Pharmaceutically acceptable salts of substituted tetrahydrofuran compounds, crystalline forms thereof, and uses thereof

Abstract

The present disclosure relates to a pharmaceutically acceptable salt of a substituted tetrahydrofuran compound, a crystalline form thereof and uses. Specifically, the present disclosure provides a pharmaceutically acceptable salt of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxyformamidino)pyridin-4-yl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formamide, a crystalline form thereof and a preparation method thereof, and the corresponding salt has good stability and can be better used for clinical treatment.

Description

Technical Field

[0001] This disclosure pertains to the field of pharmaceutical technology and relates to a pharmaceutically acceptable salt that replaces a tetrahydrofuran compound, its crystalline form, 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'-methoxymethamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, having the structure shown in Formula 1.

[0004]

[0005] Salt formation can improve some of the less desirable physicochemical or biological properties of drugs. Developing salts of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxyformamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide with superior physicochemical or pharmaceutical properties is of great significance. Given the importance of solid drug crystal forms and their stability in clinical treatment, in-depth research into the polymorphs of pharmaceutically acceptable salts of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxyformamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide is also crucial for developing drugs suitable for industrial production and possessing good biological activity. Summary of the Invention

[0006] This disclosure provides a pharmaceutically acceptable salt of the compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethylammonium)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, wherein the pharmaceutically acceptable salt is selected from sulfates, phosphates, L-tartrates, maleates, methanesulfonates, and p-toluenesulfonates.

[0007]

[0008] This disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of formula 1, comprising the step of reacting the compound of formula 1 with an acid selected from sulfuric acid, phosphoric acid, L-tartaric acid, maleic acid, methanesulfonic acid, and p-toluenesulfonic acid.

[0009] The solvents used in the salt formation of this disclosure are selected from, but are not limited to, acetone, acetonitrile / water, isopropanol, ethyl acetate, 4-methyl-2-pentanone, ethanol, and n-heptane.

[0010] Furthermore, in an optional embodiment, the method for preparing the aforementioned pharmaceutically usable salt also includes steps such as crystallization, filtration, washing, or drying.

[0011] In an optional embodiment, the chemical ratio of the compound of Formula 1 to the acid is 3:1 to 1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, and 1:3.

[0012] In another embodiment, the chemical ratio of the compound of Formula 1 to the acid is 2:1 to 1:2.

[0013] In an optional embodiment, the chemical ratio of the compound of Formula 1 to sulfuric acid is 1:1.

[0014] In an optional embodiment, the chemical ratio of the compound of Formula 1 to phosphoric acid is 1:1 or 1:2.

[0015] In an optional embodiment, the chemical ratio of the compound of Formula 1 to methanesulfonic acid is 1:1.

[0016] In an optional embodiment, the chemical ratio of the compound of Formula 1 to L-tartaric acid is 1:1.

[0017] In an optional embodiment, the chemical ratio of the compound of Formula 1 to p-toluenesulfonic acid is 1:1.

[0018] In an optional embodiment, the chemical ratio of the compound of Formula 1 to maleic acid is 1:1.

[0019] The sulfate crystal form I of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 7.218, 7.851, 16.936, 20.850, and 22.636 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0020] In some embodiments, the sulfate crystal form I of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 7.218, 7.851, 10.629, 13.366, 15.655, 16.936, 20.850, 22.636, 23.191, 24.749, and 25.449.

[0021] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 7.218, 7.851, 8.692, 10.629, 13.366, 15.655, 16.936, 20.850, 22.636, 23.191, 24.749, and 25.449.

[0022] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 3 As shown.

[0023] This disclosure also provides a method for preparing sulfate crystal form I of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethanol, adding a sulfuric acid ethanol solution, adding n-heptane, and stirring.

[0024] The sulfate crystal form Ⅱ of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.476, 15.814, 19.698, and 23.336 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0025] In some embodiments, the sulfate crystal form Ⅱ of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 6.108, 7.476, 8.937, 10.631, 12.269, 13.557, 15.814, 18.994, 19.698, and 23.336.

[0026] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form Ⅱ of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 4 As shown.

[0027] This disclosure also provides a method for preparing the sulfate crystal form Ⅱ of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding a sulfuric acid ethanol solution, adding n-heptane, and stirring.

[0028] The phosphate crystal form I of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.698, 10.704, 12.787, 17.041, and 18.373 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0029] In some embodiments, the phosphate crystal form I of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles 2θ, has characteristic peaks at 7.698, 10.704, 12.787, 17.041, 18.373, 19.312, 23.145, 25.926, and 27.345.

[0030] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 7.698, 10.244, 10.704, 12.787, 17.041, 18.373, 19.312, 19.852, 21.506, 22.237, 23.145, 24.113, 25.926, and 27.345.

[0031] In some embodiments, the X-ray powder diffraction pattern of the phosphate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 5 As shown.

[0032] This disclosure also provides a method for preparing phosphate crystal form I of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding a phosphoric acid ethanol solution, adding n-heptane, and stirring.

[0033] The methanesulfonate crystal form I of the compound of Formula 1 provided in this disclosure has characteristic peaks at 4.529, 8.919, 13.439, 18.015, and 27.791 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0034] In some embodiments, the methanesulfonate crystal form I of the compound shown in Formula 1 has characteristic peaks at 4.529, 8.919, 13.439, 18.015, 19.330, 21.038, 23.527, 24.143, and 27.791 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0035] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate crystal form I of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 6 As shown.

[0036] This disclosure also provides a method for preparing methanesulfonate crystal form I of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding a methanesulfonic acid ethanol solution, adding n-heptane, and stirring.

[0037] The methanesulfonate crystal form II of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.829, 9.821, 15.829, 16.796, and 24.122 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0038] In some embodiments, the methanesulfonate crystal form II of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has characteristic peaks at 7.829, 9.821, 11.826, 15.829, 16.796, 17.337, 19.867, 21.103, 22.976, 24.122, 26.427, and 27.381.

[0039] In some embodiments, the methanesulfonate crystal form II of the compound shown in Formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2θ, has characteristic peaks at 7.829, 9.821, 11.826, 15.829, 16.796, 17.337, 19.867, 21.103, 22.976, 24.122, 26.427, 27.381, 28.118, and 29.646.

[0040] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate form II of the compound shown in Formula 1, expressed in terms of the diffraction angle 2θ, is as follows: Figure 7 As shown.

[0041] This disclosure also provides a method for preparing the methanesulfonate crystal form II of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in acetone, adding a methanesulfonate ethanol solution, and evaporating the solvent.

[0042] The L-tartrate crystal form I of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 8.543, 15.499, 17.395, 19.016, and 21.812 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0043] In some embodiments, the X-ray powder diffraction pattern of the L-tartrate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 8.543, 9.487, 12.984, 14.924, 15.499, 17.395, 19.016, 20.711, 21.812, and 23.064.

[0044] In some embodiments, the X-ray powder diffraction pattern of the L-tartrate crystal form I of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 8.543, 9.487, 12.984, 14.924, 15.499, 17.395, 19.016, 20.711, 21.812, 23.064, 26.530, 27.612, 29.741, and 30.409.

[0045] In some embodiments, the X-ray powder diffraction pattern of the L-tartrate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is as follows: Figure 8 As shown.

[0046] This disclosure also provides a method for preparing L-tartrate crystal form I of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in acetone, adding an L-tartrate ethanol solution, adding n-heptane, and stirring.

[0047] The L-tartrate crystal form Ⅱ of the compound of Formula 1 provided in this disclosure has characteristic peaks at 4.383, 8.207, 16.523, 18.994, 20.709, and 25.202 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0048] In some embodiments, the X-ray powder diffraction pattern of the L-tartrate crystal form Ⅱ of the compound shown in Formula 1, expressed as a diffraction angle 2θ, has characteristic peaks at 4.383, 8.207, 9.359, 11.363, 16.523, 18.994, 20.709, 22.969, 25.202, and 28.851.

[0049] In some embodiments, the X-ray powder diffraction pattern of the L-tartrate crystal form Ⅱ of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is as follows: Figure 9 As shown.

[0050] This disclosure also provides a method for preparing L-tartrate crystal form Ⅱ of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding an L-tartrate ethanol solution, adding n-heptane, and stirring.

[0051] The p-toluenesulfonic acid crystal form I of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 6.975, 8.109, 12.126, 16.343, and 24.527 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0052] In some embodiments, the X-ray powder diffraction pattern of p-toluenesulfonic acid crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is as follows: Figure 10 As shown.

[0053] This disclosure also provides a method for preparing p-toluenesulfonic acid crystal form I of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding an ethanol solution of p-toluenesulfonic acid, adding n-heptane, and stirring.

[0054] The p-toluenesulfonic acid crystal form IⅠ of the compound shown in Formula 1 provided in this disclosure has characteristic peaks at 8.280, 10.954, 12.443, 16.687, and 24.000 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0055] In some embodiments, the p-toluenesulfonic acid crystal form ⅠⅠ of the compound shown in Formula 1 has characteristic peaks at 8.280, 10.954, 12.443, 13.992, 16.687, 22.969, 24.000, and 24.836 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0056] In some embodiments, the X-ray powder diffraction pattern of the p-toluenesulfonic acid crystal form IⅠ of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is as follows: Figure 11 As shown.

[0057] This disclosure also provides a method for preparing p-toluenesulfonic acid crystal form IⅠ of the compound of Formula 1, the method comprising heating p-toluenesulfonic acid crystal form I of the compound of Formula 1 to 173°C.

[0058] The maleate crystal form I of the compound of Formula 1 provided in this disclosure has characteristic peaks at 4.962, 12.518, 15.045, and 26.562 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0059] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form I of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is as follows: Figure 12 As shown.

[0060] This disclosure also provides a method for preparing maleate crystal form I of the compound shown in Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding a maleic acid ethanol solution, adding n-heptane, and stirring.

[0061] The maleate crystal form II of the compound of Formula 1 provided in this disclosure has characteristic peaks at 7.642, 11.426, 15.309, 16.991, 18.708, and 20.870 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2θ.

[0062] In some embodiments, the maleate crystal form II of the compound shown in Formula 1 has characteristic peaks at 7.642, 11.426, 15.309, 16.991, 18.708, 20.870, 22.078, and 23.605 in its X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

[0063] In some embodiments, the X-ray powder diffraction pattern of maleate crystal form II of the compound shown in Formula 1, expressed in terms of diffraction angle 2θ, is as follows: Figure 13 As shown.

[0064] This disclosure also provides a method for preparing maleate crystal form II of the compound shown in Formula 1, the method comprising heating maleate crystal form I of the compound shown in Formula 1 to 110°C.

[0065] This disclosure also provides a pharmaceutical composition comprising the aforementioned sulfate crystal form I, sulfate crystal form II, phosphate crystal form I, methanesulfonate crystal form I, methanesulfonate crystal form II, L-tartrate crystal form I, L-tartrate crystal form II, p-toluenesulfonic acid crystal form I, p-toluenesulfonic acid crystal form II, maleate crystal form I or maleate crystal form II, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0066] This disclosure also provides a pharmaceutical composition prepared from the aforementioned sulfate crystal form I, sulfate crystal form II, phosphate crystal form I, methanesulfonate crystal form I, methanesulfonate crystal form II, L-tartrate crystal form I, L-tartrate crystal form II, p-toluenesulfonic acid crystal form I, p-toluenesulfonic acid crystal form II, maleate crystal form I or maleate crystal form II, and optionally a pharmaceutically acceptable excipient.

[0067] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned sulfate crystal form I, sulfate crystal form II, phosphate crystal form I, methanesulfonate crystal form I, methanesulfonate crystal form II, L-tartrate crystal form I, L-tartrate crystal form II, p-toluenesulfonic acid crystal form I, p-toluenesulfonic acid crystal form II, maleate crystal form I, or maleate crystal form II with a pharmaceutically acceptable excipient.

[0068] This disclosure also provides the use of the aforementioned sulfate crystal form I, sulfate crystal form II, phosphate crystal form I, methanesulfonate crystal form I, methanesulfonate crystal form II, L-tartrate crystal form I, L-tartrate crystal form II, p-toluenesulfonic acid crystal form I, p-toluenesulfonic acid crystal form II, maleate crystal form I or maleate crystal form II, or the aforementioned compositions, in the preparation for the prevention and / or treatment of pain and pain-related diseases.

[0069] 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.

[0070] 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.

[0071] 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%.

[0072] 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.

[0073] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0074] 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.

[0075] 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.

[0076] 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,

[0077] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0078] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0079] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0080] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0081] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0082] 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

[0083] Figure 1 The analgesic effect of compound 1 in a rat incision pain model is shown.

[0084] Figure 2 The effect of compound 1 on body weight in a rat incision pain model.

[0085] Figure 3 The image shows the XRPD spectrum of compound 1 sulfate crystal form I.

[0086] Figure 4 The image shows the XRPD spectrum of compound 1 sulfate crystal form II.

[0087] Figure 5 The image shows the XRPD spectrum of phosphate form I of compound 1.

[0088] Figure 6 The image shows the XRPD spectrum of compound 1 methanesulfonate crystal form I.

[0089] Figure 7 The image shows the XRPD spectrum of compound 1 methanesulfonate crystal form II.

[0090] Figure 8 The image shows the XRPD spectrum of compound 1L-tartrate crystal form I.

[0091] Figure 9 The image shows the XRPD spectrum of compound 1L-tartrate crystal form Ⅱ.

[0092] Figure 10 The image shows the XRPD spectrum of compound 1, p-toluenesulfonic acid, crystal form I.

[0093] Figure 11 The image shows the XRPD spectrum of compound 1, p-toluenesulfonic acid, crystal form Ⅱ.

[0094] Figure 12 The image shows the XRPD spectrum of maleate form I of compound 1.

[0095] Figure 13 The image shows the XRPD spectrum of maleate form II of compound 1. Detailed Implementation

[0096] 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.

[0097] Test conditions of the instruments used in the experiment:

[0098] 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.

[0099] 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).

[0100] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetec-tor / waters SQ Detector)

[0101] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO QExactive)

[0102] 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.

[0103] Chiral HPLC analysis was performed using an Agilent 1260DAD high-performance liquid chromatograph.

[0104] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0105] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0106] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0107] 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.

[0108] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0109] The average inhibition rate and IC50 value of the kinase were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0110] 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.

[0111] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0112] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0113] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0114] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0115] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0116] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0117] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0118] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0119] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used 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.

[0120] 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): 5°~45°.

[0121] 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 25-270℃), and the nitrogen purging rate was 50mL / min.

[0122] 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.

[0123] DVS stands for Dynamic Moisture Adsorption: The detection method is SMSDVS Advantage, with humidity changing from 50% to 95% to 0% to 95% to 50% at 25℃, in 10% increments (the final step is 5%) (the specific humidity range is subject to the corresponding spectrum; the methods listed here are the most commonly used). The judgment criteria are Tmax 360min and dm / dt not greater than 0.002%.

[0124] Example 1: Preparation of Compound 1

[0125] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethylammonium)pyridin-4-yl)-4,5-dimethyl

[0126] -5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0127]

[0128] first step

[0129] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-1

[0130] (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-2

[0131] 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%).

[0132] MS m / z(ESI): 353.2 [M-1].

[0133] Single-configuration compound (shorter retention time) 1b-1 (5.5 g, yield: 45.8%)

[0134] MS m / z(ESI): 353.2 [M-1].

[0135] 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).

[0136] Single-configuration compound (longer retention time) 1b-2 (5.08 g, yield: 42.3%).

[0137] MS m / z(ESI): 353.2 [M-1].

[0138] 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).

[0139] 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

[0140] 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%).

[0141] MS m / z(ESI):456.2[M+1].

[0142] Step 3

[0143] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethylammonium)pyridin-4-yl)-4,5-dimethyl

[0144] -5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0145] Compound 1d (100 mg, 219.6 μmol) was dissolved in 10 mL of isopropanol, and N,N-diisopropylethylamine (85.1 mg, 658.8 μmol), mercaptoacetic acid (40.5 mg, 439 μmol, Shanghai Bide), and methoxyamine hydrochloride (55 mg, 658.8 μmol) were added. The mixture was reacted at 80 °C for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to give title compound 1 (10 mg, yield: 18%).

[0146] MS m / z(ESI): 503.2 [M+1].

[0147] 1H NMR (500MHz, DMSO-d6): δ10.69(s,1H),8.44(d,1H),8.11(d,1H),7.72(dd,1H),7.18(dt,2H),6.07(s,1H) ,5.09(d,1H),4.25(dd,1H),3.96(d,3H),3.79(d,3H),2.78(t,1H),2.01(q,1H),1.61(s,3H),0.73(d,3H).

[0148] Test Example 1: Determination of the inhibitory activity of the disclosed compound against Nav1.8

[0149] 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.

[0150] 1. Experimental Materials and Instruments

[0151] 1) Patch clamp amplifier: PC-505B (WARNER instruments) / MultiClamp700A (Axon instruments)

[0152] 2) Digital-to-analog converters: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon Instruments)

[0153] 3) Microcontroller: MP-225 (SUTTER instrument)

[0154] 4) Inverted microscope: TL4 (Olympus)

[0155] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0156] 6) Microelectrode glass capillary: B12024F (Wuhan Microprobe Scientific Instruments Co., Ltd.)

[0157] 7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

[0158] 8)TTX AF3014 (Affix Scientific)

[0159] 2 Experimental Procedure

[0160] 2.1 Compound Preparation

[0161] 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.

[0162] 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.

[0163] 2.2 Manual Patch Clamp Test Procedure

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 2.3 Test Voltage Equation (resting) and Results

[0169] 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.

[0170] 3. Data Analysis

[0171] 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.

[0172] 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.

[0173] Table 1. IC50 of the disclosed compounds on the inhibition of Nav1.8 channel activity. 50

[0174] Example number <![CDATA[IC 50 (nM)]]> 1 0.33

[0175] Conclusion: The compounds disclosed herein have a significant inhibitory effect on Nav1.8 channel activity.

[0176] Test Example 2: Pharmacokinetic Evaluation

[0177] I. SD Rat Experiment

[0178] 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.

[0179] 1.1 Test Plan

[0180] 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.

[0181] 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.

[0182] Dosage: The dosage is 2 mg / kg, and the administration volume is 10.0 mL / kg.

[0183] Operating method

[0184] 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.

[0185] 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.

[0186] 1.2 Results of pharmacokinetic parameters

[0187] Table 2. Pharmacokinetic parameters of the compounds of the present disclosure

[0188]

[0189] Conclusion: The compounds of the present disclosure have high blood drug concentrations and high exposure levels in SD rats, showing obvious pharmacokinetic advantages.

[0190] II. Experiments on C57 mice

[0191] 2.1 Experimental animals

[0192] Eighteen 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.

[0193] 2.2 Drug preparation

[0194] 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).

[0195] 2.3 Administration

[0196] Gavage administration group: The administration dose is 2.0 mg / kg, and the administration volume is 20 mL / kg.

[0197] Intravenous injection administration group: The administration dose is 1.0 mg / kg, and the administration volume is 10 mL / kg.

[0198] 2.4 Operations

[0199] 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.

[0200] 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.

[0201] 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 100 ng / ml camptothecin (internal standard) to each sample to precipitate the protein. Vortex mix for 5 minutes and centrifuge at 3700 rpm for 10 minutes. Take 50 μL of the supernatant, add 100 μL of water, vortex for 5 minutes, and inject 1 μL for LC / MS / MS analysis.

[0202] 2.5 Pharmacokinetic Parameter Results

[0203] Table 3. Pharmacokinetic parameters of the compounds disclosed herein

[0204]

[0205] Conclusion: The compound disclosed herein exhibits high blood concentrations, high exposure, low clearance, and high bioavailability in C57 mice, demonstrating pharmacokinetic advantages.

[0206] Test Example 3: Pharmacodynamic Test

[0207] 1. Experimental Objective

[0208] To evaluate the analgesic efficacy of the disclosed compound in inhibiting pain in a rat incision pain model.

[0209] 2. Experimental reagents

[0210] Compound of Example 1.

[0211] A 25% PEG400 + 75% (10% TPGS + 1% HPMC K100LV) solution was used.

[0212] 3. Experimental methods and materials

[0213] 3.1 Laboratory animals and their housing conditions

[0214] 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.

[0215] Feeding conditions: Raised at 5 rats per cage, with a 12 / 12-hour light / dark cycle regulation, a constant temperature of 23 ± 1°C, a humidity of 50 to 60%, and free access to food and water.

[0216] 3.2 Animal grouping

[0217] After the SD rats were adaptively raised, the grouping was as follows:

[0218] Table 4

[0219]

[0220] Note: one dose means administering the drug only once; i.g. means intragastric administration.

[0221] 3.3 Experimental method:

[0222] Select 9 SD rats with a body weight of 170 - 190 g, and use an electronic tactile measuring instrument to measure the mechanical pain threshold. Then perform an incision pain surgery. During the surgery, after anesthesia with Zoletil (Zoletil-50, 250 mg, diluted to 50 ml with normal saline after dissolution, and 2 ml is injected for a 200 g body weight), 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 with an electronic tactile measuring instrument 5 h after the drug administration (about 24 h after the surgery).

[0223] 3.4 Data statistics

[0224] Use Excel statistical software to record the 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 the graph, and perform statistical analysis on the data using one-way ANOVA and t-test.

[0225] Percentage increase in threshold (%) = [(G t - G0) / G0] × 100 (%), where G t is the plantar pain threshold of the drug administration group, and G0 is the plantar pain threshold of the vehicle group.

[0226] 4. Results

[0227] The analgesic efficacy of the compound in Example 1 in the rat incision pain model is as Figure 1As shown in Table 5, the effect of body weight is... Figure 2 ;

[0228] Table 5. Analgesic efficacy of the disclosed compounds in a rat model of incision pain.

[0229]

[0230] Note: one dose means administer only once; ig means administer by gavage.

[0231] 5. Conclusion

[0232] The tenderness threshold of normal rats (weighing 170-190g) was 26.2±1.6gf, while that of the solvent control group was 10.0±0.7gf. The tenderness thresholds of the compound in Example 1 at 200, 100, and 50 mg / kg were 22.3, 14.9, and 10.8gf, respectively, significantly higher than those in the solvent control group by 122% (p<0.001), 49% (p<0.05), and 7%, respectively. The tenderness threshold at 200 mg / kg was significantly higher than that at 100 mg / kg (p<0.01), and the tenderness threshold at 100 mg / kg was significantly higher than that at 50 mg / kg (p<0.05), indicating a clear dose-dependent analgesic effect. Furthermore, administration had no effect on the rat's body weight.

[0233] Example 2: Preparation of Sulfate Crystal Form I

[0234] 7 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of ethanol, 7.4 μL of 2M sulfuric acid ethanol solution was added, 0.3 mL of n-heptane was added, the mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0235] X-ray powder diffraction analysis identified the product as sulfate crystal form I. The XRPD spectrum is shown below. Figure 3 The positions of its characteristic peaks are shown in Table 6. Ion chromatography analysis revealed a sulfate ion content of 17.3%. DSC chromatograms showed endothermic peaks at 58.15℃, 123.47℃, and 170.80℃. TGA chromatograms showed a weight loss of 1.79% from 30℃ to 100℃.

[0236] Table 6

[0237]

[0238]

[0239] Example 3: Preparation of Sulfate Crystal Form II

[0240] 7 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of ethyl acetate, 7.4 μL of 2M sulfuric acid ethanol solution was added, 0.3 mL of n-heptane was added, the mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0241] X-ray powder diffraction analysis identified the product as sulfate crystal form IⅠ, 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 108.14℃. The TGA spectrum shows that the weight loss is 0.41% from 30℃ to 140℃.

[0242] Table 7

[0243]

[0244] Example 4: Preparation of Phosphate Crystal Form I

[0245] 7 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of ethyl acetate, 7.4 μL of 2 M phosphate ethanol solution was added, and 0.3 mL of n-heptane was added. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0246] X-ray powder diffraction analysis identified the product as phosphate crystal form I, and the XRPD spectrum is shown below. Figure 5 The positions of its characteristic peaks are shown in Table 8. Ion chromatography analysis revealed a phosphate ion content of 22.8%. DSC chromatograms showed endothermic peaks at 39.48℃, 67.46℃, 85.46℃, 94.78℃, and 138.94℃. TGA chromatograms showed a weight loss of 2.78% between 30℃ and 120℃.

[0247] Table 8

[0248]

[0249] Example 5: Preparation of Methanesulfonate Crystal Form I

[0250] 100 mg of the compound shown in Formula 1 was dissolved in 1 mL of ethyl acetate, 95.0 μL of 2 M methanesulfonic acid ethanol solution was added, 3 mL of n-heptane was added, the mixture was stirred to induce crystallization, filtered under reduced pressure, and the solid was collected and dried under vacuum to obtain the product.

[0251] X-ray powder diffraction analysis identified the product as methanesulfonate crystal form I, and the XRPD spectrum is shown below. Figure 6 The positions of its characteristic peaks are shown in Table 9. Ion chromatography analysis revealed a methanesulfonate ion content of 17.6%. The DSC spectrum showed an endothermic peak at 195.03℃. The TGA spectrum showed no significant weight loss.

[0252] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 0.99%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 1.62%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 4.75%. Furthermore, retesting of the crystal form after DVS testing showed no change in crystal form.

[0253] Table 9

[0254]

[0255]

[0256] Example 6 Preparation of Methanesulfonate Crystal Form II

[0257] 7 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of acetone, followed by the addition of 7.4 μL of 2M methanesulfonic acid ethanol solution. The mixture was then evaporated to obtain the product. X-ray powder diffraction analysis identified the product as methanesulfonate crystal form II. The XRPD spectrum is shown below. Figure 7 The positions of its characteristic peaks are shown in Table 10. Ion chromatography analysis revealed a methanesulfonate ion content of 20.0%. DSC chromatograms showed endothermic peaks at 83.44℃, 148.77℃, and 186.07℃. TGA chromatograms showed a weight loss of 4.36% between 30℃ and 120℃.

[0258] Table 10

[0259]

[0260]

[0261] Example 7: Preparation of L-tartrate crystal form I

[0262] 7 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of acetone, 7.4 μL of 2 M L-tartaric acid ethanol solution was added, 0.3 mL of n-heptane was added, the mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0263] X-ray powder diffraction analysis identified the product as L-tartrate crystal form I, and the XRPD spectrum is shown below. Figure 8 The positions of its characteristic peaks are shown in Table 11. Ion chromatography analysis revealed that its L-tartrate ion content was 29.8%. DSC chromatograms showed endothermic peaks at 70.48℃ and 150.79℃. TGA chromatograms showed a weight loss of 1.78% from 30℃ to 100℃.

[0264] Table 11

[0265]

[0266] Example 8: Preparation of L-tartrate crystal form Ⅱ

[0267] 120 mg of the compound shown in Formula 1 was dissolved in 1 mL of ethyl acetate, followed by 115.0 μL of 2 M L-tartaric acid ethanol solution, and 5 mL of n-heptane. The mixture was stirred to induce crystallization, filtered under reduced pressure, and the solid was collected and dried under vacuum to obtain the product.

[0268] X-ray powder diffraction analysis identified the product as L-tartrate crystal form IⅠ, and the XRPD spectrum is shown below. Figure 9 The positions of its characteristic peaks are shown in Table 12. Ion chromatography analysis revealed that its L-tartrate ion content was 24.3%. The DSC spectrum showed an endothermic peak at 156.90℃. The TGA spectrum showed a weight loss of 0.24% from 30℃ to 100℃.

[0269] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 1.98%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 3.37%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 13.42%. Furthermore, retesting of the crystal form after DVS testing revealed that the crystal transformed into L-tartrate crystal form I.

[0270] Table 12

[0271]

[0272] Example 9: Preparation of p-Toluenesulfonic Acid Crystal Form I

[0273] 120 mg of the compound shown in Formula 1 was dissolved in 1 mL of ethyl acetate, 115.0 μL of 2 M p-toluenesulfonic acid ethanol solution was added, 3 mL of n-heptane was added, the mixture was stirred to induce crystallization, filtered under reduced pressure, and the solid was collected and dried under vacuum to obtain the product.

[0274] X-ray powder diffraction analysis identified the product as p-toluenesulfonate crystal form I, and the XRPD spectrum is shown below. Figure 10 The positions of its characteristic peaks are shown in Table 13. Ion chromatography analysis revealed a p-toluenesulfonate ion content of 26.9%. DSC chromatograms showed endothermic peaks at 170.08℃ and 176.29℃. TGA chromatograms showed no significant weight loss.

[0275] DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample's moisture absorption weight gain was approximately 0.28%; under accelerated testing conditions (i.e., 70% RH), the moisture absorption weight gain was approximately 0.38%; and under extreme conditions (90% RH), the moisture absorption weight gain was approximately 0.66%. Furthermore, retesting of the crystal form after DVS testing showed no change in crystal form.

[0276] Table 13

[0277]

[0278] Example 10: Preparation of p-Toluenesulfonic Acid Crystal Form IⅠ

[0279] The compound shown in Formula 1, p-toluenesulfonate crystal form I, was heated to 173 °C to obtain the product.

[0280] X-ray powder diffraction analysis identified the product as p-toluenesulfonate crystal form II. The XRPD spectrum is shown below. Figure 11 The positions of its characteristic peaks are shown in Table 14. The DSC spectrum shows that the endothermic peak has a peak value of 177.48℃. The TGA spectrum shows that the weight loss is 1.68% from 30℃ to 140℃.

[0281] Table 14

[0282]

[0283] Example 11 Preparation of maleate crystal form I

[0284] 7 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of ethyl acetate, 14.7 μL of 2M maleic acid ethanol solution was added, and 0.3 mL of n-heptane was added. The mixture was stirred to induce crystallization, centrifuged, and the solid was collected and dried under vacuum to obtain the product.

[0285] X-ray powder diffraction analysis identified the product as maleate crystal form I, and the XRPD spectrum is shown below. Figure 12 The positions of its characteristic peaks are shown in Table 15. NMR analysis showed that the molar ratio of compound 1 to maleate was 1:1. DSC spectra showed endothermic peaks at 103.47℃ and 118.63℃. TGA spectra showed a weight loss of 0.83% between 30℃ and 120℃.

[0286] Table 15

[0287]

[0288] Example 12 Preparation of maleate crystal form II

[0289] The maleate crystal form I of the compound shown in Formula 1 was heated to 110°C to obtain the product.

[0290] X-ray powder diffraction analysis identified the product as maleate crystal form II, and the XRPD spectrum is shown below. Figure 13 The positions of its characteristic peaks are shown in Table 16. The DSC spectrum shows that the endothermic peak has a peak value of 119.81℃. The TGA spectrum shows that the weight loss is 1.71% from 30℃ to 100℃.

[0291] Table 16

[0292]

[0293] Example 13 Stability Study of Influencing Factors

[0294] The methanesulfonate crystal form I and p-toluenesulfonate crystal form I were laid out flat in the open, and the stability of the samples was investigated under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions. The sampling period was 1 month.

[0295] Table 17 Factors Affecting the Stability of Methanesulfonate Crystal Form I

[0296]

[0297]

[0298] Conclusion: Methanesulfonate crystal form I exhibits good physicochemical stability under the influence of various factors.

[0299] Table 18 Factors affecting the stability of p-toluenesulfonate crystal form I

[0300]

[0301] Conclusion: p-Toluenesulfonate crystal form I is stable under high humidity and light conditions, but its chemical purity decreases under high temperature conditions.

[0302] Example 14 Long-term / Accelerated Stability

[0303] The stability of methanesulfonate crystal form I and p-toluenesulfonate crystal form I was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH, respectively.

[0304] Table 19 Long-term / Accelerated Stability of Methanesulfonate Crystal Form I

[0305]

[0306] Conclusion: Methanesulfonate crystal form I exhibits good physical and chemical stability under long-term accelerated conditions.

[0307] Table 20 Long-term / Accelerated Stability of p-Toluenesulfonate Crystal Form I

[0308]

[0309] Conclusion: p-Toluenesulfonate crystal form I exhibits good physical and chemical stability under long-term accelerated conditions.

Claims

1. A pharmaceutically acceptable salt of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethylammonium)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide of Formula 1, wherein the pharmaceutically acceptable salt is selected from sulfates, phosphates, L-tartrates, maleates, methanesulfonates, and p-toluenesulfonates.

2. The medicinal salt according to claim 1, characterized in that, The chemical ratio of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide to acid is 3:1 to 1:

3.

3. The medicinal salt according to claim 2, characterized in that, The chemical ratio of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide to the acid is 2:1 to 1:

2.

4. The medicinal salt according to claim 3, characterized in that, The chemical ratio of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide to the acid is 1:

1.

5. The medicinal salt according to claim 3, characterized in that, The chemical ratio of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymethamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide to the acid is 1:

2.

6. The method for preparing a pharmaceutically acceptable salt according to any one of claims 1-5, comprising the step of reacting the compound of formula 1 with an acid, wherein the acid is selected from sulfuric acid, phosphoric acid, L-tartaric acid, maleic acid, methanesulfonic acid, and p-toluenesulfonic acid.

7. A methanesulfonate crystal form I of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 4.529, 8.919, 13.439, 18.015, and 27.

791.

8. The methanesulfonate crystal form I according to claim 7, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 4.529, 8.919, 13.439, 18.015, 19.330, 21.038, 23.527, 24.143, and 27.

791.

9. The methanesulfonate crystal form I according to claim 7, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 6.

10. A method for preparing methanesulfonate crystal form I according to any one of claims 7-9, the method comprising the steps of dissolving the compound of formula 1 in ethyl acetate, adding a methanesulfonic acid ethanol solution, adding n-heptane, and stirring.

11. A p-toluenesulfonic acid crystal form I of the compound shown in Formula 1, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 6.975, 8.109, 12.126, 16.343, and 24.

527.

12. The p-toluenesulfonic acid crystal form I according to claim 11, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 10.

13. A method for preparing p-toluenesulfonic acid crystal form I as described in claim 11 or 12, the method comprising the steps of dissolving the compound of formula 1 in ethyl acetate, adding a p-toluenesulfonic acid ethanol solution, adding n-heptane, and stirring.

14. The crystal form according to any one of claims 7-9 and 11-12, wherein the 2θ angle error range is ±0.

20.

15. A pharmaceutical composition comprising a pharmaceutically acceptable salt of a compound of formula 1 according to any one of claims 1-5, or a crystal form according to any one of claims 7-9, 11-12, and optionally a pharmaceutically acceptable excipient.

16. A method for preparing a pharmaceutical composition, comprising the following steps: The step of mixing a pharmaceutically acceptable salt of the compound of formula 1 according to any one of claims 1-5, or the crystal form according to any one of claims 7-9, 11-12, with a pharmaceutically acceptable excipient.

17. Use of a pharmaceutically acceptable salt of the compound of formula 1 according to any one of claims 1-5, or the crystal form according to any one of claims 7-9, 11-12, or the pharmaceutical composition according to claim 15 in the preparation of a Nav1.8 inhibitor.

18. Use of a pharmaceutically acceptable salt of the compound of formula 1 according to any one of claims 1-5, or the crystal form according to any one of claims 7-9, 11-12, or the pharmaceutical composition according to claim 15 as a Nav1.8 inhibitor in the preparation of a medicament for the treatment and / or prevention of pain and pain-related diseases.

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