佳地±4℃，±3℃，±2℃或±1℃)和处开始出现吸热峰；
所述的酒石酸盐晶型H的差示扫描量热分析(DSC)图基本如图20所示；
所述的酒石酸盐晶型H的热重分析(TGA)图在加热至150℃时具有约0.72％(较佳地±0.1％，±0.05％，±0.02％或±0.01％)的重量损失；
所述的酒石酸盐晶型H的热重分析(TGA)图基本如图20所示。
在另一优选例中，在所述酒石酸盐晶型H中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与酒石酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为焦谷氨酸盐晶型I，所述的焦谷氨酸盐晶型I的X-射线粉末衍射图谱在下述2θ值有特征峰：9.29±0.2°、10.76±0.2°、17.98±0.2°、23.72±0.2°。
在另一优选例中，所述的焦谷氨酸盐晶型I的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、23.72±0.2°。
在另一优选例中，所述的焦谷氨酸盐晶型I的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、30.86±0.2°。
在另一优选例中，所述的焦谷氨酸盐晶型I的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：

在另一优选例中，所述的焦谷氨酸盐晶型I具有基本如图9所示的X-射线粉末衍射图谱。
在另一优选例中，所述的焦谷氨酸盐晶型I包括选自下组的一个或多个特征：
所述的焦谷氨酸盐晶型I的差示扫描量热分析(DSC)图在加热至155.4±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的焦谷氨酸盐晶型I的差示扫描量热分析(DSC)图基本如图21所示；
所述的焦谷氨酸盐晶型I的热重分析(TGA)图在加热至120℃时具有约1.3％(较佳地±0.2％，±0.15％，±0.1％或±0.05％)的重量损失；
所述的焦谷氨酸盐晶型I的热重分析(TGA)图基本如图21所示。
在另一优选例中，在所述焦谷氨酸盐晶型I中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与焦谷氨酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为苯磺酸盐晶型J，所述的苯磺酸盐晶型J的X-射线粉末衍射图谱在下述2θ值有特征峰：13.69±0.2°、19.48±0.2°、21.07±0.2°、22.15±0.2°。
在另一优选例中，所述的苯磺酸盐晶型J的X-射线粉末衍射图谱在下述2θ值有征 峰：11.53±0.2°、13.69±0.2°、17.96±0.2°、19.48±0.2°、21.07±0.2°、22.15±0.2°、23.06±0.2°。
在另一优选例中，所述的苯磺酸盐晶型J的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、29.58±0.2°。
在另一优选例中，所述的苯磺酸盐晶型J的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：
在另一优选例中，所述的苯磺酸盐晶型J具有基本如图10所示的X-射线粉末衍射图谱。
在另一优选例中，所述的苯磺酸盐晶型J包括选自下组的一个或多个特征：
所述的苯磺酸盐晶型J的差示扫描量热分析(DSC)图在加热至164.9±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的苯磺酸盐晶型J的差示扫描量热分析(DSC)图基本如图22所示；
所述的苯磺酸盐晶型J的热重分析(TGA)图在加热至150℃时具有约1.3％(较佳地±0.2％，±0.15％，±0.1％或±0.05％)的重量损失；
所述的苯磺酸盐晶型J的热重分析(TGA)图基本如图22所示。
在另一优选例中，在所述苯磺酸盐晶型J中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与苯磺酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为丙二酸盐晶型K，所述的丙二酸盐晶型K的X-射线粉末衍射图谱在下述2θ值有特征峰：15.28±0.2°、19.66±0.2°、20.42±0.2°。
在另一优选例中，所述的丙二酸盐晶型K的X-射线粉末衍射图谱在下述2θ值有特征峰：15.28±0.2°、19.43±0.2°、19.66±0.2°、20.42±0.2°、23.66±0.2°。
在另一优选例中，所述的丙二酸盐晶型K的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、27.82±0.2°。
在另一优选例中，所述的丙二酸盐晶型K的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：

在另一优选例中，所述的丙二酸盐晶型K具有基本如图11所示的X-射线粉末衍射图谱。
在另一优选例中，所述的丙二酸盐晶型K包括选自下组的一个或多个特征：
所述的丙二酸盐晶型K的差示扫描量热分析(DSC)图在加热至139.8±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的丙二酸盐晶型K的差示扫描量热分析(DSC)图基本如图23所示；
所述的丙二酸盐晶型K的热重分析(TGA)图在加热至130℃时具有约1.58％(较佳地±0.2％，±0.15％，±0.1％或±0.05％)的重量损失；
所述的丙二酸盐晶型K的热重分析(TGA)图基本如图23所示。
在另一优选例中，在所述丙二酸盐晶型K中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与丙二酸的摩尔比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述固体形式为半富马酸盐晶型L，所述的半富马酸盐晶型L的X-射线粉末衍射图谱在下述2θ值有特征峰：11.57±0.2°、17.25±0.2°、23.08±0.2°、24.33±0.2°。
在另一优选例中，所述的半富马酸盐晶型L的X-射线粉末衍射图谱在下述2θ值有特征峰：11.57±0.2°、12.12±0.2°、17.25±0.2°、23.08±0.2°、24.33±0.2°、25.68±0.2°。
在另一优选例中，所述的半富马酸盐晶型L的X-射线粉末衍射图谱在下述2θ值有特征峰：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°、25.68±0.2°。
在另一优选例中，所述的半富马酸盐晶型L的X-射线粉末衍射图谱具有下述2θ值的特征峰和峰强度：

在另一优选例中，所述的半富马酸盐晶型L具有基本如图12所示的X-射线粉末衍射图谱。
在另一优选例中，所述的半富马酸盐晶型L包括选自下组的一个或多个特征：
所述的半富马酸盐晶型L的差示扫描量热分析(DSC)图在加热至171.5±5℃(较佳地±4℃，±3℃，±2℃或±1℃)处开始出现吸热峰；
所述的半富马酸盐晶型L的差示扫描量热分析(DSC)图基本如图24所示；
所述的半富马酸盐晶型L的热重分析(TGA)图在加热至150±2℃时具有约0.3％(较佳地±0.1％或±0.05％)的重量损失；
所述的半富马酸盐晶型L的热重分析(TGA)图基本如图24所示。
在另一优选例中，在所述半富马酸盐晶型L中，所述N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺与富马酸的摩尔比为1-1.5:0.5-0.75，优选1-1.2:0.5-0.6，更优选1:0.5。
在本发明的第二方面，提供了一种制备如本发明第一方面所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式的方法，所述的方法包括方法一至方法八中的任意一种：
所述方法一包括：
(a1)将制备得到的化合物粗品溶于第一溶剂，升温，混合至体系澄清；
(a2)加入第二溶剂，之后冷却析晶，得到游离态晶型A。
在另一优选例中，在方法一中，所述的化合物粗品为根据申请号为202110666168.6的方法经过滤、洗涤、减压干燥得到的粗品。
在另一优选例中，在步骤(a1)中，所述第一溶剂选自下组：二氯甲烷、甲基 叔丁基醚、甲苯、四氢呋喃、二甲基亚砜，或其组合。优选二甲基亚砜。
在另一优选例中，在步骤(a1)中，所述第一溶剂与所述粗品的体积比为1.5-3:1，优选2:1。
在另一优选例中，在步骤(a1)中，所述升温是指升温至50-70℃，优选60-70℃。
在另一优选例中，在步骤(a1)中，所述混合的时间在0.3-1h，优选0.5h。
在另一优选例中，在步骤(a2)中，所述第二溶剂选自下组：甲醇、无水乙醇、95％乙醇、乙醇/水、丙酮/水、乙腈/水，或其组合。优选甲醇、无水乙醇、95％乙醇，更优选无水乙醇。
在另一优选例中，在步骤(a2)中，所述第二溶剂与所述粗品的体积比为1.5-5:1，例如2:1、3:1。
在另一优选例中，在步骤(a2)中，所述第二溶剂在50-70℃，优选60-70℃加入。
在另一优选例中，在步骤(a2)中，所述冷却析晶包括分段冷却析晶。
在另一优选例中，在步骤(a2)中，所述冷却析晶包括：搅拌0.5小时后，关闭加热，缓慢降温至0～10℃，保温0～10℃搅拌4小时。
所述方法二包括：化合物原料和富马酸溶解于第三溶剂中，低温混合析晶，得到所述富马酸盐晶型B。
在另一优选例中，所述第三溶剂选自下组：甲醇、无水乙醇、95％乙醇、乙醇/水、丙酮/水、乙腈/水、乙酸乙酯、丙酮，或其组合。优选甲醇、95％乙醇，更优选甲醇。
在另一优选例中，在方法二中，所述化合物原料和富马酸的摩尔比为1:1-1.5，优选1:1-1.2，例如1:1.02、1:1.04、1:1.06、1:1.1、1:1.12、1:1.15、1:1.2。
在另一优选例中，在方法二中，所述化合物原料和第三溶剂的质量体积比为1g:1-20ml，优选1g:1-10ml，例如1g:3ml、1g:6ml、1g:9ml。
在另一优选例中，在方法二中，所述混合在0-15℃下进行，优选3-10℃，更优选4-6℃。
在另一优选例中，在方法二中，所述混合的时间为0.5-2天，优选1天。
在另一优选例中，所述方法二包括：将化合物原料和富马酸溶解于第三溶剂中，5℃搅拌1天。
在另一优选例中，所述方法二还包括抽滤、真空干燥的后处理步骤。
所述方法三包括：
(b1)将化合物原料溶解于第四溶剂中；
(b2)将浓盐酸溶解于第四溶剂中；
(b3)将步骤(b2)得到的盐酸在第四溶剂中的溶液滴入步骤(b1)得到的混合物中，混合析晶，得到所述盐酸盐晶型C。
在另一优选例中，在步骤(b1)中，所述第四溶剂选自下组：二氯甲烷、甲基叔丁基醚、甲苯、四氢呋喃，或其组合。优选四氢呋喃。
在另一优选例中，所述浓盐酸为质量分数为35-40％的HCl水溶液。
在另一优选例中，在方法三中，所述化合物原料与所述浓盐酸的摩尔比为1:1-1.5，优选1:1-1.4，例如1:1.02、1:1.04、1:1.06、1:1.1、1:1.12、1:1.15、1:1.2、1:1.4。
在另一优选例中，所述步骤(b1)与所述步骤(b2)使用的第四溶剂的体积比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，在步骤(b3)中，所述混合在10-35℃下进行。
在另一优选例中，在步骤(b3)中，所述混合的时间为0.5-2h，优选1h。
在另一优选例中，所述步骤(b3)包括：在搅拌条件下将盐酸在第四溶剂的溶 液缓慢滴入化合物原料的悬浊液中，室温搅拌1小时。
在另一优选例中，所述方法三还包括抽滤、真空干燥的后处理步骤。
所述方法四包括：
(c1)将化合物原料溶解于第五溶剂中；
(c2)将浓硫酸溶解于第五溶剂中；
(c3)将步骤(c2)得到的硫酸在第五溶剂中的溶液滴入步骤(c1)得到的混合物中，溶清；
(c4)向步骤(c3)得到的混合物中滴入第六溶剂，混合析晶，得到所述硫酸盐晶型D。
在另一优选例中，在步骤(c1)中，所述第五溶剂为有机溶剂和水的混合溶剂。所述第五溶剂选自下组：乙醇/水、丙酮/水、乙腈/水，或其组合。优选乙腈/水。
在另一优选例中，在步骤(c1)中，所述第五溶剂中所述有机溶剂和水的混合体积比10-30:1，例如15:1、19:1、20:1、25:1、30:1。
在另一优选例中，所述浓硫酸为质量分数为95～98％的H2SO4水溶液。
在另一优选例中，在方法四中，所述化合物原料与所述浓硫酸的摩尔比为1:1-1.5，例如1:1.1、1:1.15、1:1.2、1:3、1:4。
在另一优选例中，所述化合物原料与所述方法四中使用的第五溶剂总量的体积比为1g:10-40ml，优选1g:10-30ml，例如1g:15ml、1g:20ml、1g:25ml、1g:30ml。
在另一优选例中，所述步骤(c1)与所述步骤(c2)使用的第五溶剂的体积比为1-1.5:1-1.5，优选1-1.2:1-1.2，更优选1:1。
在另一优选例中，所述步骤(c3)包括：搅拌条件下将硫酸的第五溶剂溶液缓慢滴入游离态样品的悬浊液中，样品溶清。
在另一优选例中，在步骤(c4)中，所述第六溶剂选自下组：二氯甲烷、甲基叔丁基醚、甲苯、四氢呋喃，或其组合。优选甲基叔丁基醚。
在另一优选例中，所述方法四中使用的第五溶剂总量与所述第六溶剂体积比为1:1.5-3，例如1:1.7、1:2、1:2.5、1:3。
在另一优选例中，在步骤(c4)中，所述混合在10-35℃下进行。
在另一优选例中，在步骤(c4)中，所述混合的时间为0.5-2h，优选1h。
在另一优选例中，所述步骤(c4)包括：搅拌条件下，向体系中缓慢滴加第六溶剂后，室温搅拌1小时析晶。
在另一优选例中，所述方法四还包括抽滤、真空干燥的后处理步骤。
所述方法五包括：
将化合物原料与琥珀酸溶解于第七溶剂中，混合析晶得到所述琥珀酸盐晶型E。
在另一优选例中，所述第七溶剂选自下组：甲醇、无水乙醇、95％乙醇、乙醇/水、丙酮/水、乙腈/水、乙酸乙酯、丙酮，或其组合。优选甲醇、95％乙醇，更优选甲醇。
在另一优选例中，在方法五中，所述化合物原料和琥珀酸的摩尔比为1:1-1.5，优选1:1-1.2，例如1:1.02、1:1.04、1:1.06、1:1.1、1:1.12、1:1.15、1:1.2。
在另一优选例中，在方法五中，所述化合物原料和第七溶剂的质量体积比为1g:1-20ml，优选1g:1-10ml，例如1g:3ml、1g:6ml、1g:9ml。
在另一优选例中，在方法五中，所述混合在10-35℃下进行。
在另一优选例中，在方法五中，所述混合的时间为0.5-2天，优选1天。
在另一优选例中，所述方法五包括：将化合物原料和琥珀酸溶解于第七溶剂中，室温搅拌1天。
在另一优选例中，所述方法五还包括抽滤、真空干燥的后处理步骤。
所述方法六包括：
将化合物原料与苹果酸溶解于第八溶剂中，混合析晶得到所述苹果酸盐晶型F。
在另一优选例中，所述第八溶剂选自下组：二氯甲烷、甲基叔丁基醚、甲苯、四氢呋喃，或其组合。优选四氢呋喃。
在另一优选例中，在方法六中，所述化合物原料和苹果酸的摩尔比为1:1-1.5，优选1:1-1.2，例如1:1.02、1:1.04、1:1.06、1:1.1、1:1.12、1:1.15、1:1.2。
在另一优选例中，在方法六中，所述化合物原料和第八溶剂的质量体积比为1g:1-20ml，优选1g:1-15ml，例如1g:5ml、1g:9ml、1g:10ml、1g:12ml。
在另一优选例中，在方法六中，所述混合在10-35℃下进行。
在另一优选例中，在方法六中，所述混合的时间为0.5-2天，优选1天。
在另一优选例中，所述方法六包括：将化合物原料和苹果酸溶解于第八溶剂中，室温搅拌1天。
在另一优选例中，所述方法六还包括抽滤、真空干燥的后处理步骤。
所述方法七包括：
将化合物原料与酸溶解于第九溶剂中，混合析晶得到所述酸对应的磷酸盐晶型G、酒石酸盐晶型H、焦谷氨酸盐晶型I、苯磺酸盐晶型J或丙二酸盐晶型K；其中，所述酸选自下组：磷酸、酒石酸、焦谷氨酸、苯磺酸或丙二酸。
在另一优选例中，所述第九溶剂选自下组：二氯甲烷、甲基叔丁基醚、甲苯、四氢呋喃，或其组合。优选四氢呋喃。
在另一优选例中，在方法七中，所述化合物原料和所述酸的摩尔比为1:1-1.5，优选1:1-1.2，例如1:1.02、1:1.04、1:1.06、1:1.1、1:1.12、1:1.15、1:1.2。
在另一优选例中，在方法七中，所述化合物原料在第九溶剂中的浓度为0.05-0.5mol/L，优选0.05-0.3mol/L，例如0.08mol/L、0.1mol/L、0.12mol/L、0.15mol/L。
在另一优选例中，在方法七中，所述混合在10-35℃下进行。
在另一优选例中，所述方法七还包括抽滤、真空干燥的后处理步骤。
所述方法八包括：
化合物原料和富马酸溶解于第三溶剂中，混合析晶，得到所述半富马酸盐晶型L。
在另一优选例中，所述第三溶剂选自下组：甲醇、无水乙醇、95％乙醇、乙醇/水、丙酮/水、乙腈/水、乙酸乙酯、丙酮，或其组合。优选甲醇、95％乙醇，更优选甲醇。
在另一优选例中，在方法八中，所述化合物原料和富马酸的摩尔比为1:0.5-0.75，优选1:0.5-0.6，例如1:0.5、1:0.55、1:0.58、1:0.6。
在另一优选例中，在方法八中，所述化合物原料和第三溶剂的质量体积比为1g:1-10ml，优选1g:1-5ml，例如1g:2ml、1g:3ml、1g:4ml。
在另一优选例中，在方法八中，所述混合在室温下进行，优选10-35℃，更优选15-25℃。
在另一优选例中，在方法八中，所述混合的时间为1-7天，优选4天。
在另一优选例中，所述方法八包括：将化合物原料和富马酸溶解于第三溶剂中，室温悬浮搅拌4天。
在另一优选例中，所述方法八还包括抽滤、真空干燥的后处理步骤。
在另一优选例中，所述方法中，所述化合物原料包括N-(2-(呋喃-2-基)-4-((甲基氨 基)甲基)苯基)噻吩-3-磺酰胺的无定形或晶型，优选游离态晶型A。
在本发明的第三方面，提供了一种药物组合物，所述药物组合物包含：
(a)如本发明第一方面所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式中的一种或多种，以及
(b)药学上可接受的辅料、载体、赋形剂、稀释剂。
在本发明的第四方面，提供了一种如本发明第一方面所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式的用途，用于(a)制备瞬时受体电位通道蛋白TRPA1抑制剂；和/或(b)制备预防和/或治疗与瞬时受体电位通道蛋白TRPA1相关的疾病的药物。
在另一优选例中，所述的与瞬时受体电位通道蛋白TRPA1相关的疾病选自下组：炎症性肠病、肠易激综合征、疼痛、炎症、咳嗽，或其组合。
在另一优选例中，所述的炎症性肠病包括克罗恩病和/或溃疡性结肠炎。
在另一优选例中，所述的疼痛包括内脏痛、急性炎性疼痛、慢性炎性疼痛、神经源性疼痛、肌纤维痛、头痛、神经痛或癌症引起的疼痛。
在本发明的第五方面，提供了一种(a)抑制瞬时受体电位通道蛋白TRPA1；和/或(b)预防和/或治疗与瞬时受体电位通道蛋白TRPA1相关的疾病的方法，所述方法包括：将本发明第一方面所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式施用于有此需要的对象。
在另一优选例中，所述对象为人或非人哺乳动物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是游离态晶型A的特征XPRD图。
图2是富马酸盐晶型B的特征XPRD图。
图3是盐酸盐晶型C的特征XPRD图。
图4是硫酸盐晶型D的特征XPRD图。
图5是琥珀酸盐晶型E的特征XPRD图。
图6是苹果酸盐晶型F的特征XPRD图。
图7是磷酸盐晶型G的特征XPRD图。
图8是酒石酸盐晶型H的特征XPRD图。
图9是焦谷氨酸盐晶型I的特征XPRD图。
图10是苯磺酸盐晶型J的特征XPRD图。
图11是丙二酸盐晶型K的特征XPRD图。
图12是半富马酸盐晶型L的特征XPRD图。
图13是游离态晶型A的DSC与TGA的叠加图。
图14是富马酸盐晶型B的DSC与TGA的叠加图。
图15是盐酸盐晶型C的DSC与TGA的叠加图。
图16是硫酸盐晶型D的DSC与TGA的叠加图。
图17是琥珀酸盐晶型E的DSC与TGA的叠加图。
图18是苹果酸盐晶型F的DSC与TGA的叠加图。
图19是磷酸盐晶型G的DSC与TGA的叠加图。
图20是酒石酸盐晶型H的DSC与TGA的叠加图。
图21是焦谷氨酸盐晶型I的DSC与TGA的叠加图。
图22是苯磺酸盐晶型J的DSC与TGA的叠加图。
图23是丙二酸盐晶型K的DSC与TGA的叠加图。
图24是半富马酸盐晶型L的DSC与TGA的叠加图。
图25是游离态晶型A的DVS图。
图26是富马酸盐晶型B的DVS图。
图27是盐酸盐晶型C的DVS图。
图28是硫酸盐晶型D的DVS图。
图29是琥珀酸盐晶型E的DVS图。
图30是苹果酸盐晶型F的DVS图。
图31是不同盐晶型的动态溶解图。
具体实施方式
本发明人通过广泛而深入的研究，首次意外地开发了一种N-取代苯基磺酰胺类化合物或其药学上可接受的盐，及固体形式。本发明的盐晶型使得化合物的溶解度明显增加，有利于改善化合物的理化性质以及药代动力学特征。在此基础上，完成了本发明。
术语
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用，术语“包含”、“包括”、“含有”可互换使用，不仅包括封闭式定义，还包括半封闭、和开放式的定义。换言之，所述术语包括了“由……构成”、“基本上由……构成”。
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，室温指的是25±5℃。
药物组合物和施用
本发明的各种固体形式，以及含有本发明固体形式为主要活性成分的药物组合物可用于治疗、预防以及缓解TRPA1相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明固体形式或其药学上可接受的盐及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有0.1-1000mg本发明的固体形式/剂，更佳地，含有0.5-500mg本发明的固体形式/剂。较佳地，所述的“一剂”为一个胶囊或药片。
本发明的药物组合物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。药学上可接受的载体有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的药物组合物施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内)、局部施用，优选的施用方式为口服施用。
本发明的药物组合物的剂型为口服制剂、外用制剂或注射制剂。代表性地，用于口服施用或给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂。
用于口服施用或给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，药物组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、娇味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的药物组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明的固体形式可以单独施用或给药，或者与其它预防和/或治疗TRPA1相关的疾病的药物联合施用或给药。
施用药物组合物时，是将安全有效量的本发明无细胞脂肪提取物适用于需要治疗的人或非人动物(如大鼠、小鼠、狗、猫、牛、羊、鸡、鸭等)，其中施用时剂量为药学上可接受认为的有效给药剂量。本领域的普通技术人员应该理解，“安全有效量”可随着药物组合物的形式、给药途径、所用药物的辅料、疾病的严重程度以及与其他药物联合用药等情况的不同而有所不同。例如，对于60kg体重的人而言，日给药剂量通常为0.1～1000mg，优选1～600mg，更优选为2-300mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
本发明化合物的盐晶型，具有优良的溶解度性质和稳定性，有利于改善化合物的理化性质以及药代动力学特征。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未标明具体条件的实施方法，通常按照常规条件，或者按照制造厂商建议的条件。
测试方法
XRPD：X射线粉末衍射；DSC：差示扫描量热分析；TGA：热重分析；DVS：动态水分吸附。
本发明所用X射线粉末衍射分析方法为：PANalytical X射线粉末衍射分析仪，工作电压：45kV，工作电流：40mA，使用Cu靶获得X射线粉末衍射图。
本发明所用差示扫描量热(DSC)分析方法为：仪器为TA Q2000/Discovery DSC2500；扫描速度：10℃/min；保护气体，氮气。
本发明所用热重分析(TGA)分析方法：仪器为TA Q5000/Discovery TGA5500；扫描速度：10℃/min；保护气体，氮气。
本发明所用动态水分吸附(DVS)分析方法：仪器为SMS公司(Surface Measurement Systems)生产的DVS Intrinsic；温度，25℃；载气，流速：氮气，200毫升/分钟；单位时间质量变换：0.002％/分钟；相对湿度范围：0％RH-95％RH。
本发明所用液态核磁分析方法：仪器为Bruker 400M核磁共振仪。
本发明所述的高效液相色谱纯度(HPLC)在Agilent 1260高效液相色谱仪上采集。
本发明所述的离子色谱(IC)测试反荷离子确定摩尔比由Thermo ICS1100采集。
实施例1：N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺(I)游离态晶型A
按照申请号为202110666168.6的方法制备N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺。反应完成后，调温至0～10℃滴加纯化水、氢氧化钠水溶液，过滤，滤饼先用纯化水浸洗两次，然后用无水甲醇浸洗两次，得到滤饼，减压干燥得到黄色粗品化合物。将粗品倒入反应釜，加入2倍体积的二甲基亚砜，升温至60～70℃，搅拌0.5小时，体系澄清，在60～65℃下滴加3倍体积的无水甲醇，搅拌0.5小时后，关闭加热，缓慢降温至0～10℃，保温0～10℃搅拌4小时后过滤，得到黄色游离态晶型A，收率：79.8％。
实施例2：N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺(I)游离态晶型A的表征
N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺为结晶态，命名为游离态晶型A，X射线粉末衍射数据如表1和如图1所示，TGA/DSC叠加图如图13所示，样品加热至150℃时有0.9％的失重，在181.0℃、181.8℃(峰值温度)及182.3℃有吸热峰。
表1

实施例3：N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的盐型和晶型的筛选
本发明人通过悬浮搅拌的方法，对N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺进行了多种盐型筛选。选择进行筛选的酸包括盐酸、硫酸、马来酸、磷酸、富马酸、L-酒石酸、柠檬酸、D-葡萄糖醛酸、L-苹果酸、琥珀酸、焦谷氨酸、对甲苯磺酸、甲磺酸、苯磺酸、乙酸、丙二酸、苯甲酸和马尿酸。其中，大多数酸配体与N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺形成较好的盐型固体，对所得盐型样品进行了热重分析(TGA)和差示扫描量热(DSC)表征，并通过高效液相色谱(HPLC)与离子色谱(IC)联用或液态核磁氢谱(1H NMR)对样品的化学计量比进行了测定。
富马酸盐晶型B的制备方法：
称取300.0mg(0.86mmol)化合物(优选实施例1得到的游离态晶型A)和101.0mg富马酸(0.87mmol)，加入1mL MeOH并在室温下磁力搅拌，转至低温搅拌1天，抽滤，滤饼经真空干燥至恒重，得到固体305.2mg,收率为76.1％。
富马酸盐晶型B的X射线粉末衍射数据如表2所示，XRPD图如图2，TGA/DSC叠加图如图14。
表2

从图14可以看出，DSC显示富马盐酸晶型B在加热至189.4℃(峰值温度)附近开始出现吸热峰，TGA显示富马酸盐晶型B在加热至150℃时具有约0.8％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
盐酸盐晶型C的制备方法：
称取500.10mg(1.43mmol)化合物溶解于6.25mL的四氢呋喃溶液中，涡旋、超声促使样品溶解，移取167.8μL(2.00mmol)质量分数为36～38％的浓盐酸稀释于6.25mL的四氢呋喃溶液中，于搅拌条件下将盐酸的四氢呋喃溶液缓慢滴入游离态样品的悬浊液中，室温搅拌1小时，抽滤，滤饼经真空干燥至恒重，得到固体466.95mg，收率为84.54％。
盐酸盐晶型C的X射线粉末衍射数据如表3所示，XRPD图如图3，TGA/DSC叠加图如图15。
表3

从图15可以看出，样品在加热至93.1℃和150.7℃(峰值温度)附近开始出现吸热峰，在加热至100℃时具有约4.2％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
硫酸盐晶型D的制备方法：
称取499.63mg(1.43mmol)化合物溶解于6.25mL的乙腈/水(v/v＝19:1)混合溶液中，涡旋、超声促使样品溶解，移取91.8μL(1.72mmol)质量分数为95～98％的浓硫酸稀释于6.25mL的乙腈/水(v/v＝19:1)混合溶液中，于搅拌条件下将硫酸溶液滴入游离态样品悬浊液中，样品溶清。于搅拌条件下，向体系中缓慢添加25mL MTBE后析出固体。室温下搅拌约一个小时后，抽滤，滤饼经真空干燥至恒重，共获得固体557.98mg，收率为87.08％。
硫酸盐晶型D的X射线粉末衍射数据如表4所示，XRPD图如图4，TGA/DSC叠加图如图16。
表4

从图16可以看出，样品在加热至175.8℃(峰值温度)附近开始出现吸热峰，在加热至150℃时具有约0.6％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
琥珀酸盐晶型E的制备方法：
称取300.3mg(0.86mmol)化合物和102.7mg(0.87mmol)琥珀酸溶解于2mL的甲醇溶液中，室温搅拌1天，抽滤，滤饼经真空干燥至恒重，得到固体370.0mg，收率为91.8％。
琥珀酸盐晶型E的X射线粉末衍射数据如表5所示，XRPD图如图5，TGA/DSC叠加图如图17。
表5

从图17可以看出，样品在加热至172.9℃(峰值温度)附近开始出现吸热峰，在加热至150℃时具有约1.2％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
苹果酸盐晶型F的制备方法：
称取300.1mg(0.86mmol)化合物和117.0mg(0.87mmol)苹果酸溶解于3mL的四氢呋喃溶液中，室温搅拌1天，抽滤，滤饼经真空干燥至恒重，得到固体315.4mg，收率为75.6％。
苹果酸盐晶型F的X射线粉末衍射数据如表6所示，XRPD图如图6，TGA/DSC叠加图如图18。
表6

从图18可以看出，样品在加热至144.7℃和160.6℃(峰值温度)附近开始出现吸热峰，在加热至100℃时具有约2.0％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
磷酸盐晶型G的制备方法：
称取20mg(0.06mmol)化合物和6.9mg磷酸溶解于0.5mL的四氢呋喃溶液中，室温搅拌，抽滤，滤饼经真空干燥至恒重，得到固体18.5mg，收率为69.1％。
磷酸盐晶型G的X射线粉末衍射数据如表7所示，XRPD图如图7，TGA/DSC叠加图如图19。
表7
从图19可以看出，样品在加热至164.1℃(峰值温度)附近开始出现吸热峰，在加热至150℃时具有约1.8％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
酒石酸盐晶型H的制备方法：
称取20mg(0.06mmol)化合物和9mg酒石酸溶解于0.5mL的四氢呋喃溶液中，室温搅拌，抽滤，滤饼经真空干燥至恒重，得到固体24.4mg，收率为81.6％。
酒石酸盐晶型H的X射线粉末衍射数据如表8所示，XRPD图如图8，TGA/DSC叠加图如图20。
表8
从图20可以看出，样品在加热至164.7℃(峰值温度)附近开始出现吸热峰，在加热至150℃时具有约0.7％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
焦谷氨酸盐晶型I的制备方法：
称取20mg(0.06mmol)化合物和7.7mg焦谷氨酸溶解于0.5mL的四氢呋喃溶液中，室温搅拌，抽滤，滤饼经真空干燥至恒重，得到固体25.1mg，收率为87.6％。
焦谷氨酸盐晶型I的X射线粉末衍射数据如表9所示，XRPD图如图9，TGA/DSC叠加图如图21。
表9
从图21可以看出，样品在加热至155.4℃(峰值温度)附近开始出现吸热峰，在加热至120℃时具有约1.3％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
苯磺酸盐晶型J的制备方法：
称取20mg(0.06mmol)化合物和9.5mg苯磺酸溶解于0.5mL的四氢呋喃溶液中，室温搅拌，抽滤，滤饼经真空干燥至恒重，得到固体28.3mg，收率为93.1％。
苯磺酸盐晶型J的X射线粉末衍射数据如表10所示，XRPD图如图10，TGA/DSC叠加图如图22。
表10
从图22可以看出，样品在加热至164.9℃(峰值温度)附近开始出现吸热峰，在加热至150℃时具有约1.3％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
丙二酸盐晶型K的制备方法：
称取20mg(0.06mmol)化合物和6.2mg丙二酸溶解于0.5mL的四氢呋喃溶液中，室温搅拌，抽滤，滤饼经真空干燥至恒重，得到固体21.7mg，收率为80.1％。
丙二酸盐晶型K的X射线粉末衍射数据如表11所示，XRPD图如图11，TGA/DSC叠加图如图23。
表11
从图23可以看出，样品在加热至139.8℃(峰值温度)附近开始出现吸热峰，在 加热至130℃时具有约1.6％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:1。
半富马酸盐晶型L的制备方法：
称取500.8mg(1.44mmol)化合物和83.6mg富马酸(0.72mmol)，加入2.0mL的甲醇溶液，室温悬浮搅拌4天，抽滤，滤饼经真空干燥至恒重，得到固体489.2mg，收率为83.7％。
半富马酸盐晶型L的X射线粉末衍射数据如表12所示，XRPD图如图12所示，TGA/DSC叠加图如图24所示。
表12
从图24可以看出，样品在加热至173.8℃(峰值温度)附近开始出现吸热峰，在加热至150℃时具有约0.3％的重量损失。进一步HPLC/IC结果显示，游离态/酸的摩尔比为1:0.5。
实施例4：评估实施例制备的部分盐晶型的特性
引湿性
采用动态水分吸附(DVS)仪测试引湿性，结果如图25-30所示，在0％RH～95％RH的吸附曲线上，在25℃/80RH条件下，游离态晶型A的水分吸附量为1.6％，略有引湿性；富马酸盐晶型B的水分吸附量为0.2％，略有引湿性；盐酸盐晶型C的水分吸附量为5.5％，样品有引湿性；硫酸盐晶型D的水分吸附量为1.3％，样品略有引湿性；琥珀酸盐晶型E的水分吸附量为0.6％，样品略有引湿性；苹果酸盐晶型F的水分吸附量为1.4％，样品略有引湿性(参考中国药典2015年版(药物引湿性试验指导原则))。
动态溶解度
测试富马酸晶型B、盐酸盐晶型C、硫酸盐晶型D、琥珀酸晶型E、苹果酸晶型F及游离态晶型A在37℃下在生物溶媒SGF、FaSSIF和水中的动态溶解度。实验中，所有样品在三种溶剂中的固体投料量均为10mg/mL。将样品密封固定在转速为25转/分钟的旋转盘上，并将旋转盘放置于37℃恒温箱中。分别在平衡1、2、4和24小时时间点取样，分离滤液测试HPLC浓度及PH，所得固体测试XRPD。结果如图31所示，可以看出，各盐的晶型物在生物溶媒SGF、FaSSIF和水中溶解度相对于游离态均有明显的提升，起始样品在水和FaSSIF几乎不溶解，而盐晶型的溶解度则可以提升至6-10mg/mL。
固态稳定性
分别称取约10毫克固体加入HPLC小瓶中，瓶口用封口膜封口，膜上扎10个小孔，将小瓶置于25℃/60％RH和40℃/75％RH环境中放置4周，分别于第1周、2周和第4周取样，对样品进行HPLC纯度和XRPD测试。HPLC结果显示，游离态及各盐型样品在对应的条件储存后未见明显纯度变化；XRPD结果显示，游离态及各盐型样品于稳定性测试前后未见明显晶型变化。固体稳定性结果总结如表13所示。
表13


粗略溶解度
于3-mL玻璃瓶中加入对应晶型样品，分步加入纯水(50、50、200及700μL)涡旋、超声振荡助溶，并观察固体样品是否完全溶解。当固体完全溶解或加入纯水量总体积达到1mL后停止加入溶剂。根据加入溶剂体积计算粗略溶解度。
粗略溶解度的测试结果如表14所示，与游离态晶型A相比，各个盐型晶型在纯水中的溶解度均有显著提升。
表14
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (18)

  1. 一种N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，
    所述的固体形式包括游离态晶型、或盐晶型；
    所述盐晶型为该化合物与药学上可接受的酸反应形成的盐晶型，所述药学上可接受的酸选自下组：盐酸、硫酸、马来酸、磷酸、富马酸、L-酒石酸、柠檬酸、D-葡萄糖醛酸、L-苹果酸、琥珀酸、焦谷氨酸、对甲苯磺酸、甲磺酸、苯磺酸、乙酸、丙二酸、苯甲酸和马尿酸。
  2. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为游离态晶型A，所述的游离态晶型A的X-射线粉末衍射图谱在下述2θ值有特征峰：16.24±0.2°、19.23±0.2°、23.17±0.2°、24.45±0.2°、32.76±0.2°。
  3. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为富马酸盐晶型B，所述的富马酸盐晶型B的X-射线粉末衍射图谱在下述2θ值有特征峰：11.34±0.2°、14.40±0.2°、19.71±0.2°、19.86±0.2°。
  4. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为盐酸盐晶型C，所述的盐酸盐晶型C的X-射线粉末衍射图谱在下述2θ值有特征峰：17.20±0.2°、20.34±0.2°、24.74±0.2°、25.25±0.2°。
  5. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为硫酸盐晶型D，所述的硫酸盐晶型D的X-射线粉末衍射图谱在下述2θ值有特征峰：16.84±0.2°、23.08±0.2°、24.38±0.2°。
  6. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为琥珀酸盐晶型E，所述的琥珀酸盐晶型E的X-射线粉末衍射图谱在下述2θ值有特征峰：12.57±0.2°、19.18±0.2°、19.89±0.2°、22.68±0.2°。
  7. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为苹果酸盐晶型F，所述的苹果酸盐晶型F的X-射线粉末衍射图谱在下述2θ值有特征峰：12.70±0.2°、14.57±0.2°、19.13±0.2°、19.47±0.2°。
  8. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为磷酸盐晶型G，所述的磷酸盐晶型G的X-射线粉末衍射图谱在下述2θ值有特征峰：11.20±0.2°、19.70±0.2°、21.24±0.2°、22.49±0.2°。
  9. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为酒石酸盐晶型H，所述的酒石酸盐晶型H的X-射线粉末衍射图谱在下述2θ值有特征峰：14.19±0.2°、18.64±0.2°、18.95±0.2°、23.70±0.2°。
  10. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为焦谷氨酸盐晶型I，所述的焦谷氨酸盐晶型I的X-射线粉末衍射图谱在下述2θ值有特征峰：9.29±0.2°、10.76±0.2°、17.98±0.2°、23.72±0.2°。
  11. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为苯磺酸盐晶型J，所述的苯磺酸盐晶型J的X-射线粉末衍射图谱在下述2θ值有特征峰：13.69±0.2°、19.48±0.2°、21.07±0.2°、 22.15±0.2°。
  12. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为丙二酸盐晶型K，所述的丙二酸盐晶型K的X-射线粉末衍射图谱在下述2θ值有特征峰：15.28±0.2°、19.66±0.2°、20.42±0.2°。
  13. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为半富马酸盐晶型L，所述的半富马酸盐晶型L的X-射线粉末衍射图谱在下述2θ值有特征峰：11.57±0.2°、17.25±0.2°、23.08±0.2°、24.33±0.2°。
  14. 如权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式，其特征在于，所述固体形式为富马酸盐晶型B，所述的富马酸盐晶型B的X-射线粉末衍射图谱在下述2θ值有特征峰：11.34±0.2°、14.40±0.2°、19.23±0.2°、19.71±0.2°。
  15. 一种制备权利要求1所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式的方法，其特征在于，所述的方法包括方法一至方法八中的任意一种：
    所述方法一包括：
    (a1)将制备得到的化合物粗品溶于第一溶剂，升温，混合至溶清；
    (a2)加入第二溶剂，冷却析晶，得到游离态晶型A；
    所述方法二包括：
    将化合物原料和富马酸溶解于第三溶剂中混合，冷却析晶，得到所述富马酸盐晶型B；
    所述方法三包括：
    (b1)将化合物原料溶解于第四溶剂中；
    (b2)将浓盐酸溶解于第四溶剂中；
    (b3)将步骤(b2)得到的盐酸在第四溶剂中的溶液滴入步骤(b1)得到的混合物中，混合析晶，得到所述盐酸盐晶型C；
    所述方法四包括：
    (c1)将化合物原料溶解于第五溶剂中；
    (c2)将浓硫酸溶解于第五溶剂中；
    (c3)将步骤(c2)得到的硫酸在第五溶剂中的溶液滴入步骤(c1)得到的混合物中，溶清；
    (c4)向步骤(c3)得到的混合物中滴入第六溶剂，混合析晶，得到所述硫酸盐晶型D；
    所述方法五包括：
    将化合物原料与琥珀酸溶解于第七溶剂中，混合析晶得到所述琥珀酸盐晶型E；
    所述方法六包括：
    将化合物原料与苹果酸溶解于第八溶剂中，混合析晶得到所述苹果酸盐晶型F；
    所述方法七包括：
    将化合物原料与酸溶解于第九溶剂中，混合析晶得到所述酸对应的磷酸盐晶型G、酒石酸盐晶型H、焦谷氨酸盐晶型I、苯磺酸盐晶型J和丙二酸盐晶型K；其中，所述酸选自下组：磷酸、酒石酸、焦谷氨酸、苯磺酸或丙二酸；
    所述方法八包括：化合物原料和富马酸溶解于第三溶剂中，混合析晶，得到所述半富马酸盐晶型L；
    其中，所述化合物原料包括N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的无定形或晶型。
  16. 一种药物组合物，包含权利要求1-14中任一项所述的N-(2-(呋喃-2-基)-4-((甲 基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式；和药学上可接受的赋形剂。
  17. 一种权利要求1-14中任一项所述的N-(2-(呋喃-2-基)-4-((甲基氨基)甲基)苯基)噻吩-3-磺酰胺的固体形式的用途，其特征在于，用于(a)制备瞬时受体电位通道蛋白TRPA1的抑制剂；和/或(b)制备预防和/或治疗与瞬时受体电位通道蛋白TRPA1相关的疾病的药物。
  18. 如权利要求17所述的用途，其特征在于，所述的与瞬时受体电位通道蛋白TRPA1相关的疾病选自下组：炎症性肠病、肠易激综合征、疼痛、炎症，或其组合。
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CN108558831A (zh) * 2018-06-08 2018-09-21 上海璃道医药科技有限公司 取代吡咯-4-烷基胺类化合物及其用途
CN115135644A (zh) * 2020-02-14 2022-09-30 漳州片仔癀药业股份有限公司 3-芳氧基-3-五元杂芳基-丙胺类化合物的制备方法及晶型
CN115477626A (zh) * 2021-06-16 2022-12-16 上海璃道医药科技有限公司 N-取代苯基磺酰胺类化合物及其用途

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CN108558831A (zh) * 2018-06-08 2018-09-21 上海璃道医药科技有限公司 取代吡咯-4-烷基胺类化合物及其用途
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