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 invention belongs to the field of medical technology and relates to a pharmaceutically acceptable salt of a substituted tetrahydrofuran derivative, a crystal form thereof and a use thereof. Background Art

[0002] Nav is a class of transmembrane ion channel proteins. Depending on whether they 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 a TTX-R type, encoded by the gene SCN10A, which is mainly present in trigeminal ganglion neurons and DRG neurons, and has the electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav 1.8, the rise of action potentials is mainly composed of Nav1.8 currents. In some models of studying neuropathic pain, nerve injury will increase the expression level of Nav1.8 in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression. After carrageenan was injected into the paw of rats, the expression of Nav1.8 in DRG neurons increased. Nav1.8 knockout mice cannot show normal visceral inflammatory pain. When the human Nav1.8 gene produces a gain-of-function mutation, it will cause peripheral neuropathy. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new type of analgesic therapy, which can be used to treat inflammatory pain, neuralgia, postoperative pain, cancer pain and other types of 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'-hydroxycarbamimidyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, having a structure shown in Formula 1,

[0004]

[0005] Salt formation can improve some undesirable physical, chemical or biological properties of drugs. It is of great significance to develop salts with superior physical and chemical properties or pharmaceutical properties compared to (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. In view of the importance of solid drug crystal forms and their stability in clinical treatment, in-depth research on the polymorphic forms of pharmaceutically acceptable salts of the compound (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 is also of great significance for the development of drugs suitable for industrial production and with good biological activity. Summary of the invention

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

[0007]

[0008] The present disclosure also provides a method for preparing a pharmaceutically acceptable salt of the compound of formula 1, comprising the step of reacting the compound of 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.

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

[0010] In an alternative embodiment, the method for preparing the aforementioned pharmaceutically acceptable salts disclosed herein further comprises the step of formulating the acid into a corresponding alcohol solution.

[0011] Furthermore, in an optional embodiment, the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of crystallization, filtering, washing or drying.

[0012] In an optional 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 optional embodiment, the chemical ratio of the compound of formula 1 to hydrochloric acid is 1:1 or 1:2.

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

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

[0017] In an optional 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 optional embodiment, the chemical ratio of the compound of formula 1 to p-toluenesulfonic acid is 1:1 or 1:2.

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

[0020] In an optional embodiment, the chemical ratio of the compound of formula 1 and fumaric acid is 1:1.

[0021] In an optional 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 represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 8.468, 14.212, 16.156, 24.285, and 27.130.

[0023] In some embodiments, the hydrochloride form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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.

[0024] In some embodiments, the hydrochloride form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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.

[0025] In some embodiments, the hydrochloride salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 3 shown.

[0026] The present disclosure also provides a method for preparing hydrochloride crystal form a 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 hydrochloric acid ethanol solution, and stirring.

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

[0028] In some embodiments, the hydrochloride salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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.

[0029] In some embodiments, the hydrochloride form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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.

[0030] In some embodiments, the hydrochloride salt form b of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 4 shown.

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

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

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

[0034] In some embodiments, the sulfate crystalline 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, and 22.810 in an X-ray powder diffraction pattern represented by a diffraction angle 2θ.

[0035] In some embodiments, the sulfate crystalline form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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, and 29.502.

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

[0037] The present disclosure also provides a method for preparing 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 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 in the present disclosure has characteristic peaks at 9.882, 16.107, 17.164, 21.206 and 24.387 in an X-ray powder diffraction pattern represented by a diffraction angle 2θ.

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

[0040] In some embodiments, the sulfate crystalline form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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, and 28.512.

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

[0042] The present disclosure also provides a method for preparing sulfate crystal form II 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 sulfuric acid ethanol solution, then adding isopropyl ether, and stirring.

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

[0044] In some embodiments, the phosphate crystal form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with 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 phosphate crystal form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 7 shown.

[0046] The present disclosure also provides a method for preparing the phosphate crystal form α 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] The mesylate crystalline form I of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 13.143, 17.241, 19.935, 21.381, and 22.796.

[0048] In some embodiments, the mesylate salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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, the mesylate salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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 mesylate salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Figure 8 shown.

[0051] The present disclosure also provides a method for preparing a mesylate crystalline form 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 a methanesulfonic acid ethanol solution, and stirring.

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

[0053] In some embodiments, the mesylate salt form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, with 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.

[0054] In some embodiments, the mesylate salt form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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.

[0055] In some embodiments, the mesylate salt form II of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig. 9 shown.

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

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

[0058] In some embodiments, the mesylate salt form III of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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, and 31.118.

[0059] In some embodiments, the mesylate salt form III of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2θ, and 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, and 31.118.

[0060] In some embodiments, the mesylate salt form III of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.10 shown.

[0061] The present disclosure also provides a method for preparing the mesylate 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 a methanesulfonic acid ethanol solution, and then adding isopropyl ether, and stirring.

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

[0063] In some embodiments, the p-toluenesulfonate crystalline 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, and 22.483 in an X-ray powder diffraction pattern represented by a diffraction angle 2θ.

[0064] In some embodiments, the p-toluenesulfonate crystalline form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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, and 28.834.

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

[0066] The present disclosure also provides a method for preparing a p-toluenesulfonate crystalline 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 p-toluenesulfonic acid ethanol solution, and stirring.

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

[0068] In some embodiments, the p-toluenesulfonate crystalline form β of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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, and 28.772.

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

[0070] The present disclosure also provides a method for preparing a p-toluenesulfonate crystalline 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 p-toluenesulfonic acid ethanol solution, and stirring.

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

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

[0073] In some embodiments, the maleate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with characteristic peaks at 7.367, 8.030, 14.551, 16.196, 17.811, 19.270, 21.320, 23.183, 25.977, and 26.847.

[0074] In some embodiments, the maleate salt form a of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.13 shown.

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

[0076] The fumarate crystalline form α of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 13.096, 15.496, 17.295, 19.685, 22.745, and 28.726.

[0077] In some embodiments, the fumarate salt form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, with 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, and 28.726.

[0078] In some embodiments, the fumarate salt form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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, and 36.134.

[0079] In some embodiments, the fumarate salt crystalline form α of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.14 shown.

[0080] The present disclosure also provides a method for preparing a fumarate crystalline 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 fumaric acid, then adding isopropyl ether, and stirring.

[0081] The tartrate crystal form I of the compound represented by Formula 1 provided in the present disclosure has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and has characteristic peaks at 6.118, 8.751, 9.994, 11.959, and 20.502.

[0082] In some embodiments, the tartrate salt form I of the compound represented 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 an X-ray powder diffraction pattern represented by a diffraction angle of 2θ.

[0083] In some embodiments, the tartrate salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ, and 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.

[0084] In some embodiments, the tartrate salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2θ as shown in Fig.15 shown.

[0085] The present disclosure also provides a method for preparing tartrate crystal form 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 or acetone, adding tartaric acid ethanol solution, then adding isopropyl ether, and stirring.

[0086] In some embodiments, the tartrate salt of the compound of Formula 1 provided by the present disclosure is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peak at a diffraction angle 2θ in the range of 3-45°.

[0087] The present disclosure also provides a pharmaceutical composition, which contains optionally the aforementioned hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate or corresponding crystal forms, and pharmaceutical excipients selected from pharmaceutically acceptable excipients.

[0088] The present disclosure also provides a pharmaceutical composition, which is prepared from the aforementioned hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate or corresponding crystal forms, and optional pharmaceutically acceptable excipients.

[0089] The present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate or corresponding crystal forms with a pharmaceutically acceptable excipient.

[0090] The present disclosure also provides the use of the aforementioned hydrochloride, sulfate, phosphate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate or corresponding crystal forms or the aforementioned composition in the preparation of a drug for preventing and / or treating pain relief and pain-related diseases.

[0091] The use disclosed herein, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; the postoperative pain is preferably selected from bunionectomy pain, hernia repair pain and abdominal plastic surgery pain.

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

[0093] The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (including the case where the number exceeding 1 decimal place is rounded off), 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] The numerical values ​​in the present disclosure, such as the data of the measured and calculated content of the relevant substances, inevitably have a certain degree of error. Generally speaking, ±10% is within the reasonable error range. There is a certain degree of error variation depending on the context where it is used, and the error variation does not exceed ±10%, and can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, preferably ±5%.

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

[0096] The drying temperature in the present disclosure is generally 25° C.-100° C., preferably 40° C.-70° C., and the drying can be performed under normal pressure or reduced pressure.

[0097] The crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, volatile solvent crystallization, adding seed crystals to induce crystallization, etc. The cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be performed 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 a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.

[0099] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "9103 Drug Hygroscopicity Guidelines" in the fourth volume of the 2015 edition of the Chinese Pharmacopoeia,

[0100] Deliquesce: Absorbs enough water to form a liquid;

[0101] Highly hygroscopic: weight gain due to moisture absorption is not less than 15%;

[0102] Hygroscopic: weight gain due to moisture absorption is less than 15% but not less than 2%;

[0103] Slightly hygroscopic: weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0104] No or almost no hygroscopicity: weight gain due to moisture is less than 0.2%.

[0105] The "excipients" described in the present disclosure include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Figure 1 The analgesic efficacy of compound 1 in the rat incision pain model.

[0107] Figure 2 The effect of compound 1 on body weight in the rat incision pain model.

[0108] Figure 3 This is the XRPD spectrum of Compound 1 hydrochloride form a.

[0109] Figure 4 This is the XRPD spectrum of Compound 1 hydrochloride form b.

[0110] Figure 5 This is the XRPD spectrum of compound 1 sulfate salt form I.

[0111] Figure 6 This is the XRPD spectrum of compound 1 sulfate form II.

[0112] Figure 7 This is the XRPD spectrum of Compound 1 phosphate form α.

[0113] Figure 8 This is the XRPD spectrum of Compound 1 mesylate Form I.

[0114] Fig. 9 This is the XRPD spectrum of Compound 1 mesylate Form II.

[0115] Fig.10 This is the XRPD spectrum of Compound 1 mesylate Form III.

[0116] Fig.11 This is the XRPD spectrum of Compound 1 p-toluenesulfonate Form α.

[0117] Fig.12 This is the XRPD spectrum of Compound 1 p-toluenesulfonate crystalline form β.

[0118] Fig.13 This is the XRPD spectrum of Compound 1 maleate salt form a.

[0119] Fig.14 This is the XRPD spectrum of compound 1 fumarate form α.

[0120] Fig.15 This is the XRPD spectrum of Compound 1 tartrate salt Form I. DETAILED DESCRIPTION

[0121] The present disclosure will be explained in more detail below in conjunction with embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, and are not intended to limit the essence and scope of the present disclosure.

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

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

[0124] MS was measured using Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid spectrometer-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole 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 Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

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

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

[0130] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

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

[0132] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0133] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0134] The average kinase inhibition rate and IC50 value were determined using NovoStar microplate reader (BMG, Germany).

[0135] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals and other companies.

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

[0137] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0138] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0139] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0140] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0141] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[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, 20°C to 30°C.

[0144] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of 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 solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0145] XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, and the specific collection information is: Cu anode (40kV, 40mA), Cu-Kα1 ray Kα2 rays Kβ rays Scanning mode: θ / 2θ, scanning range (2θ range): 3°~45°.

[0146] DSC is differential scanning calorimetry: the measurement was performed 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 25-200 or 300 or 350°C), and a nitrogen purge rate of 50 mL / min.

[0147] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10°C / min, the specific temperature range refers to the corresponding spectrum (mostly 30-350°C), and a nitrogen purge rate of 50 mL / min.

[0148] DVS stands for dynamic moisture adsorption: SMSDVS Advantage is used for detection. At 25°C, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%) (the specific range of humidity is subject to the corresponding graph, and most of the methods listed here are used). The judgment criteria are Tmax360min and dm / dt not greater than 0.002%.

[0149] Example 1 Preparation of the compound of formula 1 (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 1

[0150]

[0151] 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 separated by chiral column (Waters SFC 150, chromatographic column: DAICEL IC, 40*250mm, 10μm; 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 products 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 (short 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% (chromatographic column: DAICEL IC, 100*3mm, 3μm; 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% (chromatographic column: DAICEL IC, 100*3mm, 3μm; 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] Compound 1b-1 (50 mg, 141 μmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (40 mg, 315 μmol) and 1 drop of N,N-dimethylformamide were added under ice bath, and the reaction was restored to room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (3 mL). N,N-diisopropylethylamine (60 mg, 464 μmol) was added, and a dichloromethane solution (1 mL) of 4-aminopyridine-2-carbonitrile 1c (30 mg, 251 μmol, Shanghai Hanhong) was added dropwise under ice bath. The reaction was stirred for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was purified 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'-hydroxycarbamimidoyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide 1

[0166] Compound 1d (200 mg, 439.2 μmol) was dissolved in methanol (4 mL), and hydroxylamine hydrochloride (61 mg, 877.8 μmol) and N,N-diisopropylethylamine (60 mg, 464.2 μmol) were added. The reaction was stirred for 1.5 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water and saturated sodium chloride solution in turn. The organic phase was concentrated under reduced pressure, and the residue was purified 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 ): δ8.61(s,1H),8.46(d,1H),7.87(dd,1H),7.83(d,1H),7.09(ddd,1H),6.92(td,1H),5.7 5(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 disclosed compounds on Nav1.8

[0170] The purpose of the experiment is to investigate the effect of the compound on the Nav1.8 ion channel in vitro, which is stably expressed in HEK293 cells. After the Nav1.8 current is stabilized, the magnitude of the Nav1.8 current before and after the compound is applied can be compared to obtain the effect of the compound on the Nav1.8 ion channel.

[0171] 1 Experimental materials and instruments

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

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

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

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

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

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

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

[0179] 8)TTX AF3014 (Affix Scientific)

[0180] 2 Experimental steps

[0181] 2.1 Compound preparation

[0182] The compounds used to prepare the intracellular and extracellular fluids were purchased from Sigma (St. Louis, MO) except for NaOH and KOH used for acid-base titration. The extracellular fluid (mM) was: NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2, 1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration). Intracellular fluid (mM) aspartic acid, 140; MgCl 2 , 2; EGTA 11; HEPES, 10; pH 7.2 (CsOH titration). All test compound and control compound solutions contained 1 μM TTX.

[0183] The test compound was stored at a concentration of 9 mM in dimethyl sulfoxide (DMSO). On the day of the test, it was redissolved in the extracellular fluid to prepare the required concentration.

[0184] 2.2 Manual patch clamp test process

[0185] 1) After the compound is prepared into a solution of specified concentration, the solution is added to each channel in order from low to high concentration, and each channel is marked.

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

[0187] 3) After the cell membrane rupture current is stable, different concentrations are perfused in sequence. If the current is stable for at least one minute, the next concentration can be perfused. The perfusion time for each concentration shall not exceed five minutes.

[0188] 4) Clean the perfusion tank. Rinse the cells according to the concentration of the drug solution from high to low, and rinse for 20 seconds at each concentration. Finally, rinse with extracellular solution for 1 minute.

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

[0190] The cells were 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 seconds. The maximum current induced by the square wave was detected, and after it stabilized, the test compound was perfused. When the response stabilized, the intensity of the blockade was calculated.

[0191] 3. Data Analysis

[0192] 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 will review the analysis results. Current stability refers to the change of current over time within a limited range. The magnitude of the current after stabilization is used to calculate the effect of the compound at this solubility.

[0193] The inhibitory activity of the disclosed compounds on Nav1.8 was determined by the above test, and the measured IC 50 See Table 1 for values.

[0194] Table 1 IC of the compounds disclosed herein for inhibition of Nav1.8 channel activity 50

[0195] Example No. <![CDATA[IC 50 (nM)]]> 1 0.93

[0196] Conclusion: The compounds disclosed in the present invention have a significant inhibitory effect on the activity of Nav1.8 channels.

[0197] Test Example 2: Pharmacokinetic Evaluation

[0198] 1. SD rat experiment

[0199] SD rats were used as test animals, and the drug concentrations in plasma at different times after gavage (ig) of the example compounds were determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compounds in SD rats was studied, and their pharmacokinetic characteristics were evaluated.

[0200] 1.1 Experimental plan

[0201] Experimental animals: 4 male SD rats, provided by Weitonglihua Experimental Animal Technology Co., Ltd. After fasting overnight, the rats were gavaged and administered with drugs.

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

[0203] Administration: The dosage is 2 mg / kg and the administration volume is 10.0 mL / kg.

[0204] How to operate

[0205] Before administration and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the eye sockets and placed in EDTA-K2 anticoagulant tubes. The blood was centrifuged at 10,000 rpm for 1 minute (4°C). The plasma was separated within 1 hour and stored on dry ice for testing. The blood collection and centrifugation process was operated under ice bath conditions. Food was taken 2 hours after administration.

[0206] Determination of 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 sample of SD rats at each time after administration, add 200 μL of acetonitrile containing internal standard (verapamil 100 ng / ml), vortex mix, and centrifuge at 3700 rpm for 10 minutes. Take 0.1 μL of the supernatant for LC / MS / MS analysis.

[0207] 1.2 Pharmacokinetic parameter results

[0208] Table 2. Pharmacokinetic parameters of the disclosed compounds

[0209]

[0210] Conclusion: The disclosed compounds have high blood drug concentration and high exposure in SD rats and have obvious pharmacokinetic advantages.

[0211] 2. C57 mouse experiment

[0212] 2.1 Experimental animals

[0213] Eighteen C57 mice, half male and half female, were equally divided into two groups of 9 mice each, with 3 mice in each group at each time point. They were provided by Weitonglihua Experimental Animal Technology Co., Ltd., with production licenses SCXK (Zhejiang) 2019-0001 and SCXK (Beijing) 2019-0006, and were administered by gavage and intravenous injection.

[0214] 2.2 Drug preparation

[0215] A certain amount of the test compound was weighed, and 5% DMSO + 5% Tween 80 + 90% saline was added to prepare 0.1 mg / mL colorless clear solution (oral administration group) and 0.1 mg / mL colorless clear solution (intravenous injection group).

[0216] 2.3 Administration

[0217] Intragastric administration group: the dosage was 2.0 mg / kg, and the administration volume was 20 mL / kg.

[0218] Intravenous injection group: the dosage was 1.0 mg / kg and the administration volume was 10 mL / kg.

[0219] 2.4 Operation

[0220] Intragastric administration group: Before administration and 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 eye sockets and placed in EDTA-K2 anticoagulant tubes. The blood was centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour and stored at -80°C for testing. The blood collection and centrifugation process was carried out under ice bath conditions.

[0221] Intravenous injection group: blood was collected before administration, 5 minutes after administration, and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0, and 24 hours, and the treatment was the same as that of the oral administration group.

[0222] Determination of the content of the test compound in the plasma of C57 mice after administration of different concentrations of drugs: Compound 1: Take 20 μL of C57 mouse plasma samples at each time after administration, add 200 μL of acetonitrile containing verapamil (internal standard 20 ng / mL) to each sample to precipitate protein, vortex mix for 5 minutes, and centrifuge at 3700 rpm for 10 minutes. Take 90 μL of the supernatant, add 90 μL of water, vortex for 5 minutes, and inject 0.1 μL for LC / MS / MS analysis.

[0223] 2.5 Pharmacokinetic parameter results

[0224] Table 3. Pharmacokinetic parameters of the disclosed compounds

[0225]

[0226] Conclusion: The disclosed compounds have high blood drug concentration, large exposure, low clearance rate, high bioavailability and pharmacokinetic advantages in C57 mice.

[0227] Test Example 3: Drug Efficacy Test

[0228] 1. Experimental purpose

[0229] The analgesic efficacy of the disclosed compounds in inhibiting pain in rats was evaluated in a rat incisional pain model.

[0230] 2. Experimental drugs

[0231] Example 1 Compound.

[0232] A 25% PEG400+75% (10% TPGS+1% HPMC K100LV) solution was used.

[0233] 3. Experimental methods and materials

[0234] 3.1 Experimental animals and housing conditions

[0235] Experimental animals: SD rats were purchased from Beijing Weitonglihua Experimental Animal Co., Ltd. (License Number: SCXK(Zhe)2019-0001), weighing approximately 180 g at the time of purchase.

[0236] Rearing conditions: 5 mice / cage, 12 / 12 h light / dark cycle, constant temperature of 23±1℃, humidity of 50 to 60%, free access to food and water.

[0237] 3.2 Animal grouping

[0238] After adaptive feeding, SD rats were divided into the following groups:

[0239] Table 4

[0240]

[0241] Note: one dose means administration only once; ig means administration by intragastric administration.

[0242] 3.3 Experimental methods:

[0243] Take SD rats, weighing 170-190g, 9 rats, and use an electronic tactile meter to measure the mechanical pain threshold. Then perform incision pain surgery, use Shutai anesthesia (Shutai-50, 250mg, diluted to 50ml with normal saline after dissolution, 200g body weight injected 2ml), use a No. 10 surgical blade to cut a 1cm long incision in the middle of the plantar of the left hind paw, through the skin and fascia, suture the skin with 3-0 sterile silk surgical sutures. The injured part was disinfected with penicillin, and the animal was returned to its original place to recover overnight. After the operation recovered overnight, oral gavage was administered, and the mechanical pain threshold of the rat was measured with an electronic tactile meter 5h after administration (about 24h after surgery).

[0244] 3.4 Statistics

[0245] Excel statistical software was used to record data: the mean value was calculated as avg; the SD value was calculated as STDEV; the SEM value was calculated as STDEV / SQRT (number of animals in each group); GraphPad Prism software was used to draw graphs, and one-way ANOVA and t-test were used to perform statistical analysis on the data.

[0246] Threshold rise percentage (%) = [(G t -G 0 ) / G 0 ]×100(%), where G t is the plantar pain threshold of the drug-treated group, 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 follows Figure 1 As shown in Table 5, the effect of body weight is shown in Figure 2 ;

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

[0250]

[0251] Note: one dose means administration only once; ig means administration by intragastric administration.

[0252] 5. Conclusion

[0253] The pain threshold of normal rats (weight 170-190g) is 26.3±0.8gf, and that of the vehicle control group is 10.4±0.9gf. The pain thresholds of Example 1 compound at 200, 100, and 30mg / kg are 22.4, 22.3, and 12.0gf, respectively, which are significantly higher than those of the vehicle control group by 114% (p<0.001), 114% (p<0.001), and 15%, respectively. The pain threshold of 200mg / kg is equivalent to that of 100mg / kg, and the analgesic effect reaches saturation. The pain threshold of 100mg / kg is significantly higher than that of 30mg / kg (p<0.01). The analgesic effect has obvious dose dependence, and the administration has no effect on the weight of rats.

[0254] Example 2 Preparation of hydrochloride

[0255] 6 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of acetone, 6.7 μL of 2M hydrochloric 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 an amorphous hydrochloride salt, and the XRPD spectrum had no obvious characteristic peaks.

[0256] Example 3 Preparation of Hydrochloride Form a

[0257] 6 mg of the compound represented by formula 1 was dissolved in 0.2 mL of methyl tert-butyl ether, and 6.7 μL of 2M hydrochloric 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.

[0258] The product was defined as hydrochloride crystal form a by X-ray powder diffraction detection. The XRPD spectrum is as follows: Figure 3 The characteristic peak positions are shown in Table 6. The DSC spectrum shows that the endothermic peak value is 134.88°C. The TGA spectrum shows that the weight loss is 6.07% at 30°C-140°C. The ion detection results show that the chloride ion content is 7.1%.

[0259] DVS testing showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample gained about 0.1% of its weight due to moisture absorption; under accelerated experimental conditions (i.e. 70% RH), the weight gain due to moisture absorption was about 0.1%; under extreme conditions (90% RH), the weight gain due to moisture absorption was about 0.3%; after the DVS test, the crystal form was retested and the crystal form did not change.

[0260] Table 6

[0261]

[0262]

[0263] Example 4 Preparation of Hydrochloride Form a

[0264] 6 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of ethyl acetate, and 6.7 μL of 2M hydrochloric 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.

[0265] Example 5 Preparation of Hydrochloride Form b

[0266] 6 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of ethyl acetate, and 12.9 μL of 2M hydrochloric 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.

[0267] The product was defined as hydrochloride crystal form b by X-ray powder diffraction detection. The XRPD spectrum is as follows: Figure 4 The characteristic peak positions are shown in Table 7. The DSC spectrum shows that the endothermic peak value is 129.24℃. The TGA spectrum shows that the weight loss is 10.74% at 30℃-150℃. The ion detection results show that the chloride ion content is 14.0%.

[0268] Table 7

[0269]

[0270]

[0271] Example 6 Preparation of Sulfate Crystal Form I

[0272] 6 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of acetone, and 6.7 μL of 2M sulfuric acid ethanol solution and 1 mL of isopropyl ether were added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0273] The product was defined as sulfate crystal form I by X-ray powder diffraction detection. The XRPD spectrum is as follows: Figure 5 The characteristic peak positions are shown in Table 8. The DSC spectrum shows that the endothermic peaks are 81.46℃, 153.11℃, and 197.93℃. The TGA spectrum shows that the weight loss is 3.21% at 30℃-120℃, 3.89% at 120℃-180℃, and 1.86% at 180℃-220℃. The ion detection results show that the sulfate content is 23.1%.

[0274] Table 8

[0275]

[0276]

[0277] Example 7 Preparation of Sulfate Crystal Form II

[0278] 6 mg of the compound of formula 1 was dissolved in 0.2 mL of methyl tert-butyl ether, 6.7 μL of 2M sulfuric acid ethanol solution was added, 1 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.

[0279] The product was defined as sulfate crystal form II by X-ray powder diffraction detection. The XRPD spectrum is as follows: Figure 6 The characteristic peak positions are shown in Table 9. The DSC spectrum shows that the endothermic peak is 87.42°C. The TGA spectrum shows that the weight loss is 4.33% at 30°C-130°C.

[0280] Table 9

[0281]

[0282] Example 8 Preparation of Phosphate Crystalline Form α

[0283] 6 mg of the compound represented by formula 1 was dissolved in 0.1 mL of acetone, and 6.7 μL of 2M ethanolic phosphoric acid solution and 1 mL of isopropyl ether were added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0284] The product was defined as phosphate crystal form α by X-ray powder diffraction detection. The XRPD spectrum is as follows: Figure 7 The characteristic peak positions are shown in Table 10. The DSC spectrum shows that the endothermic peak value is 166.11°C. The TGA spectrum shows that the weight loss is 0.21% at 32°C-150°C. The ion detection results show that the phosphate ion content is 22.1%.

[0285] Table 10

[0286]

[0287]

[0288] Example 9 Preparation of Methanesulfonate Form I

[0289] 80 mg of the compound of formula 1 was dissolved in 1 mL of ethyl acetate, and 168 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.

[0290] The product was defined as mesylate crystal form I by X-ray powder diffraction detection, and the XRPD spectrum was as follows: Figure 8 The characteristic peak positions are shown in Table 11. The DSC spectrum shows that the endothermic peak value is 183.61°C. The TGA spectrum shows that the weight loss is 0.18% from 32°C to 180°C. The ion detection results show that the methanesulfonate ion content 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: Fig. 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: Fig.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: Fig.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 crystalline form β by X-ray powder diffraction detection. The XRPD spectrum is as follows: Fig.12 The characteristic peak positions are shown in Table 15. The DSC spectrum shows that the endothermic peak value is 193.75°C. The TGA spectrum shows that the weight loss is 0.21% from 32°C to 190°C. The ion detection results show that the p-toluenesulfonate ion content is 41.8%.

[0319] DVS testing showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample gained about 0.3% of its weight due to moisture absorption; under accelerated experimental conditions (i.e. 70% RH), the weight gain due to moisture absorption was about 0.5%; under extreme conditions (90% RH), the weight gain due to moisture absorption was about 1.5%; after the DVS test, the crystal form was retested and the crystal form did not change.

[0320] Table 15

[0321]

[0322] Example 16 Preparation of Maleate Crystal Form a

[0323] 6 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, 6.7 μL of 2M maleic acid ethanol solution and 1 mL of isopropyl ether were added, the mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0324] The product was defined as maleate crystalline form a by X-ray powder diffraction detection. The XRPD spectrum is as follows: Fig.13 The characteristic peak positions are shown in Table 16. The DSC spectrum shows that the endothermic peak value is 126.96°C. The TGA spectrum shows that the weight loss is 0.51% at 30°C-125°C. The ion detection results show that the maleate ion content is 23.5%.

[0325] Table 16

[0326]

[0327]

[0328] Example 17 Preparation of Fumarate Crystalline Form α

[0329] 6 mg of the compound represented by Formula 1 was dissolved in 0.1 mL of ethyl acetate, 1.5 mg of fumaric acid and 1 mL of isopropyl ether were added, the mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

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

[0331] Table 17

[0332]

[0333] Example 18 Preparation of tartrate

[0334] 6 mg of the compound shown in Formula 1 was dissolved in 0.1 mL of acetone, 6.7 μL of 2M tartaric 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 an amorphous tartrate salt, and the XRPD spectrum had no obvious characteristic peaks.

[0335] Example 19 Preparation of Tartrate Crystal Form I

[0336] 100 mg of the compound shown in Formula 1 was dissolved in 0.5 mL of ethyl acetate, 106.6 μL of 2M tartaric acid ethanol solution was added, 5 mL of isopropyl ether was added, and the mixture was stirred at room temperature for crystallization, centrifuged, and vacuum dried to obtain a solid. The product was defined as tartrate salt form I by X-ray powder diffraction detection, and the XRPD spectrum was as follows: Fig.15 The characteristic peak positions are shown in Table 18. The DSC spectrum shows that the endothermic peak value is 138.92°C. The TGA spectrum shows that the weight loss is 0.74% at 30°C-135°C. The ion detection results show that the tartrate ion content is 23.92%.

[0337] DVS testing showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample gained about 1.1% of its weight due to moisture absorption; under accelerated experimental conditions (i.e. 70% RH), the weight gain due to moisture absorption was about 1.5%; under extreme conditions (90% RH), the weight gain due to moisture absorption was about 3.8%; after the DVS test, the crystal form was retested and the crystal form did not change.

[0338] Table 18

[0339]

[0340] Example 20 Preparation of Tartrate Crystal Form I

[0341] 6 mg of the compound of formula 1 was dissolved in 0.2 mL of methyl tert-butyl ether, 6.7 μL of 2M tartaric 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.

[0342] Example 21 Preparation of Tartrate Crystal Form I

[0343] 6 mg of the compound of formula 1 was dissolved in 0.1 mL of acetone, and 12.9 μL of 2M tartaric acid ethanol solution and 1 mL of isopropyl ether were added. The mixture was stirred at room temperature for crystallization, centrifuged, and the solid was vacuum dried to obtain a solid product.

[0344] Example 22: Crystal Stability Study

[0345] The hydrochloride crystal form a was laid open and placed flat, and the stability of the sample was investigated under the conditions of high temperature (40°C and 60°C), high humidity (RH 75%, RH 92.5%) and light (4500lux), and the sampling period was 30 days.

[0346] Table 19

[0347]

[0348]

[0349] Conclusion: The influencing factor experiment shows that the hydrochloride crystal form a has good physical and chemical stability for 30 days under the influencing factors of high temperature (40℃, 60℃), high humidity (75%RH, 92.5%RH) and light conditions.

[0350] Example 23: Long-term / accelerated stability

[0351] The hydrochloride salt form a and the methanesulfonate salt form III were placed under 25°C / 60% RH and 40°C / 75% RH conditions, respectively, to investigate their stability.

[0352] Table 20

[0353]

[0354] Conclusion: Long-term accelerated experiments show that hydrochloride crystal form a is physically and chemically stable at 25°C / 60%RH for 3 months, and has good chemical stability at 40°C / 75%RH for 3 months under nitrogen packaging. Methanesulfonate crystal form III has good physical and chemical stability for 3 months under nitrogen packaging.

Claims

1. A mesylate crystalline form III 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 9.885, 15.923, 17.601, 19.261, 21.130, and 24.082, preferably 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, more preferably 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, 2. The mesylate salt form III according to claim 1, characterized in that The X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in FIG10 .

3. A method for preparing the mesylate salt form III as claimed in claim 1 or 2, comprising the steps of dissolving the compound represented by formula 1 in ethyl acetate, adding methanesulfonic acid ethanol solution, and then adding isopropyl ether, and stirring.

4. A tartrate salt 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 6.118, 8.751, 9.994, 11.959, and 20.502, preferably has characteristic peaks at 6.118, 8.751, 9.994, 11.959, 13.745, 15.420, 16.693, 17.594, and 20.502, and more preferably 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.

5. The tartrate 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 FIG15 .

6. A method for preparing the tartrate salt form I as claimed in claim 4 or 5, comprising dissolving the compound represented by formula 1 in ethyl acetate or methyl tert-butyl ether or acetone, adding tartaric acid ethanol solution, then adding isopropyl ether, and stirring.

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

20.

8. A pharmaceutical composition comprising the crystal form according to any one of claims 1-2, 4-5 and optionally a pharmaceutically acceptable excipient.

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

10. Use of the crystal form according to any one of claims 1-2, 4-5, or the pharmaceutical composition according to claim 8 in the preparation of a Nav1.8 inhibitor.

11. Use of the crystal form according to any one of claims 1-2, 4-5, or the 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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