Crystal form of substituted tetrahydrofuran derivative and application thereof

Abstract

The present disclosure relates to crystalline forms of substituted tetrahydrofuran derivatives and uses thereof. Specifically, the invention provides a crystal form A, a crystal form B and a crystal form C of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N '-hydroxyformamidino) pyridin-4-yl)-4, 5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carboxamide, and the crystal form A, the crystal form B and the crystal form C have good stability and can be better used for clinical treatment.

Description

Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical technology and relates to a crystalline form of a substituted tetrahydrofuran derivative and its use. Background Art

[0002] Nav is a class of transmembrane ion channel proteins. According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium channels are divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). Nav1.8 is of the TTX-R type, and its encoding gene is SCN10A, which is mainly present in trigeminal ganglion neurons and DRG neurons and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav 1.8, the upstroke of the action potential is mainly composed of Nav1.8 current. In some models of neuropathic pain research, nerve injury will increase the expression level of Nav1.8 in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression. After injecting carrageenan into the rat paw, the expression of Nav1.8 in DRG neurons increased. Nav1.8 knockout mice cannot exhibit normal visceral inflammatory pain. After the human Nav1.8 gene produces a gain-of-function mutation, it will cause peripheral neuropathic pain. Based on a series of animal experiments and human gene evidence, selective inhibition of Nav1.8 has the potential to become a new type of analgesic therapy and can be used for the treatment of various pain types such as inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

[0003] PCT / CN2023 / 114740 provides a Nav1.8 inhibitor, whose chemical name is (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-hydroxyformamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, and has the structure shown in Formula 1,

[0004]

[0005] The crystal form of a pharmaceutical active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, and sometimes other crystal forms may also be produced. Generally speaking, amorphous drug products do not have a regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy caking, poor fluidity, etc. The polymorphs of drugs have different requirements for product storage, production, and scale-up. Therefore, it is necessary to deeply study the crystal form of the aforementioned compound and improve various properties of the aforementioned compound. Summary of the Invention

[0006] The present disclosure provides a new crystal form of the compound shown in Formula 1, which has good stability and can be better applied clinically.

[0007]

[0008] The crystal form A of the compound shown in Formula 1 provided by the present disclosure has characteristic peaks at 9.604, 14.327, 23.230, 26.325, and 29.916 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0009] In some embodiments, the crystal form A of the compound shown in Formula 1 has characteristic peaks at 9.604, 9.889, 11.538, 14.327, 19.238, 19.784, 20.852, 23.230, 26.325, and 29.916 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0010] In some embodiments, the crystal form A of the compound shown in Formula 1 has characteristic peaks at 9.604, 9.889, 10.669, 11.538, 14.327, 17.376, 19.238, 19.784, 20.852, 23.230, 24.052, 24.301, 26.325, 27.668, 28.616, 28.865, and 29.916 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0011] In some embodiments, the X-ray powder diffraction pattern of the crystal form A of the compound shown in Formula 1 expressed in terms of diffraction angle 2θ is as Figure 3 shown.

[0012] The present disclosure also provides a method for preparing the crystal form A of the compound shown in Formula 1, the method including the step of dissolving the compound shown in Formula 1 in methanol or 10% water / methanol and stirring.

[0013] The crystal form B of the compound shown in Formula 1 provided by the present disclosure has characteristic peaks at 4.694, 10.150, 10.755, 13.119, and 14.078 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0014] In some embodiments, the crystal form B of the compound shown in Formula 1 has characteristic peaks at 4.694, 10.150, 10.755, 11.621, 13.119, 14.078, 16.010, 16.636, 20.546, 22.475, 26.172, 26.734, 29.369, and 32.343 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0015] In some embodiments, the X-ray powder diffraction pattern of crystalline form B of the compound of formula 1, expressed in terms of diffraction angle 2θ, has characteristic peaks at 4.694, 10.150, 10.755, 11.621, 13.119, 14.078, 16.010, 16.636, 17.429, 19.568, 20.546, 21.477, 22.475, 23.090, 23.400, 26.172, 26.734, 29.369, 32.343.

[0016] In some embodiments, the X-ray powder diffraction pattern of crystalline form B of the compound of formula 1, expressed in terms of diffraction angle 2θ, is as Figure 4 shown.

[0017] The present disclosure also provides a method for preparing crystalline form B of the compound of formula 1, and the method is selected from any one of the following methods:

[0018] Method 1: Dissolve the compound of formula 1 in solvent I and stir. Solvent I is selected from one of ethanol, isopropanol, n-propanol, isopropyl acetate, 10% water / isopropanol, 7% water / ethanol, 50% ethyl acetate / n-heptane.

[0019] Method 2: Add the compound of formula 1 to solvent II and stir. Solvent II is selected from one of water, n-heptane, 50% methanol / water, cyclohexane, isopropyl ether.

[0020] Method 3: Dissolve the compound of formula 1 in solvent III and evaporate the solvent. Solvent III is selected from one of methyl tert-butyl ether, acetone / isopropyl ether (1:40, v / v), tetrahydrofuran / isopropyl ether (1:40, v / v), methyl tert-butyl ether / isopropyl ether (1:40, v / v), ethyl acetate / isopropyl ether (1:40, v / v).

[0021] Method 4: Dissolve the compound of formula 1 in solvent IV, and then add solvent V and stir. Solvent IV is selected from one or more of acetone, ethyl acetate, acetonitrile, methyl tert-butyl ether; Solvent V is selected from one or more of water, n-heptane.

[0022] The X-ray powder diffraction pattern of crystalline form C of the compound of formula 1 provided by the present disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 10.060, 11.896, 13.738, 17.372, 19.829, 26.226.

[0023] In some embodiments, for crystalline form C of the compound represented by Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 10.060, 10.964, 11.896, 13.738, 15.979, 17.372, 18.630, 19.829, 23.150, 24.445, 26.226, 30.519.

[0024] In some embodiments, for crystalline form C of the compound represented by Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 10.060, 10.964, 11.896, 13.738, 15.979, 17.372, 18.630, 19.829, 21.475, 21.945, 23.150, 24.445, 26.226, 27.002, 30.519, 32.912.

[0025] In some embodiments, the X-ray powder diffraction pattern of crystalline form C of the compound represented by Formula 1 expressed in terms of diffraction angle 2θ is as Figure 5 shown.

[0026] The present disclosure also provides a method for preparing crystalline form C of the compound represented by Formula 1, the method comprising the steps of dissolving the compound represented by Formula 1 in dimethyl sulfoxide, adding water, and stirring.

[0027] For crystalline form D of the compound represented by Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 8.979, 16.419, 18.164, 19.461, 24.391.

[0028] In some embodiments, for crystalline form D of the compound represented by Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 7.999, 8.979, 9.634, 15.292, 16.062, 16.419, 18.164, 19.461, 20.920, 24.391, 32.925.

[0029] In some embodiments, for crystalline form D of the compound represented by Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 7.999, 8.979, 9.634, 11.321, 13.607, 15.292, 16.062, 16.419, 18.164, 19.461, 20.920, 22.982, 24.391, 25.543, 27.296, 27.950, 29.175, 32.436, 32.925.

[0030] In some embodiments, the X-ray powder diffraction pattern of crystalline form D of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is as follows Figure 6 shown.

[0031] The present disclosure also provides a method for preparing crystalline form D of the compound shown in Formula 1, the method comprising the step of dissolving the compound shown in Formula 1 in N,N-dimethylacetamide and evaporating the solvent.

[0032] For crystalline form E of the compound shown in Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, has characteristic peaks at 11.259, 16.010, 17.252, 19.022, 19.891, and 23.276.

[0033] In some embodiments, for crystalline form E of the compound shown in Formula 1, the X-ray powder diffraction pattern, expressed in terms of diffraction angle 2θ, has characteristic peaks at 11.259, 13.743, 16.010, 16.911, 17.252, 18.153, 19.022, 19.519, 19.891, and 23.276.

[0034] In some embodiments, the X-ray powder diffraction pattern of crystalline form E of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is as follows Figure 7 shown.

[0035] The present disclosure also provides a method for preparing crystalline form E of the compound shown in Formula 1, the method comprising the step of heating crystalline form D of the compound shown in Formula 1 to 100 °C.

[0036] In certain embodiments, the preparation method described in the present disclosure further includes any one of the steps of crystallization, centrifugation (filtration), washing, or drying.

[0037] The crystallization methods of the present disclosure include, but are not limited to, stirring crystallization, static crystallization, or evaporation crystallization. In some embodiments, the crystallization is stirring crystallization. In some embodiments, the crystallization is static crystallization.

[0038] The present disclosure also provides a pharmaceutical composition comprising any one of the aforementioned crystalline forms A, B, C, D, or E, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0039] The present disclosure also provides a pharmaceutical composition prepared from any one of the aforementioned crystalline forms A, B, C, D, or E, and an optionally pharmaceutically acceptable excipient.

[0040] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing any one of the aforementioned crystalline forms A, B, C, D, or E with a pharmaceutically acceptable excipient.

[0041] The present disclosure also provides the use of the foregoing Form A, Form B, Form C, Form D or Form E or the foregoing composition in the preparation for preventing and / or treating pain alleviation and pain-related diseases.

[0042] The use according to the present disclosure, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominoplasty pain.

[0043] The "2θ or 2θ angle" as described in the present disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case after rounding for numbers with more than 1 decimal place), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0044] In the present disclosure, numerical values such as the content of related substances are data obtained by measurement and calculation, and there will inevitably be a certain degree of error. Generally, ±10% is within the reasonable error range. There will be a certain degree of error variation depending on the context where it is used, and this error variation does not exceed ±10%, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, preferably ±5%.

[0045] The starting materials used in the preparation method of the crystal form of the present disclosure can be compounds in any form, and the specific forms include but are not limited to: amorphous, any crystal form, hydrate, solvate, etc.

[0046] The drying temperature in the present disclosure is generally 25°C - 100°C, preferably 40°C - 70°C, and it can be dried at normal pressure or under reduced pressure.

[0047] The crystallization methods described in the present disclosure include crystallization at room temperature, cooling crystallization, solvent evaporation crystallization, adding seed crystals to induce crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be carried out during the crystallization process.

[0048] "Differential scanning calorimetry or DSC" as described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference during the heating or constant temperature process of the sample, so as to characterize all physical and chemical changes related to thermal effects and obtain the phase transition information of the sample.

[0049] According to the description of hygroscopicity characteristics and the definition of hygroscopic weight gain in "Guideline for Drug Hygroscopicity" in Part IV of the Chinese Pharmacopoeia 2015 Edition,

[0050] Deliquescence: Absorbing sufficient moisture to form a liquid;

[0051] Highly hygroscopic: The hygroscopic weight gain is not less than 15%;

[0052] Hygroscopic: The hygroscopic weight gain is less than 15% but not less than 2%;

[0053] Slightly hygroscopic: The hygroscopic weight gain is less than 2% but not less than 0.2%;

[0054] Non- or almost non-hygroscopic: The hygroscopic weight gain is less than 0.2%.

[0055] "Excipient" as described in the present disclosure includes but is not limited to any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier that has been approved by the US Food and Drug Administration for use in humans or domestic animals and is acceptable. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 It is the analgesic efficacy of Compound 1 in a rat incision pain model.

[0057] Figure 2 It is the effect of Compound 1 on body weight in a rat incision pain model.

[0058] Figure 3 It is the XRPD spectrum of Crystal Form A of Compound 1.

[0059] Figure 4 It is the XRPD spectrum of Crystal Form B of Compound 1.

[0060] Figure 5 It is the XRPD spectrum of Crystal Form C of Compound 1.

[0061] Figure 6 It is the XRPD spectrum of Crystal Form D of Compound 1.

[0062] Figure 7 It is the XRPD spectrum of Crystal Form E of Compound 1.

[0063] Figure 8 It is the XRPD spectrum of the amorphous form of Compound 1. Detailed implementation manners

[0064] The present disclosure will be explained in more detail below in conjunction with examples or experimental examples. The examples or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, and do not limit the essence and scope of the present disclosure.

[0065] Test conditions of the instruments used in the experiments:

[0066] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic resonance instrument or a Bruker AVANCE NEO 500M. The solvents for the measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0067] The MS measurement is performed using an Agilent 1200 / 1290DAD-6110 / 6120Quadrupole MS liquid chromatography-mass spectrometry instrument (manufacturer: Agilent, MS model: 6110 / 6120Quadrupole MS).

[0068] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity QdaDetec-tor / wa-ters SQ Detector)

[0069] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO QExactive)

[0070] High performance liquid chromatography (HPLC) analysis is performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high performance liquid chromatography instrument.

[0071] Chiral HPLC analysis and determination are performed using an Agilent 1260DAD high performance liquid chromatography instrument.

[0072] High performance liquid chromatography for preparation is performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatography instruments.

[0073] Chiral preparation uses a Shimadzu LC-20AP preparative chromatograph.

[0074] The CombiFlash rapid preparator uses a Combiflash Rf200 (TELEDYNE ISCO).

[0075] For thin-layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used in thin-layer chromatography (TLC) are 0.15 mm - 0.2 mm, and the specifications of the silica gel plates used for thin-layer chromatography separation and purification of products are 0.4 mm - 0.5 mm.

[0076] For silica gel column chromatography, silica gel with 200 - 300 mesh from Yantai Huanghai is generally used as the carrier.

[0077] The determination of the average kinase inhibition rate and IC50 value uses a NovoStar microplate reader (BMG Labtech, Germany).

[0078] The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0079] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere.

[0080] An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0081] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0082] For the catalytic hydrogenation reaction, a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator are used.

[0083] For the hydrogenation reaction, it is usually evacuated, filled with hydrogen, and this operation is repeated 3 times.

[0084] For the microwave reaction, a CEM Discover-S 908860 microwave reactor is used.

[0085] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0086] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20 °C - 30 °C.

[0087] The progress of the reaction in the examples was monitored by thin-layer chromatography (TLC). The eluent used for the reaction, the eluent system for column chromatography for purifying the compound, and the eluent system for thin-layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system. The volume ratio of the solvents was adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0088] XRPD is X-ray powder diffraction detection: The measurement was carried out using a BRUKER D8 type X-ray diffractometer. The specific acquisition information: Cu anode (40 kV, 40 mA), Cu-Kα1 ray Kα2 ray Kβ ray Scanning mode: θ / 2θ, scanning range (2θ range): 3° to 45°.

[0089] DSC is differential scanning calorimetry: The measurement was carried out using a METTLER TOLEDO DSC 3+ differential scanning calorimeter. The heating rate was 10 °C / min, and the specific temperature range was referred to the corresponding spectrum (mostly 25 - 300 °C). The nitrogen purge rate was 50 mL / min.

[0090] TGA is thermogravimetric analysis: The detection was carried out using a METTLER TOLEDO TGA 2 type thermogravimetric analyzer. The heating rate was 10 °C / min, and the specific temperature range was referred to the corresponding spectrum (mostly 30 - 350 °C). The nitrogen purge rate was 50 mL / min.

[0091] DVS is dynamic vapor sorption: The detection was carried out using SMS DVS Advantage. At 25 °C, the humidity change was 50% - 95% - 0% - 95% - 50%, with a step of 10% (the last step was 5%) (the specific humidity range was subject to the corresponding spectrum, and the method listed here was mostly used). The judgment criterion was that dm / dt was not greater than 0.002%.

[0092] Preparation of the compound of Formula 1 in Example 1 (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-hydroxyformamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0093]

[0094] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-1

[0095] (2S,3R,4R,5S)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-2

[0096] rac-(2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (12 g, 33.87 mmol, prepared by the method disclosed in Example 3 on page 231 of the specification of patent application "WO2021113627") was resolved by a chiral column (Waters SFC 150, column: DAICEL IC, 40*250 mm, 10 μm; mobile phase A: supercritical CO 2 , mobile phase B: IPA), gradient ratio: A:B: 90:10, flow rate: 120 mL / min) to obtain the title product 1b-1 (5.5 g, yield: 45.8%) and 1b-2 (5.08 g, yield: 42.3%).

[0097] MS m / z (ESI): 353.2 [M-1].

[0098] Single-configuration compound (shorter retention time) 1b-1 (5.5 g, yield: 45.8%)

[0099] MS m / z (ESI): 353.2 [M-1].

[0100] Chiral HPLC analysis: retention time 2.414 minutes, purity: 99% (column: DAICEL IC, 100*3 mm, 3 μm; mobile phase A: supercritical CO 2 , mobile phase B: IPA (0.1% DEA)), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5 mL / min).

[0101] Single-configuration compound (longer retention time) 1b-2 (5.08 g, yield: 42.3%).

[0102] MS m / z (ESI): 353.2 [M-1].

[0103] Chiral HPLC analysis: retention time 2.724 minutes, purity: 99% (column: DAICEL IC, 100*3 mm, 3 μm; mobile phase A: supercritical CO 2 , mobile phase B: IPA (0.1% DEA)), gradient ratio: mobile phase A: 60%-95%, flow rate: 1.5 mL / min).

[0104] Step 2 (2R,3S,4S,5R)-N-(2-Cyanopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1d

[0105] Dissolve compound 1b-1 (50 mg, 141 μmol) in dichloromethane (10 mL). Add oxalyl chloride (40 mg, 315 μmol) and 1 drop of N,N-dimethylformamide under an ice bath. Resume the reaction at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure. Dissolve the residue in dichloromethane (3 mL). Add N,N-diisopropylethylamine (60 mg, 464 μmol). Dropwise add a dichloromethane solution (1 mL) of 4-aminopyridine-2-carbonitrile 1c (30 mg, 251 μmol, Shanghai Hanhong) under an ice bath. Stir the reaction for 2 hours. Concentrate the reaction solution under reduced pressure. Purify the residue by silica gel column chromatography with elution system B to obtain the title compound 1d (45 mg, yield: 70%).

[0106] MS m / z (ESI): 456.2 [M+1].

[0107] Step 3 (2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-hydroxyformamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0108] Dissolve compound 1d (200 mg, 439.2 μmol) in methanol (4 mL). Add hydroxylamine hydrochloride (61 mg, 877.8 μmol) and N,N-diisopropylethylamine (60 mg, 464.2 μmol). Stir the reaction for 1.5 hours. Concentrate the reaction solution under reduced pressure. Dissolve the residue in dichloromethane. Wash it successively with water and saturated sodium chloride solution. Concentrate the organic phase under reduced pressure. Purify the residue by silica gel column chromatography with elution system A to obtain the title compound 1 (160 mg, yield: 74.6%). After X-ray powder diffraction detection, this product is amorphous, and the XRPD spectrum is as Figure 8 .

[0109] MS m / z (ESI): 489.0 [M+1].

[0110] 1 H NMR (500 MHz, CDCl 3): δ 8.61 (s, 1H), 8.46 (d, 1H), 7.87 (dd, 1H), 7.83 (d, 1H), 7.09 (ddd, 1H), 6.92 (td, 1H), 5.75 (s, 2H), 5.02 (d, 1H), 4.10 (dd, 1H), 4.01 (d, 3H), 2.76 (p, 1H), 1.68 (s, 3H), 0.80 (dq, 3H).

[0111] Test Example 1 Determination of the inhibitory activity of the compounds of the present disclosure against Nav1.8

[0112] The purpose of the experiment was to investigate the effect of the compound on the Nav1.8 ion channel in an in vitro experiment. The Nav1.8 ion channel was stably expressed on HEK293 cells. After the Nav1.8 current was stabilized, by comparing the magnitude of the Nav1.8 current before and after the application of the compound, the effect of the compound on the Nav1.8 ion channel could be obtained.

[0113] 1 Experimental materials and instruments

[0114] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments) / MultiClamp700A (Axon in-strument)

[0115] 2) Digital-to-analog converter: Digidata 1440A (Axon CNS) / Digidata 1550A (Axoninstruments)

[0116] 3) Micromanipulator: MP-225 (SUTTER instrument)

[0117] 4) Inverted microscope: TL4 (Olympus)

[0118] 5) Glass microelectrode puller: PC-10 (NARISHIGE)

[0119] 6) Microelectrode glass capillary: B12024F (Wuhan Microprobe Scientific Instruments Co., Ltd.)

[0120] 7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

[0121] 8) TTX AF3014 (Affix Scientific)

[0122] 2 Experimental procedures

[0123] 2.1 Compound preparation

[0124] Compounds for preparing intracellular and extracellular solutions were purchased from Sigma (St. Louis, MO), except for NaOH and KOH used in acid-base titration. The extracellular solution (mM) was: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; glucose, 10; pH 7.4 (titrated with NaOH). The intracellular solution (mM) was aspartic acid, 140; MgCl 2 , 2; EGTA 11; HEPES, 10; pH 7.2 (titrated with CsOH). All test compound and control compound solutions contained 1 μM TTX.

[0125] The stock concentration of the test compound was 9 mM, dissolved in dimethyl sulfoxide (DMSO). On the day of the test, it was redissolved in the extracellular solution to prepare the required concentration.

[0126] 2.2 Manual patch clamp test procedure

[0127] 1) After the compound was prepared into a solution of the specified concentration, the drug solutions were added to each pipette in ascending order of concentration, and each pipette was labeled.

[0128] 2) The cell was transferred to the perfusion chamber, a positive pressure was applied inside the electrode, the tip of the electrode was brought into contact with the cell, the three-way valve of the aspiration device was adjusted to the three-way state, and then a negative pressure was applied to the electrode to form a high-resistance seal between the electrode and the cell. The negative pressure was continuously applied to rupture the cell membrane and form a current path.

[0129] 3) After the cell rupture current was stable, perfusions at different concentrations were carried out in sequence. If the current was stable for at least one minute, the next concentration could be used for perfusion. The perfusion time for each concentration was no more than five minutes.

[0130] 4) The perfusion chamber was cleaned. It was rinsed in descending order of drug solution concentration, with each concentration of the drug solution rinsed for 20 s. Finally, it was rinsed with the extracellular solution for 1 min.

[0131] 2.3 Test voltage equation (resting) and results

[0132] The cell was clamped at -80 mV, and then depolarized to 10 mV with a 10-ms rectangular wave to obtain Nav1.8 current. This procedure was repeated every 5 s. The maximum current induced by the rectangular wave was detected. After it was stable, the test compound was perfused. When the response was stable, the blocking strength was calculated.

[0133] 3. Data analysis

[0134] The data will be stored in a computer system for analysis. The data collection and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA), and the analysis results will be reviewed by the management staff. Current stability refers to the current varying within a limited range over time. The magnitude of the current after stabilization is used to calculate the effect of the compound at this concentration.

[0135] The inhibitory activity of the compounds of the present disclosure against Nav1.8 was determined by the above tests, and the measured IC 50 values are shown in Table 1.

[0136] Table 1 IC of the compounds of the present disclosure inhibiting Nav1.8 channel activity 50

[0137] Example number <![CDATA[IC 50 (nM)]]> 1 0.93

[0138] Conclusion: The compounds in the present disclosure have a significant inhibitory effect on Nav1.8 channel activity.

[0139] Test Example 2: Pharmacokinetic Evaluation

[0140] I. SD Rat Experiment

[0141] Using SD rats as the test animals, the LC / MS / MS method was used to determine the drug concentrations in the plasma of SD rats at different times after intragastric (i.g.) administration of the compounds of the examples. The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied to evaluate their pharmacokinetic characteristics.

[0142] 1.1 Experimental Protocol

[0143] Experimental animals: 4 male SD rats, provided by Vital River Laboratory Animal Technology Co., Ltd. After fasting overnight, they were administered drugs by gavage respectively.

[0144] Drug preparation: Weigh a certain amount of the test compound respectively, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.2 mg / mL colorless and clear solution.

[0145] Drug administration: The administration dose was 2 mg / kg, and the administration volume was 10.0 mL / kg.

[0146] Operation Method

[0147] Before drug administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after drug administration, 0.2 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 1 minute (4 °C), the plasma was separated within 1 hour, and stored in dry ice for testing. The process from blood collection to centrifugation was carried out under ice bath conditions. The animals were allowed to eat 2 hours after drug administration.

[0148] Determine the content of the compound to be measured in the plasma of SD rats after administration of drugs at different concentrations: Take 25 μL of the plasma samples of SD rats at each time point after administration, add 200 μL of acetonitrile containing the internal standard (verapamil 100 ng / ml), vortex mix, and centrifuge at 3700 rpm for 10 minutes. Take 0.1 μL of the supernatant for LC / MS / MS analysis.

[0149] 1.2 Results of pharmacokinetic parameters

[0150] Table 2. Pharmacokinetic parameters of the compounds of the present disclosure

[0151]

[0152] Conclusion: The compounds of the present disclosure have high blood drug concentration and high exposure in SD rats, and have obvious pharmacokinetic advantages.

[0153] II. Experiments on C57 mice

[0154] 2.1 Experimental animals

[0155] 18 C57 mice, half male and half female, were evenly divided into 2 groups, with 9 mice in each group, and 3 mice at each time point in each group. They were provided by Vital River Laboratory Animal Technology Co., Ltd., with production licenses SCXK(Zhe)2019-0001 and SCXK(Jing)2019-0006, and were administered by gavage and intravenous injection respectively.

[0156] 2.2 Drug preparation

[0157] Weigh a certain amount of the test compound respectively, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.1 mg / mL colorless and clear solution (gavage administration group) and a 0.1 mg / mL colorless and clear solution (intravenous injection administration group).

[0158] 2.3 Administration

[0159] Gavage administration group: The administration dose was 2.0 mg / kg, and the administration volume was 20 mL / kg.

[0160] Intravenous injection administration group: The administration dose was 1.0 mg / kg, and the administration volume was 10 mL / kg.

[0161] 2.4 Operations

[0162] Gavage administration group: Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbital sinus, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 1 minute (4 °C), the plasma was separated within 1 hour, and stored at -80 °C for later measurement. The blood collection to centrifugation process was carried out under ice bath conditions.

[0163] Intravenous injection administration group: Before administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after administration, blood was collected, and the treatment was the same as that of the gavage administration group.

[0164] Determination of the content of the compound to be measured in the plasma of C57 mice after administration of different concentrations of the drug: Compound 1: 20 μL of the plasma sample of C57 mice at each time point after administration was taken, 200 μL of acetonitrile containing verapamil (internal standard 20 ng / mL) was added to each sample to precipitate proteins, vortex-mixed for 5 minutes, and centrifuged at 3700 rpm for 10 minutes. 90 μL of the supernatant was taken, 90 μL of water was added, vortexed for 5 minutes, and 0.1 μL was injected for LC / MS / MS analysis.

[0165] 2.5 Pharmacokinetic parameter results

[0166] Table 3. Pharmacokinetic parameters of the compounds of the present disclosure

[0167]

[0168] Conclusion: The compounds of the present disclosure have high blood drug concentrations, large exposures, low clearance rates, and relatively high bioavailability in C57 mice, showing pharmacokinetic advantages.

[0169] Test Example 3 Pharmacodynamic experiment

[0170] 1. Experimental purpose

[0171] To evaluate the analgesic efficacy of the compounds of the present disclosure in inhibiting pain in a rat incision pain model.

[0172] 2. Experimental drugs

[0173] Compound of Example 1.

[0174] A solution of 25% PEG400 + 75% (10% TPGS + 1% HPMC K100LV) was used.

[0175] 3. Experimental methods and experimental materials

[0176] 3.1 Experimental animals and feeding conditions

[0177] Experimental animals: Sprague-Dawley (SD) rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (License number: SCXK(Zhe)2019-0001), and their body weight was approximately 180 g upon purchase.

[0178] Feeding conditions: The rats were housed at 5 rats per cage, with a 12 / 12-hour light / dark cycle, a constant temperature of 23 ± 1°C, a humidity of 50 to 60%, and free access to food and water.

[0179] 3.2 Animal grouping

[0180] After the SD rats were adaptively fed, the grouping was as follows:

[0181] Table 4

[0182]

[0183] Note: one dose means administering the drug only once; i.g. means intragastric administration.

[0184] 3.3 Experimental method:

[0185] Nine SD rats with a body weight of 170 - 190 g were selected, and their mechanical pain thresholds were measured using an electronic tactile measuring instrument. Then, an incision pain surgery was performed. During the surgery, after anesthesia with Zoletil (Zoletil-50, 250 mg, diluted to 50 ml with normal saline after dissolution, and 2 ml was injected for a 200 g body weight), a 1 cm long incision was made in the middle of the plantar surface of the left hind paw using a No. 10 surgical blade. After cutting through the skin and fascia, the skin was sutured with 3-0 sterile silk surgical sutures. The injured area was disinfected with penicillin, and the animals were returned to their original places to recover overnight. After overnight recovery from the surgery, the drug was administered by oral gavage. Five hours after the drug administration (about 24 hours after the surgery), the mechanical pain threshold was measured using an electronic tactile measuring instrument.

[0186] 3.4 Data statistics

[0187] The Excel statistical software was used to record the data: the average value was calculated as avg; the SD value was calculated as STDEV; the SEM value was calculated as STDEV / SQRT (the number of animals in each group); the GraphPad Prism software was used to plot the graph, and one-way ANOVA and t-test were used for statistical analysis of the data.

[0188] Percentage increase in threshold (%) = [(G t - G 0 ) / G 0 × 100 (%), where G t is the plantar pain threshold of the drug administration group, and G 0 is the plantar pain threshold of the vehicle group.

[0189] 4. Results

[0190] The analgesic efficacy of the compound in Example 1 in a rat incision pain model is as Figure 1 shown in Table 5, and the effect of body weight is shown in Figure 2 ;

[0191] Table 5 Analgesic efficacy of the compounds of the present disclosure in a rat incision pain model

[0192]

[0193] Note: One dose means administering the drug only once; i.g. means intragastric administration.

[0194] 5. Conclusion

[0195] The pain threshold of normal rats (body weight 170 - 190 g) is 26.3 ± 0.8 gf, and that of the vehicle control group is 10.4 ± 0.9 gf. The pain thresholds of the compound in Example 1 at 200, 100, and 30 mg / kg are 22.4, 22.3, and 12.0 gf respectively. The pain thresholds are significantly increased by 114% (p < 0.001), 114% (p < 0.001), and 15% respectively compared with the vehicle control group. The pain threshold at 200 mg / kg is equivalent to that at 100 mg / kg, and the analgesic efficacy reaches saturation. The pain threshold at 100 mg / kg is significantly higher than that at 30 mg / kg (p < 0.01), and the analgesic effect has an obvious dose-dependence, and the administration has no effect on the body weight of rats.

[0196] Preparation of free form crystalline form A in Example 2

[0197] Dissolve 5 mg of the compound shown in Formula 1 in 0.025 mL of methanol, stir at room temperature for crystallization, centrifuge, and dry the solid under vacuum to obtain the product. After detection by X-ray powder diffraction, this product is defined as crystalline form A, and the XRPD spectrum is as Figure 3 , and the characteristic peak positions are shown in Table 6. The DSC spectrum shows that the peak values of the endothermic peaks are 86.74 °C and 169.89 °C. The TGA spectrum shows that the weight loss is 1.04% from 30 °C to 90 °C.

[0198] Table 6

[0199]

[0200]

[0201] Preparation of free form crystalline form A in Example 3

[0202] Dissolve 5 mg of the compound shown in Formula 1 in 0.025 mL of 10% water / methanol (v / v), stir at room temperature for crystallization, centrifuge, and dry the solid under vacuum to obtain the title product.

[0203] Preparation of free form crystalline form B in Example 4

[0204] 5 mg of the compound shown in Formula 1 was dissolved in 0.025 mL of ethanol, stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain the product. The product was defined as Form B by X-ray powder diffraction detection, and the XRPD spectrum was as follows: Figure 4 The characteristic peak positions are shown in Table 7. The DSC spectrum shows that the endothermic peak is 169.95°C. The TGA spectrum shows that the weight loss is 0.27% from 30°C to 180°C.

[0205] DVS testing showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample gained about 0.6% of its weight due to moisture absorption; under accelerated experimental conditions (i.e. 70% RH), the weight gain due to moisture absorption was about 0.8%; under extreme conditions (90% RH), the weight gain due to moisture absorption was about 1.1%; after the DVS test, the crystal form was retested and the crystal form did not change.

[0206] Table 7

[0207]

[0208]

[0209] Example 5 Preparation of Free Form B

[0210] 5 mg of the compound shown in Formula 1 was dissolved in the solvent in Table 8, stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a product. The product was found to be Form B by X-ray powder diffraction.

[0211] Table 8

[0212] Solvent Crystal form 0.025 mL isopropyl alcohol Crystal form B 0.025 mL n - propyl alcohol Crystal form B 0.025 mL isopropyl acetate Crystal form B 0.025 mL 10% water / isopropyl alcohol Crystal form B 0.025 mL 7% water / ethanol Crystal form B 0.05 mL 50% ethyl acetate / n - heptane Crystal form B

[0213] Example 6 Preparation of Free Form B

[0214] 5 mg of the compound shown in Formula 1 was added with 0.5 mL of the solvent in Table 9, stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a product. The product was found to be Form B by X-ray powder diffraction.

[0215] Table 9

[0216] Solvent Crystal form n - heptane Crystal form B Cyclohexane Crystal form B Isopropyl ether Crystal form B Water Crystal form B 50% water / methanol Crystal form B

[0217] Example 7 Preparation of Free Form B

[0218] 5 mg of the compound shown in Formula 1 was dissolved in a solvent in Table 10, and the solvent was evaporated at room temperature to obtain a solid. The product was crystal form B as determined by X-ray powder diffraction.

[0219] Table 10

[0220]

[0221] Preparation of Free Crystal Form B

[0222] Dissolve 5 mg of the compound shown in Formula 1 in 0.025 mL of Solvent 1, add 0.5 mL of Solvent 2. Solvent 1 and Solvent 2 are shown in Table 11. Stir at room temperature for crystallization, centrifuge, and dry the solid under vacuum to obtain the product. After X-ray powder diffraction detection, this product is Crystal Form B.

[0223] Table 11

[0224] Solvent 1 Solvent 2 Crystal form Acetone Water Crystal form B Ethyl acetate n - heptane Crystal form B Acetonitrile Water Crystal form B Methyl tert - butyl ether n - heptane Crystal form B

[0225] Preparation of Free Crystal Form C

[0226] Dissolve 5 mg of the compound shown in Formula 1 in 0.025 mL of DMSO, add 0.5 mL of water, stir at room temperature for crystallization, centrifuge, and dry the solid under vacuum to obtain the product.

[0227] After X-ray powder diffraction detection, this product is defined as Crystal Form C. The XRPD pattern is as Figure 5 , and the characteristic peak positions are shown in Table 12. The DSC pattern shows endothermic peak maxima at 57.96 °C and 120.27 °C. The TGA pattern shows a weight loss of 10.20% from 30 °C to 150 °C.

[0228] Table 12

[0229]

[0230]

[0231] Preparation of Free Crystal Form D

[0232] Dissolve 5 mg of the compound shown in Formula 1 in 0.025 mL of N,N-dimethylacetamide, volatilize at room temperature, and dry the solid under vacuum to obtain the product.

[0233] After X-ray powder diffraction detection, this product is defined as Crystal Form D. The XRPD pattern is as Figure 6 , and the characteristic peak positions are shown in Table 13. The DSC pattern shows endothermic peak maxima at 90.74 °C and 123.72 °C. The TGA pattern shows a weight loss of 19.76% from 30 °C to 125 °C and a weight loss of 2.92% from 125 °C to 170 °C.

[0234] Table 13

[0235]

[0236]

[0237] Preparation of Free Crystal Form E

[0238] The free crystalline form D in Example 10 was heated to 100 °C to obtain a product.

[0239] After detection by X-ray powder diffraction, this product was defined as crystalline form E, and the XRPD pattern was as Figure 7 , and the characteristic peak positions are shown in Table 14.

[0240] Table 14

[0241]

[0242] Example 9: Study on Crystal Stability

[0243] The free crystalline form B was placed flat and open, and the stability of the samples was investigated under the conditions of high temperature (40 °C and 60 °C), high humidity (RH 75%, RH 92.5%) and light (4500 lux) respectively. The sampling investigation period was 30 days.

[0244] Table 15

[0245]

[0246]

[0247] Conclusion: The stress testing experiments showed that the free crystalline form B had good physical and chemical stability under the stress conditions of high temperature (40 °C, 60 °C), high humidity (75% RH, 92.5% RH) and light for 30 days.

[0248] II. Long-term Accelerated Experiment

[0249] Example 10: Long-term / Accelerated Stability

[0250] The free crystalline form B was placed under the conditions of 25 °C / 60% RH and 40 °C / 75% RH respectively to investigate its stability.

[0251] Table 16

[0252]

[0253] Conclusion: The long-term accelerated experiments showed that the free crystalline form B had good physical and chemical stability under the conditions of 25 °C / 60% RH and 40 °C / 75% RH for 3 months.

Claims

1. A crystalline form A of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 9.604, 14.327, 23.230, 26.325, and 29.916, preferably at 9.604, 9.889, 11.538, 14.327, 19.238, 19.784, 20.852, 23.230, 26.325, and 29.916 There are characteristic peaks at 9.604, 9.889, 10.669, 11.538, 14.327, 17.376, 19.238, 19.784, 20.852, 23.230, 24.052, 24.301, 26.325, 27.668, 28.616, 28.865, and 29.916, more preferably, there are characteristic peaks at 9.604, 9.889, 10.669, 11.538, 14.327, 17.376, 19.238, 19.784, 20.852, 23.230, 24.052, 24.301, 26.325, 27.668, 28.616, 28.865, and 29.916, 2. The crystalline form A according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG3 .

3. A method for preparing the crystalline form A as claimed in claim 1 or 2, comprising the step of dissolving the compound represented by formula 1 in methanol or 10% water / methanol and stirring.

4. A crystalline form B of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 4.694, 10.150, 10.755, 13.119, and 14.078, preferably at 4.694, 10.150, 10.755, 11.621, 13.119, 14.078, 16.010, 16.636, 20.546, 22.475, 26.172, 26.734, 29.369 , and 32.343, and more preferably, there are characteristic peaks at 4.694, 10.150, 10.755, 11.621, 13.119, 14.078, 16.010, 16.636, 17.429, 19.568, 20.546, 21.477, 22.475, 23.090, 23.400, 26.172, 26.734, 29.369, and 32.

343.

5. The crystal form B according to claim 4, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG4 .

6. A method for preparing the crystalline form B according to claim 4 or 5, wherein the method is selected from any of the following methods: Method 1: dissolving the compound of formula 1 in solvent I and stirring, wherein the solvent I is selected from one of ethanol, isopropanol, n-propanol, isopropyl acetate, 10% water / isopropanol, 7% water / ethanol, and 50% ethyl acetate / n-heptane; Method 2: Add the compound of formula 1 into solvent II and stir, wherein the solvent II is selected from water, n-heptane, 50% methanol / water, cyclohexane, and isopropyl ether; Method 3: dissolving the compound of formula 1 in solvent III, and volatilizing the solvent, wherein the solvent III is selected from one of methyl tert-butyl ether, acetone / isopropyl ether (1:40, v / v), tetrahydrofuran / isopropyl ether (1:40, v / v), methyl tert-butyl ether / isopropyl ether (1:40, v / v), and ethyl acetate / isopropyl ether (1:40, v / v); Method 4: dissolving the compound of formula 1 in solvent IV, adding solvent V, and stirring, wherein the solvent IV is selected from one or more of acetone, ethyl acetate, acetonitrile, and methyl tert-butyl ether; and the solvent V is selected from one or more of water and n-heptane.

7. A crystalline form C of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 10.060, 11.896, 13.738, 17.372, 19.829, and 26.226, preferably at 10.060, 10.964, 11.896, 13.738, 15.979, 17.372, 18.630, 19.829, 23.150, 24.445 , 26.226, and 30.519, and more preferably, there are characteristic peaks at 10.060, 10.964, 11.896, 13.738, 15.979, 17.372, 18.630, 19.829, 21.475, 21.945, 23.150, 24.445, 26.226, 27.002, 30.519, and 32.

912.

8. The crystal form C according to claim 7, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG5 .

9. A method for preparing the crystalline form C as claimed in claim 7 or 8, comprising the steps of dissolving the compound represented by formula 1 in dimethyl sulfoxide, adding water, and stirring.

10. According to the crystal form according to any one of claims 1-2, 4-5, 7-8, the 2θ angle error range is ±0.

20.

11. A pharmaceutical composition comprising the crystal form according to any one of claims 1-2, 4-5, 7-8 and optionally selected from pharmaceutically acceptable excipients.

12. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form according to any one of claims 1-2, 4-5, 7-8 and a pharmaceutically acceptable excipient.

13. Use of the crystalline form according to any one of claims 1-2, 4-5, 7-8, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating and / or preventing pain and pain-related diseases.

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