Medicinal salt of substituted tetrahydrofuran compound, and crystal form and application thereof

Abstract

The present disclosure relates to a pharmaceutically acceptable salt of a substituted tetrahydrofuran compound, a crystalline form and use thereof. Specifically, the invention provides pharmaceutically acceptable salts of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N '-methoxyformamidino) pyridine-4-yl)-4, 5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2-carboxamide, crystal forms and preparation methods thereof, and the corresponding salts have good stability and can be better used for clinical treatment.

Description

Technical Field

[0001] The present disclosure belongs to the technical field of medicine, and relates to a pharmaceutically acceptable salt of a substituted tetrahydrofuran compound, its crystalline form and uses. Background Art

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

[0003] PCT / CN2023 / 114740 provides a Nav1.8 inhibitor, whose chemical name is (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxymidamidyl)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 undesirable physicochemical or biological properties of drugs. It is of great significance to develop salts with more excellent properties in terms of physicochemical properties or pharmaceutical properties compared to (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. Given the importance of solid drug crystal forms and their stability in clinical treatment, it is also of great significance to deeply study the polymorphs of the pharmaceutically acceptable salts of the compound (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 for the development of drugs suitable for industrial production and having good biological activity. Summary of the Invention

[0006] The present disclosure provides a pharmaceutically acceptable salt of the compound (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 shown in Formula 1, and the pharmaceutically acceptable salt is selected from sulfate, phosphate, L-tartrate, maleate, mesylate, p-toluenesulfonate.

[0007]

[0008] The present disclosure also provides a preparation method of a pharmaceutically acceptable salt of the compound of Formula 1, including the step of reacting the compound of Formula 1 with an acid, and the acid is selected from sulfuric acid, phosphoric acid, L-tartaric acid, maleic acid, mesylic acid, p-toluenesulfonic acid.

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

[0010] Further, in an alternative embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt further includes steps such as crystallization, filtration, washing or drying.

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

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

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

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

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

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

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

[0018] In an alternative 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 of Formula 1 provided by the present disclosure has characteristic peaks at 7.218, 7.851, 16.936, 20.850, and 22.636 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0020] In some embodiments, the sulfate crystal form I of the compound of Formula 1 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 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0021] In some embodiments, the sulfate crystal form I of the compound of Formula 1 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 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

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

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

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

[0025] In some embodiments, for sulfate crystal form II of the compound represented by Formula 1, the X-ray powder diffraction pattern in terms of diffraction angle 2θ has characteristic peaks at 6.108, 7.476, 8.937, 10.631, 12.269, 13.557, 15.814, 18.994, 19.698, 23.336.

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

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

[0028] For phosphate crystal form I of the compound represented by Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern in terms of diffraction angle 2θ has characteristic peaks at 7.698, 10.704, 12.787, 17.041, 18.373.

[0029] In some embodiments, for phosphate crystal form I of the compound represented by Formula 1, the X-ray powder diffraction pattern in terms of diffraction angle 2θ has characteristic peaks at 7.698, 10.704, 12.787, 17.041, 18.373, 19.312, 23.145, 25.926, 27.345.

[0030] In some embodiments, for phosphate crystal form I of the compound represented by Formula 1, the X-ray powder diffraction pattern in terms of 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, 27.345.

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

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

[0033] The mesylate crystal form I of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 4.529, 8.919, 13.439, 18.015, and 27.791 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0034] In some embodiments, the mesylate crystal form I of the compound represented by 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 the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

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

[0036] The present disclosure also provides a method for preparing the mesylate crystal form I of the compound represented by Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding an ethanol solution of methanesulfonic acid, and then adding n-heptane and stirring.

[0037] The mesylate crystal form II of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 7.829, 9.821, 15.829, 16.796, and 24.122 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0038] In some embodiments, the mesylate crystal form II of the compound represented by Formula 1 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 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0039] In some embodiments, the mesylate crystal form II of the compound represented by Formula 1 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 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

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

[0041] The present 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 an ethanolic solution of methanesulfonic acid, and evaporating the solvent.

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

[0043] In some embodiments, for the L-tartrate crystal form I of the compound shown in Formula 1, the X-ray powder diffraction pattern expressed in terms of 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, for the L-tartrate crystal form I of the compound shown in Formula 1, the X-ray powder diffraction pattern expressed in terms of 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, for the L-tartrate crystal form I of the compound shown in Formula 1, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is as Figure 8 shown.

[0046] The present disclosure also provides a method for preparing the 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 ethanolic solution of L-tartaric acid, and then adding n-heptane and stirring.

[0047] For the L-tartrate crystal form II of the compound shown in Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ has characteristic peaks at 4.383, 8.207, 16.523, 18.994, 20.709, and 25.202.

[0048] In some embodiments, for the L-tartrate crystal form II of the compound shown in Formula 1, the X-ray powder diffraction pattern expressed in terms of 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 L-tartrate crystal form II of the compound shown in Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as follows Figure 9 as shown.

[0050] The present disclosure also provides a method for preparing the 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 ethanol solution of L-tartaric acid, and then adding n-heptane and stirring.

[0051] The p-toluenesulfonate crystal form I of the compound shown in Formula 1 provided by the present disclosure has characteristic peaks at 6.975, 8.109, 12.126, 16.343, and 24.527 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

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

[0053] The present disclosure also provides a method for preparing the p-toluenesulfonate 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, and then adding n-heptane and stirring.

[0054] The p-toluenesulfonate crystal form II of the compound shown in Formula 1 provided by the present disclosure has characteristic peaks at 8.280, 10.954, 12.443, 16.687, and 24.000 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0055] In some embodiments, the p-toluenesulfonate 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 the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

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

[0057] The present disclosure also provides a method for preparing the p-toluenesulfonate crystal form II of the compound shown in Formula 1, the method comprising the step of heating the p-toluenesulfonate crystal form I of the compound of Formula 1 to 173 °C.

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

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

[0060] The present disclosure also provides a method for preparing the maleate polymorph I of the compound represented by Formula 1, the method comprising the steps of dissolving the compound of Formula 1 in ethyl acetate, adding an ethanol solution of maleic acid, and then adding n-heptane, and stirring.

[0061] The X-ray powder diffraction pattern of the maleate polymorph II of the compound represented by Formula 1 provided by the present disclosure, expressed in terms of diffraction angle 2θ, has characteristic peaks at 7.642, 11.426, 15.309, 16.991, 18.708, 20.870.

[0062] In some embodiments, the X-ray powder diffraction pattern of the maleate polymorph II of the compound represented by Formula 1, expressed in terms of diffraction angle 2θ, has characteristic peaks at 7.642, 11.426, 15.309, 16.991, 18.708, 20.870, 22.078, 23.605.

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

[0064] The present disclosure also provides a method for preparing the maleate polymorph II of the compound represented by Formula 1, the method comprising the step of heating the maleate polymorph I of the compound represented by Formula 1 to 110 °C.

[0065] The present disclosure also provides a pharmaceutical composition, which contains the aforementioned sulfate polymorph I, sulfate polymorph II, phosphate polymorph I, mesylate polymorph I, mesylate polymorph II, L-tartrate polymorph I, L-tartrate polymorph II, p-toluenesulfonate polymorph I, p-toluenesulfonate polymorph II, maleate polymorph I or maleate polymorph II, and a pharmaceutical excipient optionally selected from pharmaceutically acceptable excipients.

[0066] The present disclosure also provides a pharmaceutical composition, which is prepared from the aforementioned sulfate polymorph I, sulfate polymorph II, phosphate polymorph I, mesylate polymorph I, mesylate polymorph II, L-tartrate polymorph I, L-tartrate polymorph II, p-toluenesulfonate polymorph I, p-toluenesulfonate polymorph II, maleate polymorph I or maleate polymorph II, and an optionally pharmaceutically acceptable excipient.

[0067] The present disclosure also provides a method for preparing a pharmaceutical composition, which includes the step of mixing the aforementioned sulfate crystal form I, sulfate crystal form II, phosphate crystal form I, mesylate crystal form I, mesylate crystal form II, L-tartrate crystal form I, L-tartrate crystal form II, p-toluenesulfonate crystal form I, p-toluenesulfonate crystal form II, maleate crystal form I or maleate crystal form II with a pharmaceutically acceptable excipient.

[0068] The present disclosure also provides the use of the aforementioned sulfate crystal form I, sulfate crystal form II, phosphate crystal form I, mesylate crystal form I, mesylate crystal form II, L-tartrate crystal form I, L-tartrate crystal form II, p-toluenesulfonate crystal form I, p-toluenesulfonate crystal form II, maleate crystal form I or maleate crystal form II or the composition prepared therefrom in the preparation for preventing and / or treating pain alleviation and pain-related diseases.

[0069] The use according to the present disclosure, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from pain after bunionectomy, pain after hernia repair and pain after abdominoplasty.

[0070] The "2θ or 2θ angle" as described in the present disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case after rounding off numbers with more than 1 decimal place), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.

[0071] In the present disclosure, numerical values such as the content of related substances are data obtained by measurement and calculation, and there will inevitably be a certain degree of error. Generally speaking, ±10% is within the reasonable error range. There will be a certain degree of error variation depending on the context in which it is used, and this error variation does not exceed ±10%, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, preferably ±5%.

[0072] The starting materials used in the preparation method of the crystalline forms of the present disclosure can be compounds in any form, and the specific forms include but are not limited to: amorphous, any crystalline form, hydrate, solvate, etc.

[0073] In the present disclosure, the drying temperature is generally 25°C - 100°C, preferably 40°C - 70°C, and it can be dried at atmospheric pressure or under reduced pressure.

[0074] The crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, solvent evaporation crystallization, seeding-induced crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be carried out during the crystallization process.

[0075] The "differential scanning calorimetry or DSC" described in the present disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference during the heating or constant temperature process of the sample to characterize all physical and chemical changes related to thermal effects and obtain the phase transition information of the sample.

[0076] According to the description of the hygroscopicity characteristics and the definition of the increase in hygroscopicity weight in the "Guideline for Drug Hygroscopicity" in Part IV of the Chinese Pharmacopoeia 2015 Edition,

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

[0078] Highly hygroscopic: The increase in hygroscopicity weight is not less than 15%;

[0079] Hygroscopic: The increase in hygroscopicity weight is less than 15% but not less than 2%;

[0080] Slightly hygroscopic: The increase in hygroscopicity weight is less than 2% but not less than 0.2%;

[0081] Non-hygroscopic or almost non-hygroscopic: The increase in hygroscopicity weight is less than 0.2%.

[0082] The "excipients" described in the present disclosure include but are not limited to any adjuvants, carriers, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents or emulsifiers that have been approved by the US Food and Drug Administration for use in humans or livestock animals. Brief Description of the Drawings

[0083] Figure 1 It is the analgesic efficacy of Compound 1 in the rat incision pain model.

[0084] Figure 2 It is the effect of Compound 1 on body weight in the rat incision pain model.

[0085] Figure 3 It is the XRPD spectrum of Compound 1 sulfate crystalline form I.

[0086] Figure 4 It is the XRPD pattern of Compound 1 sulfate crystal form II.

[0087] Figure 5 It is the XRPD pattern of Compound 1 phosphate crystal form I.

[0088] Figure 6 It is the XRPD pattern of Compound 1 mesylate crystal form I.

[0089] Figure 7 It is the XRPD pattern of Compound 1 mesylate crystal form II.

[0090] Figure 8 It is the XRPD pattern of Compound 1 L-tartrate crystal form I.

[0091] Figure 9 It is the XRPD pattern of Compound 1 L-tartrate crystal form II.

[0092] Figure 10 It is the XRPD pattern of Compound 1 p-toluenesulfonate crystal form I.

[0093] Figure 11 It is the XRPD pattern of Compound 1 p-toluenesulfonate crystal form II.

[0094] Figure 12 It is the XRPD pattern of Compound 1 maleate crystal form I.

[0095] Figure 13 It is the XRPD pattern of Compound 1 maleate crystal form II. Detailed implementation manners

[0096] The present disclosure will be explained in more detail below in combination with examples or experimental examples. The examples or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and do not limit the essence and scope of the present disclosure.

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

[0098] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10-6 (ppm). The NMR measurement is carried out using a Bruker AVANCE-400 nuclear magnetic resonance instrument or a Bruker AVANCE NEO 500M, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0099] For the determination of MS, an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry instrument is used (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS).

[0100] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0101] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO QExactive)

[0102] For high performance liquid chromatography (HPLC) analysis, Agilent HPLC 1200 DAD, Agilent HPLC 1200 VWD and Waters HPLC e2695-2489 high performance liquid chromatography instruments are used.

[0103] For chiral HPLC analysis and determination, an Agilent 1260 DAD high performance liquid chromatography instrument is used.

[0104] For high performance liquid chromatography preparation, Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatography instruments are used.

[0105] For chiral preparation, a Shimadzu LC-20AP preparative chromatography instrument is used.

[0106] For the CombiFlash rapid preparator, Combiflash Rf200 (TELEDYNE ISCO) is used.

[0107] For thin layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used for thin layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications of the silica gel plates used for thin layer chromatography separation and purification of products are 0.4 mm to 0.5 mm.

[0108] For silica gel column chromatography, silica gel with 200 - 300 mesh from Yantai Huanghai is generally used as the carrier.

[0109] For the determination of the average kinase inhibition rate and IC50 value, a NovoStar microplate reader (BMG, Germany) is used.

[0110] The known starting materials of the present invention can be adopted, synthesized according to methods known in the art, or purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, etc.

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

[0112] An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0113] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0114] The pressure hydrogenation reaction uses a Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen gas generator or an HC2-SS type hydrogenator.

[0115] For the hydrogenation reaction, it is usually evacuated, filled with hydrogen, and this operation is repeated 3 times.

[0116] The microwave reaction uses a CEM Discover-S 908860 type microwave reactor.

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

[0118] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0119] The progress of the reactions in the examples was monitored by thin layer chromatography (TLC). The eluent systems for column chromatography used to purify the compounds and the developing agent systems for thin layer chromatography included: A: dichloromethane / methanol system; B: n-hexane / ethyl acetate system; C: petroleum ether / ethyl acetate system. The volume ratios of the solvents were adjusted according to the polarity of the compounds, and a small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0120] XRPD is X-ray powder diffraction detection: The measurement was carried out using a BRUKER D8 type X-ray diffractometer. The specific acquisition information was as follows: Cu anode (40 kV, 40 mA), Cu-Kα1 ray Kα2 ray Kβ ray Scanning mode: θ / 2θ, scanning range (2θ range): 5° to 45°.

[0121] DSC is differential scanning calorimetry: The measurement was carried out using a METTLER TOLEDO DSC 3+ differential scanning calorimeter, with a heating rate of 10 °C / min. The specific temperature range was referred to the corresponding spectrum (mostly 25 - 270 °C), and the nitrogen purge rate was 50 mL / min.

[0122] TGA is thermogravimetric analysis: The detection was carried out using a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10 °C / min. The specific temperature range was referred to the corresponding spectrum (mostly 30 - 350 °C), and the nitrogen purge rate was 50 mL / min.

[0123] DVS is dynamic vapor sorption: The detection was carried out using an SMS DVS Advantage. At 25 °C, the humidity changed as 50% - 95% - 0% - 95% - 50%, with a step of 10% (the last step was 5%) (the specific humidity range was subject to the corresponding spectrum, and the method listed here was mostly used). The judgment criteria were Tmax 360 min and dm / dt not greater than 0.002%.

[0124] Preparation of Compound of Formula 1 in Example 1

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

[0126] -5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0127]

[0128] The 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 on page 231, Example 3 of the specification in the patent application "WO2021113627") was resolved by a chiral column (Waters SFC 150, chromatographic column: DAICEL IC, 40 * 250 mm, 10 μm; Mobile phase A: supercritical CO 2 , Mobile phase B: IPA), Gradient ratio: A:B: 90:10, Flow rate: 120 mL / min) to obtain the title product 1b-1 (5.5 g, Yield: 45.8%) and 1b-2 (5.08 g, Yield: 42.3%).

[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 minutes, Purity: 99% (Column: DAICEL IC, 100 * 3 mm, 3 μm; Mobile phase A: supercritical CO 2 , Mobile phase B: IPA (0.1% DEA)), Gradient ratio: Mobile phase A: 60% - 95%, Flow rate: 1.5 mL / min).

[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 minutes, Purity: 99% (Column: DAICEL IC, 100 * 3 mm, 3 μm; Mobile phase A: supercritical CO 2 , Mobile phase B: IPA (0.1% DEA)), Gradient ratio: Mobile phase A: 60% - 95%, Flow rate: 1.5 mL / min).

[0139] Second step (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). Oxalyl chloride (40 mg, 315 μmol) and 1 drop of N,N-dimethylformamide were added under an ice bath. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (60 mg, 464 μmol) was added. A solution of 4-aminopyridine-2-carbonitrile 1c (30 mg, 251 μmol, Shanghai Hanhong) in dichloromethane (1 mL) was added dropwise under an ice bath. The reaction mixture 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 obtain the title compound 1d (45 mg, yield: 70%).

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

[0142] The third step

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

[0144] -5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0145] Compound 1d (100 mg, 219.6 μmol) was dissolved in 10 mL of isopropanol. N,N-Diisopropylethylamine (85.1 mg, 658.8 μmol), mercaptoacetic acid (40.5 mg, 439 μmol, Shanghai Bide), and methoxylamine hydrochloride (55 mg, 658.8 μmol) were added. The reaction mixture was heated at 80 °C for 14 hours. The reaction solution was concentrated under reduced pressure. 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 obtain the title compound 1 (10 mg, yield: 18%).

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

[0147] 1 H NMR (500 MHz, DMSO-d 6): δ 10.69 (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 compounds of the present disclosure against Nav1.8

[0149] The purpose of the experiment was to investigate the effect of the compound on the Nav1.8 ion channel in in vitro experiments. The Nav1.8 ion channel was stably expressed on HEK293 cells. After the Nav1.8 current was stabilized, the magnitude of the Nav1.8 current before and after the application of the compound was compared to obtain the effect of the compound on the Nav1.8 ion channel.

[0150] 1 Experimental materials and instruments

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

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

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

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

[0155] 5) Glass microelectrode puller: 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 procedures

[0160] 2.1 Compound preparation

[0161] Compounds for preparing intracellular and extracellular solutions were purchased from Sigma (St. Louis, MO), except for NaOH and KOH used in acid-base titration. The extracellular solution (mM) was: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2 , 1; HEPES, 10; glucose, 10; pH 7.4 (titrated with NaOH). The intracellular solution (mM) was aspartic acid, 140; MgCl 2 , 2; EGTA 11; HEPES, 10; pH 7.2 (titrated with CsOH). All test compound and control compound solutions contained 1 μM TTX.

[0162] The stock concentration of the test compound was 9 mM, dissolved in dimethyl sulfoxide (DMSO). It was redissolved in the extracellular solution on the day of the test to prepare the required concentration.

[0163] 2.2 Manual patch clamp test procedure

[0164] 1) After the compound was prepared into a solution of the specified concentration, the drug solutions were added to each pipette in ascending order of concentration, and each pipette was labeled.

[0165] 2) The cell was transferred to the perfusion chamber, a positive pressure was applied inside the electrode, the tip of the electrode was brought into contact with the cell, the three-way valve of the aspiration device was adjusted to the three-way state, and then a negative pressure was applied to the electrode to form a high-resistance seal with the cell. The negative pressure was continuously applied to rupture the cell membrane and form a current path.

[0166] 3) After the cell rupture current was stable, perfusions at different concentrations were carried out in sequence. If the current was stable for at least one minute, the next concentration could be used for perfusion. The perfusion time for each concentration was no more than five minutes.

[0167] 4) The perfusion chamber was cleaned. It was rinsed in descending order of drug solution concentration, and each concentration of the drug solution was rinsed for 20 s. Finally, it was rinsed with the extracellular solution for 1 min.

[0168] 2.3 Test voltage equation (resting) and results

[0169] The cell was clamped at -80 mV, and then depolarized to 10 mV with a 10-ms square wave to obtain Nav1.8 current. This procedure was repeated every 5 s. The maximum current induced by the square wave was detected. After it was stable, the test compound was perfused. When the response was stable, the blocking strength was calculated.

[0170] 3. Data analysis

[0171] The data will be stored in a computer system for analysis. Data collection and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA), and the management staff will review the analysis results. Current stability refers to the current varying within a limited range over time. The magnitude of the current after stabilization is used to calculate the effect of the compound at this concentration.

[0172] The inhibitory activity of the compounds of the present disclosure against Nav1.8 was determined by the above tests, and the measured IC 50 values are shown in Table 1.

[0173] Table 1 IC of the compounds of the present disclosure inhibiting Nav1.8 channel activity 50

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

[0175] Conclusion: The compounds in the present disclosure 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 LC / MS / MS method was used to determine the drug concentrations in the plasma of SD rats at different times after intragastric (i.g.) administration of the compounds of the examples. The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied to evaluate their pharmacokinetic characteristics.

[0179] 1.1 Experimental Protocol

[0180] Experimental animals: 4 male SD rats, provided by Vital River Laboratory Animal Technology Co., Ltd. After fasting overnight, they were administered drugs by gavage respectively.

[0181] Drug preparation: Weigh a certain amount of the test compound respectively, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a 0.2 mg / mL colorless and clear solution.

[0182] Drug administration: The administration dose was 2 mg / kg, and the administration volume was 10.0 mL / kg.

[0183] Operation Method

[0184] Before drug administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after drug administration, 0.2 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 1 minute (4 °C), the plasma was separated within 1 hour, and stored in dry ice for testing. The process from blood collection to centrifugation was carried out under ice bath conditions. The animals were allowed to eat 2 hours after drug administration.

[0185] Determine the content of the compound to be measured in the plasma of SD rats after administration of drugs at different concentrations: Take 25 μL of the plasma samples of SD rats at each time point after administration, add 200 μL of acetonitrile containing the internal standard (verapamil 100 ng / ml), vortex and 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] 18 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 given intragastric administration 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 (intragastric administration group) and a 0.1 mg / mL colorless and clear solution (intravenous injection administration group).

[0195] 2.3 Administration

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

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

[0198] 2.4 Operations

[0199] Gavage administration group: Before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.1 mL of blood was collected from the orbital cavity, placed in an EDTA-K2 anticoagulant test tube, centrifuged at 10000 rpm for 1 minute (4 °C), plasma was separated within 1 hour, and stored at -80 °C for later measurement. The blood collection to centrifugation process was carried out under ice bath conditions.

[0200] Intravenous injection administration group: Before administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after administration, blood was collected, and the treatment was the same as that of the gavage administration group.

[0201] Determination of the content of the compound to be measured in the plasma of C57 mice after administration of drugs at different concentrations: Compound 1: Take 20 μL of the plasma samples of C57 mice at each time point after administration. Add 200 μL of acetonitrile containing 100 ng / ml of camptothecin (internal standard) to each sample to precipitate proteins, vortex and 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 of the present disclosure

[0204]

[0205] Conclusion: The compounds of the present disclosure have high blood drug concentrations, large exposures, low clearance rates, and relatively high bioavailability in C57 mice, showing pharmacokinetic advantages.

[0206] Test Example 3 Pharmacodynamic experiment

[0207] 1. Experimental purpose

[0208] Evaluate the analgesic pharmacodynamic effect of the compounds of the present disclosure in inhibiting pain in a rat incision pain model.

[0209] 2. Experimental drugs

[0210] Compound of Example 1.

[0211] Use a 25% PEG400 + 75% (10% TPGS + 1% HPMC K100LV) solution.

[0212] 3. Experimental methods and experimental materials

[0213] 3.1 Experimental animals and feeding conditions

[0214] Experimental animals: SD rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (License number: SCXK(Zhe)2019-0001), and their body weight was about 180 g when purchased.

[0215] Feeding conditions: Five rats were housed in each cage, with a 12 / 12-hour light / dark cycle, a constant temperature of 23 ± 1 °C, and a humidity of 50 to 60%. They had free access to food and water.

[0216] 3.2 Animal grouping

[0217] After the SD rats were adaptively fed, 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] Nine SD rats with a body weight of 170 - 190 g were selected, and their mechanical pain thresholds were measured using an electronic tactile measuring instrument. Then, an incision pain surgery was performed. During the surgery, after anesthesia with Zoletil (Zoletil-50, 250 mg, diluted to 50 ml with normal saline after dissolution, and 2 ml was injected for a 200 g body weight), a 1 cm long incision was made in the middle of the plantar surface of the left hind paw through the skin and fascia, and the skin was sutured with 3-0 sterile silk surgical sutures. The injured area was disinfected with penicillin, and the animals were returned to their original places to recover overnight. After overnight recovery from the surgery, intragastric administration was performed. Five hours after the rats were administered the drug (about 24 hours after the surgery), the mechanical pain threshold was measured using an electronic tactile measuring instrument.

[0223] 3.4 Data statistics

[0224] The Excel statistical software was used to record the data: the average value was calculated as avg; the SD value was calculated as STDEV; the SEM value was calculated as STDEV / SQRT (the number of animals in each group); the GraphPad Prism software was used to plot the graphs, and one-way ANOVA and t-test were used for statistical analysis of the data.

[0225] Percentage increase in threshold (%) = [(G t - G 0 ) / G 0 × 100 (%), where G t is the plantar pain threshold of the drug-administered group, and G 0 is the plantar pain threshold of the vehicle group.

[0226] 4. Results

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

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

[0229]

[0230] Note: one dose means administering the drug only once; i.g. means intragastric administration.

[0231] 5. Conclusion

[0232] The pain threshold of normal rats (body weight 170 - 190 g) is 26.2 ± 1.6 gf, and that of the vehicle control group is 10.0 ± 0.7 gf. The pain thresholds of the compound in Example 1 at 200, 100, and 50 mg / kg are 22.3, 14.9, and 10.8 gf respectively. The pain thresholds are significantly increased by 122% (p < 0.001), 49% (p < 0.05), and 7% respectively compared with the vehicle control group. The pain threshold at 200 mg / kg is significantly higher than that at 100 mg / kg (p < 0.01), and the pain threshold at 100 mg / kg is significantly higher than that at 50 mg / kg (p < 0.05). The analgesic effect has an obvious dose-dependence, and the administration has no effect on the body weight of rats.

[0233] Preparation of sulfate crystal form I of Example 2

[0234] Add 7 mg of the compound shown in Formula 1 to 0.1 mL of ethanol to dissolve it clearly, add 7.4 μL of 2M sulfuric acid ethanol solution, add 0.3 ml of n-heptane, stir to crystallize, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0235] Detected by X-ray powder diffraction, this product is defined as sulfate crystal form I, and the XRPD spectrum is as Figure 3 , and the characteristic peak positions are shown in Table 6. The sulfate ion content detected by ion chromatography is 17.3%. The DSC spectrum shows that the peak values of the endothermic peaks are 58.15 °C, 123.47 °C, and 170.80 °C. The TGA spectrum shows that the weight loss from 30 °C to 100 °C is 1.79%.

[0236] Table 6

[0237]

[0238]

[0239] Preparation of sulfate crystal form II of Example 3

[0240] Dissolve 7 mg of the compound shown in Formula 1 in 0.1 mL of ethyl acetate. Add 7.4 μL of 2 M sulfuric acid ethanol solution and 0.3 mL of n - heptane. Stir to crystallize, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0241] Detected by X - ray powder diffraction, this product is defined as sulfate crystal form II. The XRPD pattern is as Figure 4 , and the characteristic peak positions are shown in Table 7. The DSC pattern shows that the peak value of the endothermic peak is 108.14 °C. The TGA pattern shows that the weight loss from 30 °C to 140 °C is 0.41%.

[0242] Table 7

[0243]

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

[0245] Dissolve 7 mg of the compound shown in Formula 1 in 0.1 mL of ethyl acetate. Add 7.4 μL of 2 M phosphoric acid ethanol solution and 0.3 mL of n - heptane. Stir to crystallize, centrifuge, collect the solid and dry it under vacuum to obtain the product.

[0246] Detected by X - ray powder diffraction, this product is defined as phosphate crystal form I. The XRPD pattern is as Figure 5 , and the characteristic peak positions are shown in Table 8. The content of phosphate ions detected by ion chromatography is 22.8%. The DSC pattern shows that the peak values of the endothermic peaks are 39.48 °C, 67.46 °C, 85.46 °C, 94.78 °C and 138.94 °C. The TGA pattern shows that the weight loss from 30 °C to 120 °C is 2.78%.

[0247] Table 8

[0248]

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

[0250] Dissolve 100 mg of the compound shown in Formula 1 in 1 mL of ethyl acetate. Add 95.0 μL of 2 M methanesulfonic acid ethanol solution and 3 mL of n - heptane. Stir to crystallize, filter under reduced pressure, collect the solid and dry it under vacuum to obtain the product.

[0251] Detected by X - ray powder diffraction, this product is defined as methanesulfonate crystal form I. The XRPD pattern is as Figure 6 , and the characteristic peak positions are shown in Table 9. The content of methanesulfonate ions detected by ion chromatography is 17.6%. The DSC pattern shows that the peak value of the endothermic peak is 195.03 °C. The TGA pattern shows no obvious weight loss.

[0252] DVS detection shows that under normal storage conditions (i.e., 25 °C, 60% RH), the moisture absorption weight gain of this sample is approximately 0.99%; under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain is approximately 1.62%; under extreme conditions (90% RH), the moisture absorption weight gain is approximately 4.75%. And after DVS detection, the crystal form is retested and remains unchanged.

[0253] Table 9

[0254]

[0255]

[0256] Preparation of Methanesulfonate Crystal Form II in Example 6

[0257] Add 7 mg of the compound shown in Formula 1 to 0.1 mL of acetone to dissolve it clearly, add 7.4 μL of 2M methanesulfonic acid ethanol solution, and volatilize to obtain the product. After X-ray powder diffraction detection, this product is defined as methanesulfonate crystal form II, and the XRPD pattern is as Figure 7 , and the characteristic peak positions are shown in Table 10. Ion chromatography detects that the content of methanesulfonate ions is 20.0%. The DSC pattern shows that the peak values of the endothermic peaks are 83.44 °C, 148.77 °C, and 186.07 °C. The TGA pattern shows that the weight loss from 30 °C to 120 °C is 4.36%.

[0258] Table 10

[0259]

[0260]

[0261] Preparation of L-Tartrate Crystal Form I in Example 7

[0262] Add 7 mg of the compound shown in Formula 1 to 0.1 mL of acetone to dissolve it clearly, add 7.4 μL of 2M L-tartaric acid ethanol solution, add 0.3 ml of n-heptane, stir to crystallize, centrifuge, and collect the solid for vacuum drying to obtain the product.

[0263] After X-ray powder diffraction detection, this product is defined as L-tartrate crystal form I, and the XRPD pattern is as Figure 8 , and the characteristic peak positions are shown in Table 11. Ion chromatography detects that the content of L-tartrate ions is 29.8%. The DSC pattern shows that the peak values of the endothermic peaks are 70.48 °C and 150.79 °C. The TGA pattern shows that the weight loss from 30 °C to 100 °C is 1.78%.

[0264] Table 11

[0265]

[0266] Preparation of L-Tartrate Crystal Form II

[0267] Dissolve 120 mg of the compound shown in Formula 1 in 1 mL of ethyl acetate. Add 115.0 μL of 2 M L-tartaric acid ethanol solution, then add 5 mL of n-heptane, stir to crystallize, filter under reduced pressure, collect the solid and dry it under vacuum to obtain the product.

[0268] After detection by X-ray powder diffraction, this product is defined as L-tartrate crystal form II, and the XRPD pattern is as Figure 9 , and the characteristic peak positions are shown in Table 12. The content of L-tartrate ion detected by ion chromatography is 24.3%. The DSC pattern shows that the peak value of the endothermic peak is 156.90 °C. The TGA pattern shows that the weight loss from 30 °C to 100 °C is 0.24%.

[0269] DVS detection shows that under normal storage conditions (i.e., 25 °C, 60% RH), the moisture absorption weight gain of this sample is about 1.98%; under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain is about 3.37%; under extreme conditions (90% RH), the moisture absorption weight gain is about 13.42%. And after DVS detection, the crystal form is retested and transformed into L-tartrate crystal form I.

[0270] Table 12

[0271]

[0272] Preparation of p-Toluenesulfonate Crystal Form I

[0273] Dissolve 120 mg of the compound shown in Formula 1 in 1 mL of ethyl acetate. Add 115.0 μL of 2 M p-toluenesulfonic acid ethanol solution, then add 3 mL of n-heptane, stir to crystallize, filter under reduced pressure, collect the solid and dry it under vacuum to obtain the product.

[0274] After detection by X-ray powder diffraction, this product is defined as p-toluenesulfonate crystal form I, and the XRPD pattern is as Figure 10 , and the characteristic peak positions are shown in Table 13. The content of p-toluenesulfonate ion detected by ion chromatography is 26.9%. The DSC pattern shows that the peak values of the endothermic peaks are 170.08 °C and 176.29 °C. The TGA pattern shows no obvious weight loss.

[0275] DVS detection shows that under normal storage conditions (i.e., 25 °C, 60% RH), the moisture absorption weight gain of this sample is about 0.28%; under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain is about 0.38%; under extreme conditions (90% RH), the moisture absorption weight gain is about 0.66%. And after DVS detection, the crystal form is retested and remains unchanged.

[0276] Table 13

[0277]

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

[0279] Heat the p-toluenesulfonate crystal form I of the compound shown in Formula 1 to 173 °C to obtain a product.

[0280] Detected by X-ray powder diffraction, this product is defined as p-toluenesulfonate crystal form II, and the XRPD pattern is as Figure 11 , and the characteristic peak positions are shown in Table 14. The DSC pattern shows that the peak value of the endothermic peak is 177.48 °C. The TGA pattern shows that the weight loss is 1.68% from 30 °C to 140 °C.

[0281] Table 14

[0282]

[0283] Preparation of Maleate Crystal Form I in Example 11

[0284] Add 7 mg of the compound shown in Formula 1 to 0.1 mL of ethyl acetate solution, add 14.7 μL of 2M maleic acid ethanol solution, add 0.3 ml of n-heptane, stir to crystallize, centrifuge, collect the solid and dry it under vacuum to obtain a product.

[0285] Detected by X-ray powder diffraction, this product is defined as maleate crystal form I, and the XRPD pattern is as Figure 12 , and the characteristic peak positions are shown in Table 15. Nuclear magnetic resonance detection shows that the molar ratio of compound 1 to maleate is 1:1. The DSC pattern shows that the peak values of the endothermic peaks are 103.47 °C and 118.63 °C. The TGA pattern shows that the weight loss is 0.83% from 30 °C to 120 °C.

[0286] Table 15

[0287]

[0288] Preparation of Maleate Crystal Form II in Example 12

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

[0290] Detected by X-ray powder diffraction, this product is defined as maleate crystal form II, and the XRPD pattern is as Figure 13 , and the characteristic peak positions are shown in Table 16. The DSC pattern shows that the peak value of the endothermic peak is 119.81 °C. The TGA pattern shows that the weight loss is 1.71% from 30 °C to 100 °C.

[0291] Table 16

[0292]

[0293] Study on the Stability of Influencing Factors in Example 13

[0294] The methanesulfonate polymorph I and p-toluenesulfonate polymorph I were placed flat and open to the air, and the stability of the samples was investigated under the conditions of light (4500 Lux), high temperature (40 °C, 60 °C), and high humidity (RH 75%, RH 92.5%) respectively. The sampling investigation period was 1 month.

[0295] Table 17 Stability of Influencing Factors for Methanesulfonate Polymorph I

[0296]

[0297]

[0298] Conclusion: The physicochemical stability of methanesulfonate polymorph I is good under the influencing factor conditions.

[0299] Table 18 Stability of Influencing Factors for p-Toluenesulfonate Polymorph I

[0300]

[0301] Conclusion: p-Toluenesulfonate polymorph 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 methanesulfonate polymorph I and p-toluenesulfonate polymorph I were placed under the conditions of 25 °C / 60% RH and 40 °C / 75% RH respectively to investigate their stability:

[0304] Table 19 Long-Term / Accelerated Stability of Methanesulfonate Polymorph I

[0305]

[0306] Conclusion: The physical and chemical stability of methanesulfonate polymorph I is good under long-term and accelerated conditions.

[0307] Table 20 Long-Term / Accelerated Stability of p-Toluenesulfonate Polymorph I

[0308]

[0309] Conclusion: The physical and chemical stability of p-toluenesulfonate polymorph I is good under long-term and accelerated conditions.

Claims

1. A pharmaceutically acceptable salt of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-methoxycarbamimidyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide represented by formula 1, wherein the pharmaceutically acceptable salt is selected from sulfate, phosphate, L-tartrate, maleate, methanesulfonate, and p-toluenesulfonate.

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

2.

3. A method for preparing a pharmaceutically acceptable salt according to claim 1 or 2, 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.

4. A mesylate crystalline form I of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.529, 8.919, 13.439, 18.015, and 27.791, preferably at 4.529, 8.919, 13.439, 18.015, 19.330, 21.038, 23.527, 24.143, and 27.

791.

5. The mesylate salt form I according to claim 4, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG6 .

6. A method for preparing the mesylate salt form I as claimed in claim 4 or 5, comprising the steps of dissolving the compound of formula 1 in ethyl acetate, adding methanesulfonic acid ethanol solution, and then adding n-heptane, and stirring.

7. A p-toluenesulfonic acid crystalline form I of the compound represented by formula 1, characterized in that: The X-ray powder diffraction pattern expressed by the diffraction angle 2θ has characteristic peaks at 6.975, 8.109, 12.126, 16.343, and 24.

527.

8. The p-toluenesulfonic acid crystalline form I according to claim 7, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG10 .

9. A method for preparing p-toluenesulfonic acid crystalline form I as claimed in claim 7 or 8, comprising the steps of dissolving the compound of formula 1 in ethyl acetate, adding p-toluenesulfonic acid ethanol solution, and then adding n-heptane, and stirring.

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

20.

11. A pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula 1 according to any one of claims 1 or 2, or a crystalline form according to any one of claims 4-5, 7-8, and optionally a pharmaceutically acceptable excipient.

12. A method for preparing a pharmaceutical composition, comprising the following steps: A step of mixing a pharmaceutically acceptable salt of the compound of formula 1 according to any one of claims 1 or 2, or a crystalline form according to any one of claims 4-5, 7-8 and a pharmaceutically acceptable excipient.

13. Use of a pharmaceutically acceptable salt of the compound of formula 1 according to any one of claims 1 or 2, or a crystalline form according to any one of claims 4-5, 7-8, or a pharmaceutical composition according to claim 11 in the preparation of a Nav1.8 inhibitor.

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

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