A crystalline form of a substituted tetrahydrofuran derivative and uses thereof

Abstract

The present disclosure relates to a crystalline form of a substituted tetrahydrofuran derivative and uses thereof. In particular, the present disclosure provides a crystalline form A, a crystalline form B, a crystalline form C of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-hydroxymethylcarbamimidoyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, which has good stability and can be better used for clinical treatment.

Description

Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology and relates to a crystalline form of a substituted tetrahydrofuran derivative and its uses. Background Technology

[0002] Sodium channels (Nav) are a class of transmembrane ion channel proteins. Based on their ability to be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are classified into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R) types. Nav1.8 is a TTX-R type, encoded by the gene SCN10A, and is mainly found in trigeminal ganglion neurons and DRG neurons, exhibiting slow inactivation and rapid recovery electrophysiological characteristics. In neurons expressing Nav1.8, the rise in action potentials is primarily driven by Nav1.8 currents. In some models of neuropathic pain, nerve injury increases the expression levels of Nav1.8 in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides to reduce Nav1.8 expression significantly alleviates pain. Intraplasty of carrageenan in the paws of rats increased Nav1.8 expression in DRG neurons. Nav1.8 knockout mice do not exhibit normal visceral inflammatory pain. Mutations in the human Nav1.8 gene that result in functional gain can lead to peripheral neuropathic pain. Based on a series of animal studies and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a novel analgesic therapy, and can be used to treat various types of pain, including inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

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

[0004]

[0005] The crystal form of a pharmaceutical active ingredient often affects its chemical stability. Different crystallization and storage conditions can lead to changes in the crystal structure of the compound, sometimes even resulting in other crystal forms. Generally, amorphous drug products lack regular crystal structures and often have other defects, such as poor product stability, fine crystals, difficulty in filtration, easy agglomeration, and poor flowability. Polymorphism of drugs places different requirements on product storage, production, and scale-up. Therefore, in-depth research on the crystal forms of the aforementioned compounds and the improvement of their various properties is essential. Summary of the Invention

[0006] This disclosure provides a novel crystal form of the compound shown in Formula 1, which has good stability and can be better applied in clinical practice.

[0007]

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

[0009] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound shown in Formula 1, expressed as a diffraction angle 2θ, 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.

[0010] In some embodiments, the X-ray powder diffraction pattern of crystal form A of the compound shown in Formula 1, expressed as a diffraction angle 2θ, 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.

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

[0012] This disclosure also provides a method for preparing crystal form A of the compound shown in Formula 1, the method comprising 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 in this disclosure has characteristic peaks at 4.694, 10.150, 10.755, 13.119, and 14.078 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0014] In some embodiments, the X-ray powder diffraction pattern of crystal form B of the compound shown in Formula 1, expressed as a diffraction angle 2θ, 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.

[0015] In some embodiments, the X-ray powder diffraction pattern of crystal form B of the compound shown in Formula 1, expressed as a 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, and 32.343.

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

[0017] This disclosure also provides a method for preparing crystal form B of the compound shown in Formula 1, wherein the method is selected from any 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, and 50% ethyl acetate / n-heptane.

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

[0020] Method 3: Dissolve the compound of Formula 1 in solvent III and evaporate the solvent, wherein 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, then add solvent V and stir. Solvent IV is selected from one or more of acetone, ethyl acetate, acetonitrile, and methyl tert-butyl ether; solvent V is selected from one or more of water and n-heptane.

[0022] The X-ray powder diffraction pattern of the compound of Formula 1 shown in this disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 10.060, 11.896, 13.738, 17.372, 19.829, and 26.226.

[0023] In some embodiments, the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula 1, expressed as a 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, and 30.519.

[0024] In some embodiments, the X-ray powder diffraction pattern of crystal form C of the compound shown in Formula 1, expressed as a 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, and 32.912.

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

[0026] This disclosure also provides a method for preparing crystal form C of the compound shown in Formula 1, the method comprising the steps of dissolving the compound shown in Formula 1 in dimethyl sulfoxide, adding water, and stirring.

[0027] The crystal form D of the compound of Formula 1 provided in this disclosure has characteristic peaks at 8.979, 16.419, 18.164, 19.461, and 24.391 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0028] In some embodiments, the crystal form D of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 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, and 32.925.

[0029] In some embodiments, the X-ray powder diffraction pattern of the crystal form D of the compound shown in Formula 1, expressed as a 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, and 32.925.

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

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

[0032] The crystal form E of the compound of Formula 1 provided in this disclosure has characteristic peaks at 11.259, 16.010, 17.252, 19.022, 19.891, and 23.276 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0033] In some embodiments, the X-ray powder diffraction pattern of the crystal form E of the compound shown in Formula 1, expressed as a 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 the crystal form E of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 7 As shown.

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

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

[0037] The crystallization methods disclosed herein include, but are not limited to, stirred crystallization, static crystallization, or evaporative crystallization. In some embodiments, the crystallization is stirred crystallization. In some embodiments, the crystallization is static crystallization.

[0038] This disclosure also provides a pharmaceutical composition comprising the aforementioned crystal form A, B, C, D, or E, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0039] This disclosure also provides a pharmaceutical composition prepared from the aforementioned crystal form A, B, C, D, or E, and optionally a pharmaceutically acceptable excipient.

[0040] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystal form A, crystal form B, crystal form C, crystal form D or crystal form E with a pharmaceutically acceptable excipient.

[0041] This disclosure also provides the use of the aforementioned crystal form A, B, C, D, or E, or the aforementioned compositions, in the preparation for the prevention and / or treatment of pain and pain-related diseases.

[0042] The use described in this 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 pain from bunion removal surgery, hernia repair surgery, and abdominoplasty.

[0043] The "2θ or 2θ angle" mentioned in this 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 where the number has more than one decimal place after rounding), 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] The numerical values ​​in this disclosure, such as those relating to the content of certain substances, are calculated data and inevitably contain a certain degree of error. Generally, ±10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0045] The starting material used in the crystal form preparation method disclosed herein can be any form of compound, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.

[0046] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0047] The crystallization methods described in this disclosure include room temperature crystallization, cooling crystallization, solvent evaporation crystallization, and seed crystallization induction. The cooling temperature is selected from below 65°C, preferably from -10°C to 60°C. Stirring can also be performed during the crystallization process.

[0048] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0049] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guiding Principles on Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

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

[0051] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0052] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0053] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0054] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0055] The “excipients” described in this disclosure include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock. Attached Figure Description

[0056] Figure 1 The analgesic effect of compound 1 in a rat incision pain model is shown.

[0057] Figure 2 The effect of compound 1 on body weight in a rat incision pain model.

[0058] Figure 3 The image shows the XRPD spectrum of crystal form A of compound 1.

[0059] Figure 4 The image shows the XRPD spectrum of crystal form B of compound 1.

[0060] Figure 5 The image shows the XRPD spectrum of crystal form C of compound 1.

[0061] Figure 6 The image shows the XRPD spectrum of crystal form D of compound 1.

[0062] Figure 7 The image shows the XRPD spectrum of crystal form E of compound 1.

[0063] Figure 8 The image shows the XRPD spectrum of compound 1 in its amorphous form. Detailed Implementation

[0064] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

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

[0066] The structure of the compounds was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), or deuterated methanol (CD₃OD) as the solvents and tetramethylsilane (TMS) as the internal standard.

[0067] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole 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 was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0071] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0072] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0073] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0074] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

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

[0076] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0077] The average inhibition rate and IC50 value of the kinase were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0078] The known starting materials of this invention can be synthesized using or 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, all reactions can be carried out under an argon or nitrogen atmosphere.

[0080] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0081] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1L.

[0082] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0083] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0084] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

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

[0086] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

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

[0088] XRPD (X-ray Powder Diffraction) was used for analysis: measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data collected included: Cu anode (40 kV, 40 mA), Cu-Kα1 rays. Kα2 rays Kβ rays Scanning mode: θ / 2θ, scanning range (2θ range): 3°~45°.

[0089] DSC stands for Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10℃ / min. The specific temperature range was referenced from the corresponding spectra (mostly 25-300℃), and the nitrogen purging rate was 50mL / min.

[0090] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10℃ / min, and the specific temperature range was referenced from the corresponding spectrum (mostly 30-350℃). The nitrogen purging rate was 50mL / min.

[0091] DVS stands for Dynamic Moisture Adsorption: The detection method is SMSDVS Advantage. At 25℃, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%). (The specific humidity range is subject to the corresponding spectrum. The methods listed here are the most commonly used methods.) The judgment standard is that dm / dt is not greater than 0.002%.

[0092] Example 1 Preparation of Compound 1 (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-hydroxymethamidinyl)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 patent application "WO2021113627") was resolved by a chiral column (Waters SFC 150, column: DAICEL). IC, 40*250mm, 10μm; mobile phase A: supercritical CO2, mobile phase B: IPA), gradient ratio: A:B: 90:10, flow rate: 120mL / min) to obtain title products 1b-1 (5.5g, yield: 45.8%) and 1b-2 (5.08g, 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 min, purity: 99% (column: DAICEL) IC, 100*3mm, 3μm; Mobile phase A: supercritical CO2, Mobile phase B: IPA (0.1% DEA), Gradient ratio: Mobile phase A: 60%-95%, Flow rate: 1.5mL / 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 min, purity: 99% (column: DAICEL) IC, 100*3mm, 3μm; Mobile phase A: supercritical CO2, Mobile phase B: IPA (0.1% DEA), Gradient ratio: Mobile phase A: 60%-95%, Flow rate: 1.5mL / 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] Compound 1b-1 (50 mg, 141 μmol) was dissolved in dichloromethane (10 mL). Oxaloyl chloride (40 mg, 315 μmol) and 1 drop of N,N-dimethylformamide were added under ice bath conditions. The reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (3 mL). N,N-diisopropylethylamine (60 mg, 464 μmol) was added. A dichloromethane solution (1 mL) of 4-aminopyridine-2-carboxynitrile 1c (30 mg, 251 μmol, Shanghai Hanhong) was added dropwise under ice bath conditions. The reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using elution system B to give 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'-hydroxymethylamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0108] Compound 1d (200 mg, 439.2 μmol) was dissolved in methanol (4 mL), and hydroxylamine hydrochloride (61 mg, 877.8 μmol) and N,N-diisopropylethylamine (60 mg, 464.2 μmol) were added. The mixture was stirred for 1.5 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed successively with water and saturated sodium chloride solution. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using elution system A to give title compound 1 (160 mg, yield: 74.6%). X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum is shown below. Figure 8 .

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

[0110] 1H NMR (500MHz, CDCl3): δ8.61(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 disclosed compound against Nav1.8

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

[0113] 1. Experimental Materials and Instruments

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

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

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

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

[0118] 5) Glass microelectrode pulling instrument: 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 Procedure

[0123] 2.1 Compound Preparation

[0124] Except for NaOH and KOH used in acid-base titrations, all compounds used to prepare intracellular and extracellular solutions were purchased from Sigma (St. Louis, MO). The extracellular solution (mM) consisted of: NaCl, 137 g; KCl, 4 g; CaCl₂, 1.8 g; MgCl₂, 1 g; HEPES, 10 g; glucose, 10 g; pH 7.4 (NaOH titration). The intracellular solution (mM) consisted of: aspartic acid, 140 g; MgCl₂, 2 g; EGTA, 11 g; HEPES, 10 g; pH 7.2 (CsOH titration). All test and control solutions contained 1 μM TTX.

[0125] The test compound was stored at a concentration of 9 mM and dissolved in dimethyl sulfoxide (DMSO). It was then dissolved in extracellular fluid on the day of testing to prepare the required concentration.

[0126] 2.2 Manual Patch Clamp Test Procedure

[0127] 1) After the compound is prepared into a solution of a specified concentration, add the solution to each pipe in order of increasing concentration and label each pipe.

[0128] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, and bring the electrode tip into contact with the cell. Adjust the three-way valve of the suction device to the three-way position, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue to apply negative pressure to rupture the cell membrane and form a current pathway.

[0129] 3) After the cell membrane rupture current stabilizes, perform perfusion at different concentrations sequentially. If the current stabilizes for at least one minute, proceed to the next concentration. The perfusion time for each concentration should not exceed five minutes.

[0130] 4) Clean the perfusion tank. Rinse with the drug solution from high to low concentration, rinsing for 20 seconds for each concentration. Finally, rinse with extracellular fluid for 1 minute.

[0131] 2.3 Test Voltage Equation (resting) and Results

[0132] Cells were clamped at -80 mV and then depolarized to 10 mV using a square wave lasting 10 milliseconds to obtain the Nav1.8 current. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was detected, and after it stabilized, the test compound was perfused. Once the reaction stabilized, the strength of the blockade was calculated.

[0133] 3. Data Analysis

[0134] The data will be stored in a computer system for analysis. Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA), and the results will be reviewed by administrators. Current stability refers to the current changing within a finite range over time. The magnitude of the stable current is used to calculate the effect of the compound at that solubility.

[0135] The inhibitory activity of the disclosed compound against Nav1.8 was determined by the above experiments, and the measured IC50 values ​​were... 50 The values ​​are shown in Table 1.

[0136] Table 1. IC50 of the disclosed compounds on the inhibition of Nav1.8 channel activity. 50

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

[0138] Conclusion: The compounds disclosed herein 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 test animals, the plasma drug concentration at different time points after gavage (ig) administration of the compound of the present invention to SD rats was determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in SD rats was investigated to evaluate its pharmacokinetic characteristics.

[0142] 1.1 Test Plan

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

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

[0145] Dosage: The dosage is 2 mg / kg, and the administration volume is 10.0 mL / kg.

[0146] Operating method

[0147] Blood samples of 0.2 mL were collected from the orbital cavity 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. The samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 10,000 rpm for 1 minute (4°C). Plasma was separated within 1 hour and stored on dry ice for later analysis. The entire process, from blood collection to centrifugation, was performed under ice bath conditions. Patients ate 2 hours after administration.

[0148] Determine the content of the test compound 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 concentrations and high exposure in SD rats, showing obvious pharmacokinetic advantages.

[0153] II. Experiments on C57 mice

[0154] 2.1 Experimental animals

[0155] Eighteen C57 mice, with 9 males and 9 females, 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 colorless and clear solution of 0.1 mg / mL (gavage administration group) and a colorless and clear solution of 0.1 mg / mL (intravenous injection administration group).

[0158] 2.3 Administration

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

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

[0161] 2.4 Operations

[0162] In the gavage administration group: 0.1 mL of blood was collected from the orbital cavity 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. The blood samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 10,000 rpm for 1 minute (4℃), and the plasma was separated within 1 hour and stored at -80℃ for analysis. The blood collection and centrifugation process was performed under ice bath conditions.

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

[0164] Determination of the content of the target compound in the plasma of C57 mice after administration of different drug concentrations: Compound 1: Take 20 μL of plasma samples from C57 mice at each time point after drug administration. Add 200 μL of acetonitrile containing verapamil (internal standard 20 ng / mL) to each sample to precipitate the protein. Vortex mix for 5 minutes and centrifuge at 3700 rpm for 10 minutes. Take 90 μL of the supernatant, add 90 μL of water, vortex for 5 minutes, and inject 0.1 μL for LC / MS / MS analysis.

[0165] 2.5 Pharmacokinetic Parameter Results

[0166] Table 3. Pharmacokinetic parameters of the compounds disclosed herein

[0167]

[0168] Conclusion: The compound disclosed herein exhibits high blood concentrations, high exposure, low clearance, and high bioavailability in C57 mice, demonstrating pharmacokinetic advantages.

[0169] Test Example 3: Pharmacodynamic Test

[0170] 1. Experimental Objective

[0171] To evaluate the analgesic efficacy of the disclosed compound in inhibiting pain in a rat incision pain model.

[0172] 2. Experimental reagents

[0173] Compound of Example 1.

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

[0175] 3. Experimental methods and materials

[0176] 3.1 Laboratory animals and their housing conditions

[0177] Experimental animals: Sprague-Dawley (SD) rats, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (License number: SCXK(Zhe)2019-0001), with a body weight of approximately 180 g at the time of purchase.

[0178] Feeding conditions: Raised at 5 rats per cage, with a 12 / 12-hour light / dark cycle regulation, maintained at a constant temperature of 23 ± 1 °C, 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] Select 9 SD rats with a body weight of 170 - 190 g, and measure the mechanical pain threshold using an electronic tactile measuring instrument. Then, perform an incision pain surgery. During the surgery, after anesthesia with Zoletil (Zoletil-50, 250 mg, dissolved and diluted to 以50 ml with normal saline, and 2 ml injected for 2 body weight of 200 g), make a 1-cm long incision in the middle of the plantar surface of the left hind paw with a No. 10 surgical blade, penetrate through the skin and fascia, and suture the skin with 3-0 sterile silk surgical suture. Disinfect the injured area with penicillin, and return the animal to its original place for overnight recovery. After overnight recovery from the surgery, administer the drug by oral gavage. Measure the mechanical pain threshold using an electronic tactile measuring instrument 5 h after drug administration (about 24 h after the surgery).

[0186] 3.4 Data statistics

[0187] Use Excel statistical software to record data: The average value is calculated as avg; the SD value is calculated as STDEV; the SEM value is calculated as STDEV / SQRT(number of animals in each group); use GraphPad Prism software to plot graphs, and perform statistical analysis on the data using one-way ANOVA and t-test.

[0188] Percentage increase in threshold (%) = [(G t - G0) / G0] × 100 (%), where G t is the plantar pain threshold of the drug-administered group, and G0 is the plantar pain threshold of the vehicle group.

[0189] 4. Results

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

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

[0192]

[0193] Note: one dose means administer only once; ig means administer by gavage.

[0194] 5. Conclusion

[0195] The tenderness threshold of normal rats (weighing 170-190g) was 26.3±0.8gf, while that of the solvent control group was 10.4±0.9gf. The tenderness thresholds of the compound in Example 1 at 200, 100, and 30 mg / kg were 22.4, 22.3, and 12.0gf, respectively, significantly higher than the solvent control group by 114% (p<0.001), 114% (p<0.001), and 15%, respectively. The tenderness threshold at 200 mg / kg was comparable to that at 100 mg / kg, indicating saturation of the analgesic effect. The tenderness threshold at 100 mg / kg was significantly higher than that at 30 mg / kg (p<0.01), demonstrating a clear dose-dependent analgesic effect, and administration had no effect on rat body weight.

[0196] Example 2 Preparation of free crystal form A

[0197] 5 mg of the compound shown in Formula 1 was dissolved in 0.025 mL of methanol, stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified this product as crystal form A, and the XRPD spectrum is shown below. Figure 3 The positions of its characteristic peaks are shown in Table 6. The DSC spectrum shows that the endothermic peaks have peak values ​​of 86.74℃ and 169.89℃. The TGA spectrum shows a weight loss of 1.04% between 30℃ and 90℃.

[0198] Table 6

[0199]

[0200]

[0201] Example 3 Preparation of free crystal form A

[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 to crystallize, centrifuge, and dry the solid under vacuum to obtain the title product.

[0203] Example 4: Preparation of free crystal form B

[0204] 5 mg of the compound shown in Formula 1 was dissolved in 0.025 mL of ethanol, stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis identified the product as crystal form B, and the XRPD spectrum is shown below. Figure 4 The positions of its characteristic peaks are shown in Table 7. The DSC spectrum shows that the endothermic peak has a peak value of 169.95℃. The TGA spectrum shows that the weight loss is 0.27% from 30℃ to 180℃.

[0205] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample gained approximately 0.6% more weight due to moisture absorption; under accelerated testing conditions (i.e., 70% RH), the weight gain was approximately 0.8%; and under extreme conditions (90% RH), the weight gain was approximately 1.1%. Retesting of the crystal form after DVS testing showed no change in crystal form.

[0206] Table 7

[0207]

[0208]

[0209] Example 5: Preparation of free crystal form B

[0210] 5 mg of the compound shown in Formula 1 was dissolved in the solvent in Table 8, stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was crystal form B.

[0211] Table 8

[0212] solvent Crystal form 0.025 mL isopropanol Crystal form B 0.025 mL n-propanol Crystal form B 0.025 mL isopropyl acetate Crystal form B 0.025 mL 10% water / isopropanol 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 crystal form B

[0214] Add 5 mg of the compound shown in Formula 1 to 0.5 mL of solvent from Table 9, stir at room temperature to induce crystallization, centrifuge, and dry the solid under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product is crystal form B.

[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 crystal form B

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

[0219] Table 10

[0220]

[0221] Example 8: Preparation of Free Crystal Form B

[0222] 5 mg of the compound shown in Formula 1 was dissolved in 0.025 mL of solvent 1, and 0.5 mL of solvent 2 was added. Solvents 1 and 2 are listed in Table 11. The mixture was stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was 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] Example 9: 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 to crystallize, centrifuge, and dry the solid under vacuum to obtain the product.

[0227] X-ray powder diffraction analysis identified the product as crystal form C, and the XRPD spectrum is shown below. Figure 5 The positions of its characteristic peaks are shown in Table 12. The DSC spectrum shows that the endothermic peaks are at 57.96℃ and 120.27℃. The TGA spectrum shows a weight loss of 10.20% between 30℃ and 150℃.

[0228] Table 12

[0229]

[0230]

[0231] Example 10 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] X-ray powder diffraction analysis determined the product to be crystal form D. The XRPD spectrum is shown below. Figure 6 The positions of its characteristic peaks are shown in Table 13. The DSC spectrum shows that the endothermic peaks are at 90.74℃ and 123.72℃. The TGA spectrum shows a weight loss of 19.76% between 30℃ and 125℃, and a weight loss of 2.92% between 125℃ and 170℃.

[0234] Table 13

[0235]

[0236]

[0237] Example 11 Preparation of free crystal form E

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

[0239] X-ray powder diffraction analysis determined the product to be crystal form E. The XRPD spectrum is shown below. Figure 7 The positions of its characteristic peaks are shown in Table 14.

[0240] Table 14

[0241]

[0242] Example 9: Study on Crystal Form Stability

[0243] The free crystal form B was laid flat in the open, and the stability of the sample was investigated under high temperature (40℃ and 60℃), high humidity (RH 75% and RH 92.5%) and light (4500 lux) conditions. The sampling period was 30 days.

[0244] Table 15

[0245]

[0246]

[0247] Conclusion: The influencing factor experiment shows that the free crystalline form B has good physical and chemical stability for 30 days under the influencing factors of high temperature (40℃, 60℃), high humidity (75%RH, 92.5%RH) and light conditions.

[0248] II. Long-term accelerated experiment

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

[0250] The stability of free crystalline form B was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH.

[0251] Table 16

[0252]

[0253] Conclusion: Long-term accelerated experiments show that free crystalline form B exhibits good physical and chemical stability under conditions of 25℃ / 60%RH and 40℃ / 75%RH for 3 months.

Claims

1. A crystalline Form A of a compound of Formula 1, characterized by, X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q has characteristic peaks at 9.604, 14.327, 23.230, 26.325, 29.916, 2. The crystalline Form A of claim 1, characterized by, X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q has characteristic peaks at 9.604, 9.889, 11.538, 14.327, 19.238, 19.784, 20.852, 23.230, 26.325, 29.

916.

3. The crystalline Form A of claim 1, characterized by, X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q 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, 29.

916.

4. The crystalline Form A of claim 1, characterized by, X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q is shown in Figure 3.

5. A method for preparing the crystalline Form A of any one of claims 1-4, the method comprising the steps of dissolving the compound of Formula 1 in methanol or 10% water / methanol, and stirring.

6. A crystal form B of the compound shown in Formula 1, characterized in that, X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta angle, having characteristic peaks at 4.694, 10.150, 10.755, 13.119, 14.078, 7. The crystalline Form B of claim 6, characterized by, X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q 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, 32.

343.

8. The Form B of claim 6, characterized by an X-ray diffraction pattern substantially in accordance with Figure 18, X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q 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.

9. The Form B of claim 6, characterized by an X-ray diffraction pattern substantially in accordance with Figure 18, X-ray powder diffraction pattern expressed in terms of diffraction angle 2Q is shown in Figure 4.

10. A method for preparing the crystalline Form B of any one of claims 6-9, the method selected from any one of the following methods: Method one: dissolving the compound of Formula 1 in solvent I selected from one of ethanol, isopropanol, n-propanol, isopropyl acetate, 10% water / isopropanol, 7% water / ethanol, 50% ethyl acetate / n-heptane, and stirring to crystallize; Method two: adding the compound of Formula 1 to solvent II selected from one of water, n-heptane, 50% methanol / water, cyclohexane, isopropyl ether, and stirring to crystallize; Method three: dissolving the compound of Formula 1 in solvent III selected from one of methyl tert-butyl ether, acetone / isopropyl ether at a volume ratio of 1:40, tetrahydrofuran / isopropyl ether at a volume ratio of 1:40, methyl tert-butyl ether / isopropyl ether at a volume ratio of 1:40, ethyl acetate / isopropyl ether at a volume ratio of 1:40, and evaporating the solvent to crystallize. Method four: dissolving the compound of Formula 1 in solvent IV selected from one or more of acetone, ethyl acetate, acetonitrile, methyl tert-butyl ether, and adding solvent V selected from one or more of water, n-heptane, stirring and crystallizing.

11. A crystalline form C of a compound of Formula 1 : ###00010### Formula 1 characterized in that, X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta, having characteristic peaks at 10.060, 11.896, 13.738, 17.372, 19.829, 26.226, 12. The Form C of claim 11, characterized by: X-ray powder diffraction pattern in terms of diffraction angle 2Q 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.

13. The Form C of claim 11, characterized by: X-ray powder diffraction pattern in terms of diffraction angle 2Q 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.

14. The Form C of claim 11, characterized by: X-ray powder diffraction pattern in terms of diffraction angle 2Q is shown in Figure 5.

15. A method of preparing the crystalline Form C of any one of claims 11-14, comprising the steps of dissolving the compound of Formula 1 in dimethyl sulfoxide, adding water, and stirring.

16. The crystalline form of any one of claims 1-4, 6-9, 11-14, wherein the 2Q angle error range is ±0.

20.

17. A pharmaceutical composition comprising the crystalline form of any one of claims 1-4, 6-9, 11-14, and optionally a pharmaceutically acceptable excipient.

18. A method of preparing a pharmaceutical composition, comprising the step of mixing the crystalline form of any one of claims 1-4, 6-9, 11-14, and a pharmaceutically acceptable excipient.

19. Use of the crystalline form of any one of claims 1-4, 6-9, 11-14, or the pharmaceutical composition of claim 17, as a Nav1.8 inhibitor for the manufacture of a medicament for the treatment and / or prevention of pain and pain-related disorders.

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