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

Abstract

The invention relates to a pharmaceutically acceptable salt of a substituted tetrahydrofuran derivative, and a crystal form and application thereof. Specifically, the invention provides pharmaceutically acceptable salts of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N '-hydroxyformamidino) 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 field of pharmaceutical technologies and relates to a pharmaceutically acceptable salt of a substituted tetrahydrofuran derivative, its crystalline form, and uses thereof. 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 classified into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). Nav1.8 is of the TTX-R type, and its encoding gene is SCN10A. It is mainly present in trigeminal ganglion neurons and DRG neurons and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, 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 increases. Nav1.8 knockout mice cannot exhibit normal visceral inflammatory pain. After the human Nav1.8 gene generates a gain-of-function mutation, it will cause peripheral neuropathic pain. Based on a series of animal experiments and human gene evidence, selective inhibition of Nav1.8 has the potential to become a new type of analgesic therapy and can be used for the treatment of various pain types such as inflammatory pain, neuropathic pain, postoperative pain, and cancer pain.

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

[0004]

[0005] 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'-hydroxyformamidinyl)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'-hydroxyformamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide for developing drugs suitable for industrial production and having good biological activity. Summary of the Invention

[0006] The present disclosure provides a pharmaceutically acceptable salt of a compound represented by Formula 1, and the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, mesylate, p-toluenesulfonate, maleate, fumarate, tartrate.

[0007]

[0008] The present disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of Formula 1, which includes the step of reacting the compound of Formula 1 with an acid, and the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, tartaric acid.

[0009] The solvents used for salt formation in the present disclosure are selected from, but not limited to, acetone, ethyl acetate, methyl tert-butyl ether, isopropyl ether.

[0010] In an alternative embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt in the present disclosure further includes the step of preparing the acid into a corresponding alcohol solution.

[0011] Furthermore, in an alternative embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt further includes steps such as crystallization, filtration, washing, or drying.

[0012] 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.

[0013] In another embodiment, the chemical ratio of the compound of Formula 1 to the acid is 2:1 - 1:3.

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

[0015] In an alternative embodiment, the chemical ratio of the compound of Formula 1 to sulfuric acid is 1:1 or 1:2.

[0016] In an alternative embodiment, the chemical ratio of the compound of Formula 1 to phosphoric acid is 1:1 or 1:2.

[0017] In an alternative embodiment, the chemical ratio of the compound of Formula 1 to methanesulfonic acid is 1:1 or 1:2 or 1:3.

[0018] In an alternative embodiment, the chemical ratio of the compound of Formula 1 to p-toluenesulfonic acid is 1:1 or 1:2.

[0019] In an alternative embodiment, the chemical ratio of the compound of Formula 1 to maleic acid is 1:1.

[0020] In an alternative embodiment, the chemical ratio of the compound of Formula 1 to fumaric acid is 1:1.

[0021] In an alternative embodiment, the chemical ratio of the compound of Formula 1 to tartaric acid is 1:1.

[0022] The hydrochloride crystal form a of the compound of Formula 1 provided by the present disclosure has characteristic peaks at 8.468, 14.212, 16.156, 24.285, and 27.130 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0023] In some embodiments, the hydrochloride crystal form a of the compound of Formula 1 has characteristic peaks at 8.468, 10.524, 14.212, 15.314, 16.156, 17.118, 20.186, 22.210, 24.285, 27.130, 27.763, 31.432, and 33.864 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0024] In some embodiments, the hydrochloride crystal form a of the compound of Formula 1 has characteristic peaks at 8.468, 10.524, 14.212, 15.314, 16.156, 16.499, 17.118, 19.066, 20.186, 21.412, 22.210, 24.285, 26.422, 27.130, 27.763, 28.866, 30.794, 31.432, 33.150, and 33.864 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0025] In some embodiments, the X-ray powder diffraction pattern of the hydrochloride crystal form a of the compound of Formula 1 expressed in terms of the diffraction angle 2θ is as Figure 3 shown.

[0026] The present disclosure also provides a method for preparing crystalline form a of the hydrochloride salt of the compound shown in Formula 1, the method comprising the steps of dissolving the compound shown in Formula 1 in ethyl acetate or methyl tert-butyl ether, adding a hydrochloric acid ethanol solution, and stirring.

[0027] The crystalline form b of the hydrochloride salt of the compound shown in Formula 1 provided by the present disclosure has characteristic peaks at 8.445, 12.682, 16.463, 20.075, 21.927, and 24.627 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0028] In some embodiments, the crystalline form b of the hydrochloride salt of the compound shown in Formula 1 has characteristic peaks at 8.445, 12.682, 15.989, 16.463, 18.252, 20.075, 20.512, 20.926, 21.927, 23.430, 24.627, 28.600, and 30.416 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0029] In some embodiments, the crystalline form b of the hydrochloride salt of the compound shown in Formula 1 has characteristic peaks at 8.445, 12.682, 13.433, 14.675, 15.989, 16.463, 17.532, 18.252, 20.075, 20.512, 20.926, 21.927, 23.430, 24.627, 25.080, 26.598, 28.600, 30.416, 31.722, 33.429, and 34.081 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0030] In some embodiments, the X-ray powder diffraction pattern of the crystalline form b of the hydrochloride salt of the compound shown in Formula 1 expressed in terms of diffraction angle 2θ is as Figure 4 shown.

[0031] The present disclosure also provides a method for preparing crystalline form b of the hydrochloride salt of the compound shown in Formula 1, the method comprising the steps of dissolving the compound shown in Formula 1 in ethyl acetate, adding a hydrochloric acid ethanol solution, and stirring.

[0032] In some embodiments, the hydrochloride salt of the compound shown in Formula 1 provided by the present disclosure is amorphous, and there are no obvious characteristic peaks in the range of diffraction angle 2θ of 3-45° in its X-ray powder diffraction pattern.

[0033] The crystalline form I of the sulfate salt of the compound shown in Formula 1 provided by the present disclosure has characteristic peaks at 4.917, 9.706, 13.658, and 20.073 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0034] In some embodiments, the sulfate crystal form I of the compound represented by Formula 1 has characteristic peaks at 4.917, 9.706, 13.658, 15.631, 16.072, 17.120, 20.073, 21.568, 22.810 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0035] In some embodiments, the sulfate crystal form I of the compound represented by Formula 1 has characteristic peaks at 4.917, 9.706, 12.843, 13.658, 15.631, 16.072, 17.120, 17.873, 18.277, 20.073, 21.568, 22.810, 24.624, 27.888, 29.502 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0036] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form I of the compound represented by Formula 1 expressed in terms of diffraction angle 2θ is as Figure 5 shown.

[0037] The present disclosure also provides a method for preparing the sulfate crystal form I of the compound represented by Formula 1, the method comprising the steps of dissolving the compound represented by Formula 1 in acetone, adding a sulfuric acid ethanol solution, and then adding isopropyl ether and stirring.

[0038] The sulfate crystal form II of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 9.882, 16.107, 17.164, 21.206, 24.387 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0039] In some embodiments, the sulfate crystal form II of the compound represented by Formula 1 has characteristic peaks at 9.882, 12.098, 13.933, 16.107, 17.164, 21.206, 23.111, 24.387, 28.269, 28.512 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0040] In some embodiments, the sulfate crystal form II of the compound represented by Formula 1 has characteristic peaks at 9.882, 12.098, 13.933, 16.107, 17.164, 19.177, 19.953, 21.206, 23.111, 24.387, 28.269, 28.512 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0041] In some embodiments, the X-ray powder diffraction pattern of the sulfate crystal form II of the compound represented by Formula 1 expressed in terms of diffraction angle 2θ is as Figure 6 shown.

[0042] The present disclosure also provides a method for preparing crystalline form II of the sulfate salt of the compound shown in Formula 1, the method comprising the steps of dissolving the compound shown in Formula 1 in methyl tert-butyl ether, adding a sulfuric acid ethanol solution, and then adding isopropyl ether, and stirring.

[0043] For crystalline form α of the phosphate salt of the compound shown in Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.787, 15.021, 16.010, 19.498, and 20.814.

[0044] In some embodiments, for crystalline form α of the phosphate salt of the compound shown in Formula 1, the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 4.787, 7.955, 15.021, 16.010, 19.498, 20.814, 22.012, and 29.082.

[0045] In some embodiments, the X-ray powder diffraction pattern of crystalline form α of the phosphate salt of the compound shown in Formula 1 represented by the diffraction angle 2θ is as Figure 7 shown.

[0046] The present disclosure also provides a method for preparing crystalline form α of the phosphate salt of the compound shown in Formula 1, the method comprising the steps of dissolving the compound shown in Formula 1 in acetone, adding a phosphoric acid ethanol solution, and then adding isopropyl ether, and stirring.

[0047] For crystalline form I of the mesylate salt of the compound shown in Formula 1 provided by the present disclosure, the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 13.143, 17.241, 19.935, 21.381, and 22.796.

[0048] In some embodiments, for crystalline form I of the mesylate salt of the compound shown in Formula 1, the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 13.143, 14.030, 16.467, 17.241, 18.591, 19.935, 21.381, 22.796, 24.743, and 30.517.

[0049] In some embodiments, for crystalline form I of the mesylate salt of the compound shown in Formula 1, the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.527, 9.461, 13.143, 14.030, 15.210, 16.467, 17.241, 18.591, 19.935, 21.381, 22.089, 22.796, 24.743, 30.517, and 36.212.

[0050] In some embodiments, the methanesulfonate polymorph I of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as follows Figure 8 shown.

[0051] The present disclosure also provides a method for preparing the methanesulfonate polymorph I of the compound represented by Formula 1, the method comprising the steps of dissolving the compound represented by Formula 1 in ethyl acetate or methyl tert-butyl ether, adding an ethanol solution of methanesulfonic acid, and stirring.

[0052] The methanesulfonate polymorph II of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 8.914, 10.023, 13.928, 16.077, 17.438, and 19.813 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0053] In some embodiments, the methanesulfonate polymorph II of the compound represented by Formula 1 has characteristic peaks at 8.914, 10.023, 10.635, 12.847, 13.928, 16.077, 17.438, 19.813, 21.489, 22.803, 26.988, and 30.262 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0054] In some embodiments, the methanesulfonate polymorph II of the compound represented by Formula 1 has characteristic peaks at 8.914, 10.023, 10.635, 12.847, 13.385, 13.928, 16.077, 17.438, 17.901, 19.813, 20.522, 21.489, 22.803, 24.425, 25.201, 26.988, 29.020, and 30.262 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0055] In some embodiments, the methanesulfonate polymorph II of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as follows Figure 9 shown.

[0056] The present disclosure also provides a method for preparing the polymorph of the compound represented by Formula 1, the method comprising the steps of dissolving the compound represented by Formula 1 in acetone, adding an ethanol solution of methanesulfonic acid, and then adding isopropyl ether, and stirring.

[0057] The methanesulfonate polymorph III of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 9.885, 15.923, 17.601, 19.261, 21.130, and 24.082 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0058] In some embodiments, the methanesulfonate crystal form III of the compound represented by Formula 1 has characteristic peaks at 7.909, 9.885, 11.360, 13.842, 15.923, 17.067, 17.601, 19.261, 21.130, 21.612, 23.082, 24.082, 25.254, 31.118 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0059] In some embodiments, the methanesulfonate crystal form III of the compound represented by Formula 1 has characteristic peaks at 7.909, 9.885, 11.360, 11.912, 13.842, 15.474, 15.923, 17.067, 17.601, 19.261, 21.130, 21.612, 23.082, 24.082, 25.254, 26.738, 27.995, 28.648, 31.118 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0060] In some embodiments, the X-ray powder diffraction pattern of the methanesulfonate crystal form III of the compound represented by Formula 1 expressed in terms of diffraction angle 2θ is as Figure 10 shown.

[0061] The present disclosure also provides a method for preparing the methanesulfonate crystal form III of the compound represented by Formula 1, the method comprising the steps of dissolving the compound represented by Formula 1 in ethyl acetate, adding an ethanol solution of methanesulfonic acid, and then adding isopropyl ether and stirring.

[0062] The p-toluenesulfonate crystal form α of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 4.536, 7.961, 13.421, 18.102, 22.483 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0063] In some embodiments, the p-toluenesulfonate crystal form α of the compound represented by Formula 1 has characteristic peaks at 4.536, 7.961, 9.862, 11.166, 13.421, 15.513, 18.102, 18.960, 22.483 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0064] In some embodiments, the p-toluenesulfonate crystal form α of the compound represented by Formula 1 has characteristic peaks at 4.536, 7.961, 9.862, 11.166, 13.421, 15.513, 18.102, 18.960, 20.295, 21.258, 22.483, 24.207, 28.834 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0065] In some embodiments, the p-toluenesulfonate crystal form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as follows Figure 11 shown.

[0066] The present disclosure also provides a method for preparing the p-toluenesulfonate crystal form α of the compound represented by Formula 1, the method comprising the steps of dissolving the compound represented by Formula 1 in ethyl acetate, adding an ethanol solution of p-toluenesulfonic acid, and stirring.

[0067] The p-toluenesulfonate crystal form β of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 7.812, 9.835, 13.698, 18.244, 23.193 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0068] In some embodiments, the p-toluenesulfonate crystal form β of the compound represented by Formula 1 has characteristic peaks at 5.881, 7.812, 9.835, 11.974, 12.532, 13.698, 18.244, 19.151, 21.071, 22.282, 23.193, 26.101, 27.840, 28.772 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0069] In some embodiments, the p-toluenesulfonate crystal form β of the compound represented by Formula 1 has an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as follows Figure 12 shown.

[0070] The present disclosure also provides a method for preparing the p-toluenesulfonate crystal form β of the compound represented by Formula 1, the method comprising the steps of dissolving the compound represented by Formula 1 in methyl tert-butyl ether, adding an ethanol solution of p-toluenesulfonic acid, and stirring.

[0071] In some embodiments, the p-toluenesulfonate of the compound represented by Formula 1 provided by the present disclosure is amorphous, and there are no obvious characteristic peaks in the range of diffraction angle 2θ of 3-45° in its X-ray powder diffraction pattern.

[0072] The maleate crystal form a of the compound represented by Formula 1 provided by the present disclosure has characteristic peaks at 7.367, 14.551, 16.196, 17.811, 19.270, 21.320, 23.183, 26.847 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0073] In some embodiments, the maleate crystal form a of the compound of formula 1 has characteristic peaks at 7.367, 8.030, 14.551, 16.196, 17.811, 19.270, 21.320, 23.183, 25.977, 26.847 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0074] In some embodiments, the X-ray powder diffraction pattern of the maleate crystal form a of the compound of formula 1 expressed in terms of the diffraction angle 2θ is as Figure 13 shown.

[0075] The present disclosure also provides a method for preparing the maleate crystal form a of the compound of formula 1, the method comprising the steps of dissolving the compound of formula 1 in acetone, adding an ethanol solution of maleic acid, and then adding isopropyl ether and stirring.

[0076] The fumarate crystal form α of the compound of formula 1 provided by the present disclosure has characteristic peaks at 13.096, 15.496, 17.295, 19.685, 22.745, 28.726 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0077] In some embodiments, the fumarate crystal form α of the compound of formula 1 has characteristic peaks at 6.495, 10.413, 13.096, 15.496, 17.295, 19.194, 19.685, 21.133, 21.480, 22.745, 24.210, 24.733, 28.726 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0078] In some embodiments, the fumarate crystal form α of the compound of formula 1 has characteristic peaks at 6.495, 10.413, 13.096, 15.496, 17.295, 19.194, 19.685, 21.133, 21.480, 22.745, 24.210, 24.733, 27.829, 28.726, 29.942, 31.163, 36.134 in the X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ.

[0079] In some embodiments, the X-ray powder diffraction pattern of the fumarate crystal form α of the compound of formula 1 expressed in terms of the diffraction angle 2θ is as Figure 14 shown.

[0080] The present disclosure also provides a method for preparing the fumarate crystal form α of the compound of formula 1, the method comprising the steps of dissolving the compound of formula 1 in ethyl acetate, adding fumaric acid, and then adding isopropyl ether and stirring.

[0081] Tartrate crystal form I of the compound shown by formula 1 provided by the present disclosure has characteristic peaks at 6.118, 8.751, 9.994, 11.959, and 20.502 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0082] In some embodiments, tartrate crystal form I of the compound shown by formula 1 has characteristic peaks at 6.118, 8.751, 9.994, 11.959, 13.745, 15.420, 16.693, 17.594, and 20.502 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0083] In some embodiments, tartrate crystal form I of the compound shown by formula 1 has characteristic peaks at 6.118, 8.751, 9.994, 11.959, 13.745, 15.420, 16.693, 17.594, 20.502, 23.990, 24.797, and 26.816 in the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ.

[0084] In some embodiments, the X-ray powder diffraction pattern of tartrate crystal form I of the compound shown by formula 1 expressed in terms of diffraction angle 2θ is as Figure 15 shown.

[0085] The present disclosure also provides a method for preparing tartrate crystal form I of the compound shown by formula 1, the method comprising dissolving the compound shown by formula 1 in ethyl acetate or methyl tert-butyl ether or acetone, adding an ethanol solution of tartaric acid, and then adding isopropyl ether, and stirring.

[0086] In some embodiments, the tartrate of the compound shown by formula 1 provided by the present disclosure is amorphous, and there are no obvious characteristic peaks in the range of diffraction angle 2θ of its X-ray powder diffraction pattern.

[0087] The present disclosure also provides a pharmaceutical composition, which contains optionally the aforementioned hydrochloride, sulfate, phosphate, mesylate, tosylate, maleate, fumarate, tartrate or corresponding crystal form, and a pharmaceutical excipient selected from pharmaceutically acceptable excipients.

[0088] The present disclosure also provides a pharmaceutical composition, which is prepared from optionally the aforementioned hydrochloride, sulfate, phosphate, mesylate, tosylate, maleate, fumarate, tartrate or corresponding crystal form, and an optionally pharmaceutically acceptable excipient.

[0089] The present disclosure also provides a method for preparing a pharmaceutical composition, which includes the step of mixing the aforementioned hydrochloride, sulfate, phosphate, mesylate, tosylate, maleate, fumarate, tartrate or corresponding crystal form with a pharmaceutically acceptable excipient.

[0090] The present disclosure also provides the use of the aforementioned hydrochloride, sulfate, phosphate, mesylate, tosylate, maleate, fumarate, tartrate or corresponding crystal form or the aforementioned composition in the preparation for preventing and / or treating pain alleviation and pain-related diseases.

[0091] 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.

[0092] "A and / or B" in the present disclosure means any of the following situations: A; B; A and B, and in "A and B", the order of A and B is not restricted. For example, "including recrystallization and / or slurrying" means any of the following situations: "including recrystallization"; "including slurrying"; "including recrystallization and slurrying", and when it is "including recrystallization and slurrying", the order of recrystallization and slurrying is not restricted.

[0093] "2θ or 2θ angle" as described in the present disclosure refers to the diffraction angle, 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.

[0094] In the present disclosure, if the numerical values such as the content of related substances are data determined and calculated, 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 where it is used, and this error variation does not exceed ±10%, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, preferably ±5%.

[0095] The starting materials used in the preparation method of the disclosed crystal forms can be compounds in any form, and the specific forms include but are not limited to: amorphous, any crystal form, hydrate, solvate, etc.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] According to the description of hygroscopicity characteristics and the definition of hygroscopic weight gain in the "Guideline for Drug Hygroscopicity" in Part IV of the Chinese Pharmacopoeia 2015 Edition,

[0100] Deliquescence: Absorbing sufficient moisture to form a liquid;

[0101] Highly hygroscopic: The hygroscopic weight gain is not less than 15%;

[0102] Hygroscopic: The hygroscopic weight gain is less than 15% but not less than 2%;

[0103] Slightly hygroscopic: The hygroscopic weight gain is less than 2% but not less than 0.2%;

[0104] Non-hygroscopic or almost non-hygroscopic: The hygroscopic weight gain is less than 0.2%.

[0105] 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 domestic animals. Description of the Drawings

[0106] Figure 1 It is the analgesic efficacy of Compound 1 in the rat incision pain model.

[0107] Figure 2 It is the effect of Compound 1 on body weight in the rat incision pain model.

[0108] Figure 3 It is the XRPD pattern of crystalline form a of Compound 1 hydrochloride.

[0109] Figure 4 It is the XRPD pattern of crystalline form b of compound 1 hydrochloride.

[0110] Figure 5 It is the XRPD pattern of crystalline form I of compound 1 sulfate.

[0111] Figure 6 It is the XRPD pattern of crystalline form II of compound 1 sulfate.

[0112] Figure 7 It is the XRPD pattern of crystalline form α of compound 1 phosphate.

[0113] Figure 8 It is the XRPD pattern of crystalline form I of compound 1 mesylate.

[0114] Figure 9 It is the XRPD pattern of crystalline form II of compound 1 mesylate.

[0115] Figure 10 It is the XRPD pattern of crystalline form III of compound 1 mesylate.

[0116] Figure 11 It is the XRPD pattern of crystalline form α of compound 1 tosylate.

[0117] Figure 12 It is the XRPD pattern of crystalline form β of compound 1 tosylate.

[0118] Figure 13 It is the XRPD pattern of crystalline form a of compound 1 maleate.

[0119] Figure 14 It is the XRPD pattern of crystalline form α of compound 1 fumarate.

[0120] Figure 15 It is the XRPD pattern of crystalline form I of compound 1 tartrate. Detailed implementation manners

[0121] 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.

[0122] Test conditions of the instruments used in the experiments:

[0123] The structure of the compound was determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) was given in units of 10-6 (ppm). The NMR measurement was performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer or a Bruker AVANCE NEO 500M, and the solvents used for the measurement were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0124] The MS measurement was performed using an Agilent 1200 / 1290DAD-6110 / 6120Quadrupole MS liquid chromatography-mass spectrometry instrument (manufacturer: Agilent, MS model: 6110 / 6120Quadrupole MS).

[0125] waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity QdaDe-tec-tor / waters SQ Detector)

[0126] THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO QExactive)

[0127] High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 high performance liquid chromatography instrument.

[0128] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatography instrument.

[0129] High performance liquid chromatography preparative work was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatography instruments.

[0130] Chiral preparative work was performed using a Shimadzu LC-20AP preparative chromatography instrument.

[0131] The CombiFlash rapid preparative instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0132] For thin-layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications of the silica gel plates used in thin-layer chromatography (TLC) are 0.15 mm 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.

[0133] For silica column chromatography, silica gel with 200 - 300 mesh from Yantai Huanghai is generally used as the carrier.

[0134] The determination of the average inhibition rate and IC50 value of kinases is carried out using a NovoStar microplate reader (from BMG Labtech, Germany).

[0135] The known starting materials of the present invention can be used or synthesized according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.

[0136] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere.

[0137] 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.

[0138] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0139] For catalytic hydrogenation reactions, a Parr 3916EKX hydrogenator and Qinglan QL - 500 hydrogen generator or HC2 - SS hydrogenator are used.

[0140] For hydrogenation reactions, usually, the system is evacuated, filled with hydrogen, and this operation is repeated 3 times.

[0141] For microwave reactions, a CEM Discover - S 908860 microwave reactor is used.

[0142] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0143] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20 °C to 30 °C.

[0144] The monitoring of the reaction progress in the examples is carried out by thin-layer chromatography (TLC). The eluent systems for column chromatography used to purify compounds and the developing agent systems for thin-layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system. The volume ratio of the solvents is adjusted according to the polarity of the compounds, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0145] XRPD is X-ray powder diffraction detection: The determination was carried out using a BRUKER D8 type X-ray diffractometer. The specific acquisition information: Cu anode (40 kV, 40 mA), Cu-Kα1 ray Kα2 ray Kβ ray Scanning mode: θ / 2θ, scanning range (2θ range): 3° to 45°.

[0146] DSC is differential scanning calorimetry: The determination was carried out using a METTLER TOLEDO DSC 3+ differential scanning calorimeter. The heating rate was 10 °C / min, and the specific temperature range was referred to the corresponding spectrum (mostly 25 - 200 or 300 or 350 °C), and the nitrogen purge rate was 50 mL / min.

[0147] TGA is thermogravimetric analysis: The detection was carried out using a METTLER TOLEDO TGA 2 type thermogravimetric analyzer. The heating rate was 10 °C / min, and the specific temperature range was referred to the corresponding spectrum (mostly 30 - 350 °C), and the nitrogen purge rate was 50 mL / min.

[0148] DVS is dynamic vapor sorption: The detection was carried out using 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%.

[0149] Preparation of the compound of Formula 1 in Example 1 (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-hydroxyformamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0150]

[0151] The first step

[0152] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-1

[0153] (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1b-2

[0154] rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid 1a (12 g, 33.87 mmol, prepared by the method disclosed in Example 3 on page 231 of the specification of patent application "WO2021113627") was resolved by a chiral column (Waters SFC 150, column: DAICEL IC, 40*250 mm, 10 μm; mobile phase A: supercritical CO 2 , mobile phase B: IPA), gradient ratio: A:B: 90:10, flow rate: 120 mL / min) to obtain the title product 1b-1 (5.5 g, yield: 45.8%) and 1b-2 (5.08 g, yield: 42.3%).

[0155] MS m / z (ESI): 353.2 [M-1].

[0156] Single-configuration compound (shorter retention time) 1b-1 (5.5 g, yield: 45.8%)

[0157] MS m / z (ESI): 353.2 [M-1].

[0158] 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).

[0159] Single-configuration compound (longer retention time) 1b-2 (5.08 g, yield: 42.3%).

[0160] MS m / z (ESI): 353.2 [M-1].

[0161] 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).

[0162] 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

[0163] Dissolve compound 1b-1 (50 mg, 141 μmol) in dichloromethane (10 mL). Add oxalyl chloride (40 mg, 315 μmol) and 1 drop of N,N-dimethylformamide under ice bath. Resume the reaction at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure. Dissolve the residue in dichloromethane (3 mL). Add N,N-diisopropylethylamine (60 mg, 464 μmol). Dropwise add a dichloromethane solution (1 mL) of 4-aminopyridine-2-carbonitrile 1c (30 mg, 251 μmol, Shanghai Hanhong) under ice bath. Stir the reaction for 2 hours. Concentrate the reaction solution under reduced pressure. Purify the residue by silica gel column chromatography with elution system B to obtain the title compound 1d (45 mg, yield: 70%).

[0164] MS m / z (ESI): 456.2 [M+1].

[0165] Step 3: (2R,3S,4S,5R)-3-(3,4-Difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-hydroxyformamidinyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0166] Dissolve compound 1d (200 mg, 439.2 μmol) in methanol (4 mL). Add hydroxylamine hydrochloride (61 mg, 877.8 μmol) and N,N-diisopropylethylamine (60 mg, 464.2 μmol). Stir the reaction for 1.5 hours. Concentrate the reaction solution under reduced pressure. Dissolve the residue in dichloromethane. Wash it successively with water and saturated sodium chloride solution. Concentrate the organic phase under reduced pressure. Purify the residue by silica gel column chromatography with elution system A to obtain the title compound 1 (160 mg, yield: 74.6%).

[0167] MS m / z (ESI): 489.0 [M+1].

[0168] 1 H NMR (500 MHz, CDCl 3 ): δ 8.61 (s, 1H), 8.46 (d, 1H), 7.87 (dd, 1H), 7.83 (d, 1H), 7.09 (ddd, 1H), 6.92 (td, 1H), 5.75 (s, 2H), 5.02 (d, 1H), 4.10 (dd, 1H), 4.01 (d, 3H), 2.76 (p, 1H), 1.68 (s, 3H), 0.80 (dq, 3H).

[0169] Test Example 1: Determination of the inhibitory activity of the compounds of the present disclosure against Nav1.8

[0170] The purpose of the experiment was to investigate the effect of the compounds 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 compounds was compared to obtain the effect of the compounds on the Nav1.8 ion channel.

[0171] 1 Experimental materials and instruments

[0172] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments) / MultiClamp700A (Axoninstrument)

[0173] 2) Digital-to-analog converter: Digidata 1440A (Axon CNS) / Digidata 1550A (Axoninstruments)

[0174] 3) Micromanipulator: MP-225 (SUTTER instrument)

[0175] 4) Inverted microscope: TL4 (Olympus)

[0176] 5) Glass microelectrode puller: PC-10 (NARISHIGE)

[0177] 6) Microelectrode glass capillary: B12024F (Wuhan Microprobe Scientific Instruments Co., Ltd.)

[0178] 7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

[0179] 8) TTX AF3014 (Affix Scientific)

[0180] 2 Experimental procedures

[0181] 2.1 Compound preparation

[0182] Compounds for preparing the extracellular and intracellular solutions were purchased from Sigma (St. Louis, MO) except for NaOH and KOH used for 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; MgCl2 , 2; EGTA 11; HEPES, 10; pH 7.2 (titrated with CsOH). All test compound and control compound solutions contained 1 μM TTX.

[0183] 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.

[0184] 2.2 Manual patch clamp test procedure

[0185] 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.

[0186] 2) Transfer the cell to the perfusion chamber, apply positive pressure inside the electrode, touch the tip of the electrode to the cell, adjust the three-way valve of the aspiration device to the three-way state, then apply negative pressure to the electrode to form a high-resistance seal with the cell. Continue to apply negative pressure to rupture the cell membrane and form a current path.

[0187] 3) After the whole-cell current was stable, perfusions with different concentrations were carried out in sequence. If the current was stable for at least one minute, the next concentration could be perfused. The perfusion time for each concentration was no more than five minutes.

[0188] 4) Wash the perfusion chamber. Rinse in descending order of drug concentration, with each concentration of drug solution rinsed for 20 s. Finally, rinse with extracellular solution for 1 min.

[0189] 2.3 Test voltage equation (resting) and results

[0190] 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 program 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 degree of block was calculated.

[0191] 3. Data analysis

[0192] The data would be stored in a computer system for analysis. Data acquisition and analysis would be performed using pCLAMP 10 (Molecular Devices, Union City, CA), and the results of the analysis would be reviewed by the supervisor. Current stability meant that the current changed within a limited range over time. The magnitude of the current after stability was used to calculate the effect of the compound at this concentration.

[0193] 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.

[0194] Table 1 IC of the compounds of the present disclosure for inhibiting Nav1.8 channel activity 50

[0195] Example Number <![CDATA[IC 50 (nM)]]> 1 0.93

[0196] Conclusion: The compounds in the present disclosure have an obvious inhibitory effect on Nav1.8 channel activity.

[0197] Test Example 2: Pharmacokinetic Evaluation

[0198] I. SD Rat Experiment

[0199] Using SD rats as test animals, the drug concentrations in plasma at different times after intragastric administration (i.g.) of the compounds of the examples were determined by LC / MS / MS method. The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied to evaluate their pharmacokinetic characteristics.

[0200] 1.1 Experimental Protocol

[0201] Experimental animals: 4 male SD rats, provided by Vital River Laboratory Animal Technology Co., Ltd. After fasting overnight, they were administered intragastrically.

[0202] Drug preparation: Weigh a certain amount of the test compound respectively, add 5% DMSO + 5% Tween 80 + 90% normal saline to prepare a colorless and clear solution of 0.2 mg / mL.

[0203] Drug administration: The administration dose was 2 mg / kg, and the administration volume was 10.0 mL / kg.

[0204] Operation Method

[0205] 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 blood collection to centrifugation process was operated under ice bath conditions. Food was provided 2 hours after drug administration.

[0206] Determine the content of the test compound in the plasma of SD rats after administration of different concentrations of the drug: Take 25 μL of the plasma samples of SD rats at each time 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.

[0207] 1.2 Results of Pharmacokinetic Parameters

[0208] Table 2. Pharmacokinetic Parameters of the Compounds of the Present Disclosure

[0209]

[0210] Conclusion: The compounds of the present disclosure have high blood drug concentrations and high exposure levels in SD rats, showing significant pharmacokinetic advantages.

[0211] II. Experiments on C57 Mice

[0212] 2.1 Experimental Animals

[0213] Eighteen C57 mice, half male and half female, were evenly divided into 2 groups, with 9 mice in each group. Three mice were used 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.

[0214] 2.2 Drug Preparation

[0215] Weighed a certain amount of the test compound respectively, and added 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).

[0216] 2.3 Drug Administration

[0217] Gavage Administration Group: The administration dose was 2.0 mg / kg, and the administration volume was 20 mL / kg.

[0218] Intravenous Injection Administration Group: The administration dose was 1.0 mg / kg, and the administration volume was 10 mL / kg.

[0219] 2.4 Procedures

[0220] Gavage Administration Group: Before drug administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after drug 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), the plasma was separated within 1 hour, and stored at -80°C for later measurement. The blood collection to centrifugation process was carried out under ice bath conditions.

[0221] Intravenous Injection Administration Group: Before drug administration and at 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours after drug administration, blood was collected, and the treatment was the same as that of the gavage administration group.

[0222] 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 verapamil (internal standard 20 ng / mL) to each sample to precipitate proteins. Vortex for 5 minutes and centrifuge at 3700 rpm for 10 minutes. Take 90 μL of the supernatant, add 90 μL of water, vortex for 5 minutes, and inject 0.1 μL for LC / MS / MS analysis.

[0223] 2.5 Pharmacokinetic parameter results

[0224] Table 3. Pharmacokinetic parameters of the compounds of the present disclosure

[0225]

[0226] 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.

[0227] Test Example 3 Pharmacodynamic experiment

[0228] 1. Experimental purpose

[0229] Evaluate the analgesic efficacy of the compounds of the present disclosure in inhibiting pain in a rat incision pain model.

[0230] 2. Experimental drugs

[0231] Compound of Example 1.

[0232] Use a solution of 25% PEG400 + 75% (10% TPGS + 1% HPMC K100LV).

[0233] 3. Experimental methods and experimental materials

[0234] 3.1 Experimental animals and breeding conditions

[0235] Experimental animals: SD rats, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (License number: SCXK(Zhe)2019-0001), with a body weight of about 180 g when purchased.

[0236] Breeding conditions: Raised at 5 rats per cage, with a 12 / 12-hour light / dark cycle adjustment, a constant temperature of 23 ± 1 °C, a humidity of 50 to 60%, and free access to food and water.

[0237] 3.2 Animal grouping

[0238] After the SD rats were adaptively raised, the grouping was as follows:

[0239] Table 4

[0240]

[0241] Note: One dose means administering the drug only once; i.g. means intragastric administration.

[0242] 3.3 Experimental method:

[0243] Take 9 SD rats weighing 170 - 190 g. Measure the mechanical pain threshold using an electronic tactile measuring instrument. Then perform an incision pain surgery. During the surgery, after anesthesia with Zoletil (Zoletil - 50, 250 mg, diluted to 50 ml with normal saline after dissolution, and 2 ml is injected for 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. Pass through the skin and fascia, and suture the skin with 3 - 0 sterile silk surgical sutures. Disinfect the injured area with penicillin, and return the animal to its original place to recover overnight. After overnight recovery from the surgery, administer the drug by oral gavage. Measure the mechanical pain threshold using an electronic tactile measuring instrument 5 h after drug administration (about 24 h after the surgery).

[0244] 3.4 Data statistics

[0245] 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 use one - way ANOVA and t - test for statistical analysis of the data.

[0246] 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.

[0247] 4. Results

[0248] The analgesic efficacy of the compound in Example 1 in the rat incision pain model is as Figure 1 shown in and Table 5, and the influence of body weight is shown in Figure 2 ;

[0249] Table 5 Analgesic efficacy of the compounds of the present disclosure in the rat incision pain model

[0250]

[0251] Note: One dose means administering the drug only once; i.g. means intragastric administration.

[0252] 5. Conclusion

[0253] The pain threshold of normal rats (weighing 170 - 190 g) was 26.3 ± 0.8 gf, and that of the solvent control group was 10.4 ± 0.9 gf. For the compound of Example 1, the pain thresholds at 200, 100, and 30 mg / kg were 22.4, 22.3, and 12.0 gf respectively. The pain thresholds were significantly increased by 114% (p < 0.001), 114% (p < 0.001), and 15% respectively compared with the solvent control group. The pain threshold at 200 mg / kg was equivalent to that at 100 mg / kg, indicating that the analgesic efficacy reached saturation. The pain threshold at 100 mg / kg was significantly higher than that at 30 mg / kg (p < 0.01), showing an obvious dose-dependence of the analgesic effect, and the administration had no effect on the body weight of the rats.

[0254] Preparation of the hydrochloride salt in Example 2

[0255] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of acetone, add 6.7 μL of 2 M hydrochloric acid ethanol solution, add 1 mL of isopropyl ether, stir at room temperature for precipitation, centrifuge, and dry in vacuo to obtain a solid. Detected by X-ray powder diffraction, the product was an amorphous hydrochloride salt, and there were no obvious characteristic peaks in the XRPD spectrum.

[0256] Preparation of the crystalline form a of the hydrochloride salt in Example 3

[0257] Dissolve 6 mg of the compound shown in Formula 1 in 0.2 mL of methyl tert-butyl ether, add 6.7 μL of 2 M hydrochloric acid ethanol solution, stir at room temperature for crystallization, centrifuge, and dry the solid in vacuo to obtain a solid product.

[0258] Detected by X-ray powder diffraction, this product was defined as the crystalline form a of the hydrochloride salt, and the XRPD spectrum was as Figure 3 , and the positions of its characteristic peaks are shown in Table 6. The DSC spectrum showed that the peak value of the endothermic peak was 134.88 °C. The TGA spectrum showed that the weight loss was 6.07% from 30 °C to 140 °C. The ion detection results showed that the chloride ion content was 7.1%.

[0259] The DVS detection showed that under normal storage conditions (i.e., 25 °C, 60% RH), the moisture absorption weight gain of this sample was about 0.1%; under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain was about 0.1%; under extreme conditions (90% RH), the moisture absorption weight gain was about 0.3%; after the DVS detection, the crystalline form was retested and no crystalline form transformation occurred.

[0260] Table 6

[0261]

[0262]

[0263] Preparation of the crystalline form a of the hydrochloride salt in Example 4

[0264] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of ethyl acetate, add 6.7 μL of 2 M hydrochloric acid ethanol solution, stir at room temperature for crystallization, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0265] Preparation of hydrochloride crystal form b in Example 5

[0266] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of ethyl acetate, add 12.9 μL of 2 M hydrochloric acid ethanol solution, stir at room temperature for crystallization, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0267] Detected by X-ray powder diffraction, this product is defined as hydrochloride crystal form b, and 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 129.24 °C. The TGA pattern shows that the weight loss is 10.74% from 30 °C to 150 °C. The ion detection result shows that the chloride ion content is 14.0%.

[0268] Table 7

[0269]

[0270]

[0271] Preparation of sulfate crystal form I in Example 6

[0272] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of acetone, add 6.7 μL of 2 M sulfuric acid ethanol solution, add 1 mL of isopropyl ether, stir at room temperature for crystallization, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0273] Detected by X-ray powder diffraction, this product is defined as sulfate crystal form I, and the XRPD pattern is as Figure 5 , and the characteristic peak positions are shown in Table 8. The DSC pattern shows that the peak values of the endothermic peaks are 81.46 °C, 153.11 °C, and 197.93 °C. The TGA pattern shows that the weight loss is 3.21% from 30 °C to 120 °C, 3.89% from 120 °C to 180 °C, and 1.86% from 180 °C to 220 °C. The ion detection result shows that the sulfate content is 23.1%.

[0274] Table 8

[0275]

[0276]

[0277] Preparation of sulfate crystal form II in Example 7

[0278] Dissolve 6 mg of the compound shown in Formula 1 in 0.2 mL of methyl tert-butyl ether, add 6.7 μL of 2 M sulfuric acid ethanol solution, add 1 mL of isopropyl ether, stir and crystallize at room temperature, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0279] Detected by X-ray powder diffraction, this product was defined as sulfate crystal form II, and the XRPD pattern is as Figure 6 , and the characteristic peak positions are shown in Table 9. The DSC pattern shows that the peak value of the endothermic peak is 87.42 °C. The TGA pattern shows that the weight loss is 4.33% from 30 °C to 130 °C.

[0280] Table 9

[0281]

[0282] Preparation of phosphate crystal form α in Example 8

[0283] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of acetone, add 6.7 μL of 2 M phosphoric acid ethanol solution, add 1 mL of isopropyl ether, stir and crystallize at room temperature, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0284] Detected by X-ray powder diffraction, this product was defined as phosphate crystal form α, and the XRPD pattern is as Figure 7 , and the characteristic peak positions are shown in Table 10. The DSC pattern shows that the peak value of the endothermic peak is 166.11 °C. The TGA pattern shows that the weight loss is 0.21% from 32 °C to 150 °C. The ion detection result shows that the content of phosphate ions is 22.1%.

[0285] Table 10

[0286]

[0287]

[0288] Preparation of mesylate crystal form I in Example 9

[0289] Dissolve 80 mg of the compound shown in Formula 1 in 1 mL of ethyl acetate, add 168 μL of 2 M methanesulfonic acid ethanol solution, stir and crystallize at room temperature, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0290] Detected by X-ray powder diffraction, this product was defined as mesylate crystal form I, and the XRPD pattern is as Figure 8 , and the characteristic peak positions are shown in Table 11. The DSC pattern shows that the peak value of the endothermic peak is 183.61 °C. The TGA pattern shows that the weight loss is 0.18% from 32 °C to 180 °C. The ion detection result shows that the content of methanesulfonate ions is 32.8%.

[0291] DVS testing showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample gained about 2.6% of its weight due to moisture absorption; under accelerated experimental conditions (i.e. 70% RH), the weight gain due to moisture absorption was about 27.8%; under extreme conditions (90% RH), the weight gain due to moisture absorption was about 64.4%; after the DVS test, the crystal form was retested and the crystal form did not change.

[0292] Table 11

[0293]

[0294]

[0295] Example 10 Preparation of Methanesulfonate Crystal Form I

[0296] 6 mg of the compound represented by formula 1 was dissolved in 0.2 mL of methyl tert-butyl ether, and 12.9 μL of 2M methanesulfonic acid ethanol solution was added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0297] Example 11 Preparation of Methanesulfonate Crystalline Form II

[0298] 6 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, 6.7 μL of 2M methanesulfonic acid ethanol solution was added, 1 mL of isopropyl ether was added, the mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0299] The product was defined as mesylate crystal form II by X-ray powder diffraction detection. The XRPD spectrum is as follows: Figure 9 The characteristic peak positions are shown in Table 12. The DSC spectrum shows that the endothermic peaks are 118.79°C and 152.11°C. The TGA spectrum shows that the weight loss is 2.32% at 30°C-125°C. The ion detection results show that the methanesulfonate ion content is 15.2%.

[0300] Table 12

[0301]

[0302]

[0303] Example 12 Preparation of Methanesulfonate Form III

[0304] 100 mg of the compound of formula 1 was dissolved in 0.5 mL of ethyl acetate, 106.6 μL of 2M methanesulfonic acid ethanol solution was added, 5 mL of isopropyl ether was added, and the mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0305] The product was defined as mesylate crystal form III by X-ray powder diffraction detection. The XRPD spectrum is as follows: Figure 10The characteristic peak positions are shown in Table 13. The DSC spectrum shows that the endothermic peak value is 100.66°C. The TGA spectrum shows that the weight loss is 3.84% at 30°C-150°C. The ion detection results show that the methanesulfonate ion content is 17.5%.

[0306] DVS testing showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample gained about 1.7% of its weight due to moisture absorption; under accelerated experimental conditions (i.e. 70% RH), the weight gain due to moisture absorption was about 1.9%; under extreme conditions (90% RH), the weight gain due to moisture absorption was about 3.6%; after the DVS test, the crystal form was retested and the crystal form did not change.

[0307] Table 13

[0308]

[0309] Example 13 Preparation of p-toluenesulfonate

[0310] 6 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of acetone, 6.7 μL of 2M p-toluenesulfonic acid ethanol solution was added, 1 mL of isopropyl ether was added, stirred at room temperature to precipitate, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis showed that the product was amorphous p-toluenesulfonate, and the XRPD spectrum had no obvious characteristic peaks.

[0311] Example 14 Preparation of p-toluenesulfonate Crystalline Form α

[0312] 80 mg of the compound represented by Formula 1 was dissolved in 1 mL of ethyl acetate, and 168 μL of 2M p-toluenesulfonic acid ethanol solution was added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0313] The product was defined as p-toluenesulfonate crystalline form α by X-ray powder diffraction detection. The XRPD spectrum is as follows: Figure 11 The characteristic peak positions are shown in Table 14. The DSC spectrum shows that the endothermic peak value is 191.89°C. The TGA spectrum shows that the weight loss is 0.16% from 32°C to 197°C. The ion detection results show that the p-toluenesulfonate ion content is 45.2%.

[0314] Table 14

[0315]

[0316] Example 15 Preparation of p-toluenesulfonate Form β

[0317] 80 mg of the compound represented by Formula 1 was dissolved in 2.5 mL of methyl tert-butyl ether, and 168 μL of 2M p-toluenesulfonic acid ethanol solution was added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0318] The product was defined as p-toluenesulfonate crystal form β by X-ray powder diffraction detection. The XRPD pattern is as Figure 12 , and the characteristic peak positions are shown in Table 15. The DSC pattern shows that the peak value of the endothermic peak is 193.75 °C. The TGA pattern shows that the weight loss is 0.21% from 32 °C to 190 °C. The ion detection result shows that the content of p-toluenesulfonate ions is 41.8%.

[0319] DVS detection shows that under normal storage conditions (i.e., 25 °C, 60% RH), the moisture absorption weight gain of this sample is about 0.3%; under accelerated test conditions (i.e., 70% RH), the moisture absorption weight gain is about 0.5%; under extreme conditions (90% RH), the moisture absorption weight gain is about 1.5%; after DVS detection, the crystal form was retested and no crystal form transformation occurred.

[0320] Table 15

[0321]

[0322] Preparation of maleate crystal form a in Example 16

[0323] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of acetone, add 6.7 μL of 2M maleic acid ethanol solution, add 1 mL of isopropyl ether, stir and crystallize at room temperature, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0324] The product was defined as maleate crystal form a by X-ray powder diffraction detection. 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 126.96 °C. The TGA pattern shows that the weight loss is 0.51% from 30 °C to 125 °C. The ion detection result shows that the content of maleate ions is 23.5%.

[0325] Table 16

[0326]

[0327]

[0328] Preparation of fumarate crystal form α in Example 17

[0329] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of ethyl acetate, add 1.5 mg of fumaric acid, add 1 mL of isopropyl ether, stir and crystallize at room temperature, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0330] The product was defined as fumarate crystal form α by X-ray powder diffraction detection. The XRPD pattern is as Figure 14, and the characteristic peak positions are shown in Table 17. The DSC spectrum shows that the peak value of the endothermic peak is 143.61 °C. The TGA spectrum shows that the weight loss from 30 °C to 150 °C is 0.71%. The nuclear magnetic detection results show that the ratio of fumaric acid to the compound shown in Formula 1 is about 1:1.

[0331] Table 17

[0332]

[0333] Preparation of tartrate in Example 18

[0334] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of acetone, add 6.7 μL of 2M tartaric acid ethanol solution, add 1 mL of isopropyl ether, stir at room temperature for precipitation, centrifuge, and dry in vacuum to obtain a solid. After X-ray powder diffraction detection, this product is an amorphous tartrate, and the XRPD spectrum has no obvious characteristic peaks.

[0335] Preparation of tartrate polymorph I in Example 19

[0336] Dissolve 100 mg of the compound shown in Formula 1 in 0.5 mL of ethyl acetate, add 106.6 μL of 2M tartaric acid ethanol solution, add 5 mL of isopropyl ether, stir at room temperature for crystallization, centrifuge, and dry in vacuum to obtain a solid. After X-ray powder diffraction detection, this product is defined as tartrate polymorph I, and the XRPD spectrum is as Figure 15 , and the characteristic peak positions are shown in Table 18. The DSC spectrum shows that the peak value of the endothermic peak is 138.92 °C. The TGA spectrum shows that the weight loss from 30 °C to 135 °C is 0.74%. The ion detection results show that the content of tartrate ions is 23.92%.

[0337] DVS detection shows that under normal storage conditions (i.e., 25 °C, 60% RH), the sample absorbs moisture and gains about 1.1% in weight; under accelerated test conditions (i.e., 70% RH), the moisture absorption and weight gain is about 1.5%; under extreme conditions (90% RH), the moisture absorption and weight gain is about 3.8%; after DVS detection, the polymorph is retested and the polymorph has not changed.

[0338] Table 18

[0339]

[0340] Preparation of tartrate polymorph I in Example 20

[0341] Dissolve 6 mg of the compound shown in Formula 1 in 0.2 mL of methyl tert-butyl ether, add 6.7 μL of 2M tartaric acid ethanol solution, add 1 mL of isopropyl ether, stir at room temperature for crystallization, centrifuge, and dry the solid in vacuum to obtain a solid product.

[0342] Preparation of tartrate polymorph I in Example 21

[0343] Dissolve 6 mg of the compound shown in Formula 1 in 0.1 mL of acetone, add 12.9 μL of 2 M tartaric acid ethanol solution, add 1 mL of isopropyl ether, stir and crystallize at room temperature, centrifuge, and dry the solid under vacuum to obtain a solid product.

[0344] Example 22: Study on Crystal Form Stability

[0345] Place the hydrochloride crystal form a in an open and flat manner, and investigate the stability of the sample under the conditions of high temperature (40 °C and 60 °C), high humidity (RH 75%, RH 92.5%), and light (4500 lux) respectively. The sampling investigation period is 30 days.

[0346] Table 19

[0347]

[0348]

[0349] Conclusion: The stress testing experiments show that the hydrochloride crystal form a has good physical and chemical stability for 30 days under the stress conditions of high temperature (40 °C, 60 °C), high humidity (75% RH, 92.5% RH), and light.

[0350] Example 23: Long-Term / Accelerated Stability

[0351] Place the hydrochloride crystal form a and the mesylate crystal form III under the conditions of 25 °C / 60% RH and 40 °C / 75% RH respectively to investigate the stability.

[0352] Table 20

[0353]

[0354] Conclusion: The long-term and accelerated experiments show that the hydrochloride crystal form a is physically and chemically stable for 3 months under the condition of 25 °C / 60% RH; under nitrogen-filled packaging, it has good chemical stability for 3 months under the condition of 40 °C / 75% RH. Under nitrogen-filled packaging, the mesylate crystal form III has good physical and chemical stability for 3 months.

Claims

1. A pharmaceutically acceptable salt of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-(N'-hydroxycarbamimidyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide as shown in Formula 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, and tartrate.

2. The pharmaceutically acceptable salt according to claim 1, characterized in that The chemical ratio of the compound represented by Formula 1 to 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 represented by formula 1 with an acid, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, and tartaric acid.

4. The hydrochloride crystal form a of the compound of formula 1 according to claim 1 or 2, characterized in that: The X-ray powder diffraction pattern expressed as a diffraction angle 2θ has characteristic peaks at 8.468, 14.212, 16.156, 24.285, and 27.130, preferably at 8.468, 10.524, 14.212, 15.314, 16.156, 17.118, 20.186, 22.210, 24.285, 27.130, 27.763, 31.432, 33.864 There are characteristic peaks at 8.468, 10.524, 14.212, 15.314, 16.156, 16.499, 17.118, 19.066, 20.186, 21.412, 22.210, 24.285, 26.422, 27.130, 27.763, 28.866, 30.794, 31.432, 33.150, and 33.

864.

5. The hydrochloride salt form a according to claim 4, characterized in that: The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG3 .

6. A method for preparing the hydrochloride crystal form a as claimed in claim 4 or 5, comprising the steps of dissolving the compound represented by formula 1 in ethyl acetate or methyl tert-butyl ether, adding hydrochloric acid ethanol solution, and stirring.

7. The crystal form according to claim 4 or 5, wherein the 2θ angle error range is ±0.

20.

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

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

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

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

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