A selective Na V Pharmaceutically acceptable salts, crystalline forms and preparation methods of inhibitors

Abstract

Provided is a selective Na V pharmaceutically acceptable salts, crystalline forms, and methods of preparation thereof. In particular, provided are meglumine, ethanolamine, potassium, amine, sodium, calcium, lysine, and arginine salts of compounds of Formula (I), methods of preparation thereof, and crystalline forms.

Description

[0001] This application claims priority to Chinese patent application 202110216129.6, filed on February 26, 2021. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This disclosure relates to a pharmaceutically acceptable salt, crystalline form, and preparation method of a selective Nav1.8 inhibitor prodrug. Specifically, it provides the crystalline forms and preparation methods of the compounds shown in formula (I), namely, meglumine salt, ethanolamine salt, potassium salt, amine salt, sodium salt, calcium salt, lysine salt, and arginine salt. Background Technology

[0003] Pain is a common clinical symptom originating from nociceptors in the peripheral nervous system. These receptors are widely distributed throughout the skin, muscles, joints, and visceral tissues of the body. They convert thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are then transmitted by afferent nerve fibers to the cell body of the dorsal root ganglion (DRG), ultimately reaching higher nerve centers and causing pain. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (Na+) on the cell membrane. V When the cell membrane depolarizes, sodium ion channels are activated, opening and allowing sodium ions to flow inward, further depolarizing the cell membrane and leading to action potentials. Therefore, inhibiting abnormal sodium ion channel activity can help treat and alleviate pain.

[0004] The local anesthetic lidocaine works by inhibiting Na+. V To relieve pain. Non-selective sodium. V Inhibitors, such as lamotrigine, lacosamide, and mexiletine, have been successfully used to treat chronic pain. Due to the clinical use of sodium... V Inhibitors lack subtype selectivity, inhibiting sodium ion channels in the heart and central nervous system, thus limiting their therapeutic window and application. V 1.8 Primarily distributed in the peripheral nervous system, it selectively inhibits Na+. V 1.8 can effectively reduce side effects. Therefore, it is necessary to develop Na+ with higher activity, better selectivity, better pharmacokinetic properties, and fewer side effects. V 1.8 Inhibitor. The applicant's patent application WO2020140959 provides a selective Na... V1.8 An inhibitor, chemically named 5-chloro-2-(4-fluoro-2-(methoxy-d3)phenoxy)-N-(6-oxo-1,6-dihydropyridazin-4-yl)-4-(trifluoromethyl)benzamide (Formula A), has been found to possess good pharmaceutical activity. PCT / CN2021 / 113504 provides a selective Na... V 1.8 Inhibitors, compounds with structures as shown in formula (I),

[0005] Summary of the Invention

[0006] This disclosure provides pharmaceutically acceptable salts of compounds represented by formula (I), wherein the pharmaceutically acceptable salt is selected from meglumine salts, ethanolamine salts, sodium salts, calcium salts, amine salts, potassium salts, lysine salts, and arginine salts.

[0007]

[0008] In some embodiments, the chemical ratio of the compound represented by formula (I) to a base molecule or cation is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, and most preferably 1:1 or 1:2. In some embodiments, the chemical ratio of the compound represented by formula (I) to meglumine is 1:1 or 1:2. In some embodiments, the chemical ratio of the compound represented by formula (I) to ethanolamine is 1:1 or 1:2. In some embodiments, the chemical ratio of the compound represented by formula (I) to sodium ions is 1:1 or 1:2. In some embodiments, the chemical ratio of the compound represented by formula (I) to potassium ions is 1:1 or 1:2. In some embodiments, the chemical ratio of the compound represented by formula (I) to ammonia molecules is 1:1 or 1:2. In some embodiments, the chemical ratio of the compound represented by formula (I) to calcium ions is 1:1. In some embodiments, the chemical ratio of the compound represented by formula (I) to lysine is 1:1 or 1:2. In some embodiments, the chemical ratio of the compound represented by formula (I) to arginine is 1:1 or 1:2.

[0009] This disclosure also provides a method for preparing a pharmaceutically acceptable salt of the compound shown in formula (I), comprising the step of forming a salt with a base. In some embodiments, the solvent used in the salt-forming reaction is selected from at least one of methanol, 2-butanone, ethyl acetate, 1,4-dioxane, methyl isobutyl ketone, methyl tert-butyl ether, dichloromethane, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene, and water. In some embodiments, the method for preparing the aforementioned pharmaceutically acceptable salt further includes steps such as evaporating the solvent or stirring to crystallize, filtering, and drying.

[0010] This disclosure provides a pharmaceutical composition prepared from the aforementioned pharmaceutically acceptable salt.

[0011] This disclosure also provides a pharmaceutical composition comprising the aforementioned pharmaceutically acceptable salt or a pharmaceutically acceptable salt prepared by the aforementioned method, and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

[0012] This disclosure provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a compound of formula (I) prepared by the aforementioned method, with a pharmaceutically acceptable carrier, diluent, or excipient.

[0013] This disclosure provides the use of a pharmaceutically acceptable salt of a compound of formula (I), or a pharmaceutically acceptable salt prepared by the aforementioned method, or the aforementioned composition, or the composition prepared by the aforementioned method, in the preparation of a medicament for inhibiting a subject's voltage-gated sodium channel, preferably, wherein the voltage-gated sodium channel is Na V 1.8.

[0014] This disclosure provides a pharmaceutically acceptable salt of the compound of formula (I), or a pharmaceutically acceptable salt prepared by the aforementioned method, or the aforementioned composition, or the composition prepared by the aforementioned method, for the preparation of a drug for the treatment and / or relief of pain and pain-related diseases, multiple sclerosis, and Shamajor-Associated Pain. Figure 3 Use in medications for Schizophrenia syndrome, incontinence, or arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

[0015] This disclosure provides a diglucamine salt of the compound shown in formula (I).

[0016] This disclosure provides an amorphous form of the diglucamine salt of the compound shown in formula (I), whose X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-48° at a diffraction angle of 2θ.

[0017] This disclosure further provides a method for preparing an amorphous diglucamine salt of the compound shown in formula (I), method 1, comprising the steps of: a) mixing the compound shown in formula (I) with solvent I and heating, wherein the solvent is selected from at least one of tetrahydrofuran, ethanol, and DMSO; b) adding a diglucamine solution to react, cooling, and precipitation; c) adding isopropanol or ethanol to precipitate; or method 2, comprising the steps of: a) mixing the compound shown in formula (I), diglucamine, and solvent II and heating to react, wherein solvent II is selected from at least one of ethanol, acetone, and acetonitrile; b) precipitate.

[0018] In some embodiments, the volume (μl) of solvent I or II used in this disclosure can be 1-200 times the mass (mg) of compound I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method described in this disclosure further includes filtration, washing, or drying steps.

[0019] This disclosure provides an amorphous form of the compound shown in formula (I) – meglumine salt – whose X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-48° at a diffraction angle of 2θ.

[0020] This disclosure further provides a method for preparing an amorphous meglumine salt of the compound shown in formula (I), comprising the steps of: a) mixing the compound shown in formula (I), meglumine, and solvent methyl tert-butyl ether or toluene, b) heating to precipitate the mixture.

[0021] In some embodiments, the volume (μl) of the solvent used in this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method described in this disclosure further includes filtration, washing, or drying steps.

[0022] This disclosure provides the A crystal form of the ethanolamine salt of the compound shown in formula (I), and the X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, with characteristic peaks at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726 and 27.000. In some embodiments, the A-phase of the ethanolamine salt of the compound shown in formula (I) has characteristic peaks at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726, 24.375, 25.060, 27.000, and 27.847. In some embodiments, the A-phase of the ethanolamine salt of the compound shown in formula (I) has characteristic peaks at 9.857, 13.767, 14.953, 16.243, 16.932, 19.965, 22.654, 23.726, 24.375, 25.060, 26.102, 27.000, and 27.847. In some embodiments, the X-ray powder diffraction pattern of the A-phase of the ethanolamine salt of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 2 As shown.

[0023] This disclosure further provides a method for preparing the A crystal form of the ethanolamine salt of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I), ethanol and ethanolamine, b) heating to precipitate.

[0024] In some embodiments, the volume (μl) of ethanol used as the solvent of this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method of this disclosure further includes filtration, washing, or drying steps.

[0025] This disclosure provides the α-crystal form of the sodium salt of the compound shown in formula (I), with X-ray powder diffraction patterns expressed as diffraction angles 2θ, showing characteristic peaks at 7.242, 7.497, 9.934, 12.281, 18.354, 20.784, and 23.654. ​​In some embodiments, the α-crystal form of the sodium salt of the compound shown in formula (I) has characteristic peaks at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002, 17.442, 18.354, 20.784, and 23.654. In some embodiments, the α-crystal form of the sodium salt of the compound shown in formula (I) exhibits characteristic peaks at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002, 16.533, 17.442, 18.354, 20.168, 20.784, 22.996, and 23.654. ​​In some embodiments, the X-ray powder diffraction pattern of the α-crystal form of the sodium salt of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is shown below. Figure 3 As shown.

[0026] This disclosure further provides a method for preparing the sodium salt of the compound of formula (I) in crystal form a, comprising: a) mixing the compound of formula (I), isopropanol and sodium hydroxide solution, and b) precipitating the precipitate.

[0027] In some embodiments, the volume (μl) of isopropanol, the solvent of this disclosure, used may be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method of this disclosure further includes filtration, washing, or drying steps.

[0028] This disclosure further provides the b-crystal form of the sodium salt of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, exhibiting characteristic peaks at 8.105, 9.016, 15.193, 16.945, 21.259, 25.301, and 28.642. In some embodiments, the b-crystal form of the sodium salt of the compound shown in formula (I) exhibits characteristic peaks at 8.105, 9.016, 14.259, 15.193, 16.945, 21.259, 24.629, 25.301, 27.428, and 28.642. In some embodiments, the b-crystal form of the sodium salt of the compound shown in formula (I) exhibits characteristic peaks at 8.105, 9.016, 11.816, 14.259, 15.193, 16.945, 21.259, 24.629, 25.301, 27.428, 28.642, and 30.771. In some embodiments, the X-ray powder diffraction pattern of the b-crystal form of the sodium salt of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is shown below. Figure 4 As shown.

[0029] This disclosure further provides a method for preparing the sodium salt of the compound of formula (I) in crystal form b, comprising: a) mixing the compound of formula (I), a sodium hydroxide solution and a solvent, and heating, wherein the solvent is selected from at least one of EtOH and THF; b) precipitating out the precipitate.

[0030] In some embodiments, the volume (μl) of the solvent used in this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method described in this disclosure further includes filtration, washing, or drying steps.

[0031] This disclosure also provides the I crystal form of the potassium salt of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, showing characteristic peaks at 7.910, 11.916, 15.916, 16.931, 22.433, 24.044, and 26.297. In some embodiments, the I crystal form of the potassium salt of the compound shown in formula (I) has characteristic peaks at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433, 24.044, and 26.297, 32.079, and 39.038. In some embodiments, the potassium salt of the compound shown in formula (I) has characteristic peaks at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433, 24.044 and 26.297, 29.594, 30.585, 32.079, 36.429 and 39.038. In some embodiments, the X-ray powder diffraction pattern of the potassium salt of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 5 As shown.

[0032] This disclosure provides the II crystal form of the potassium salt of the compound shown in formula (I), with X-ray powder diffraction patterns expressed as diffraction angles of 2θ, showing characteristic peaks at 7.488, 11.277, 13.394, 15.073, 22.860, 26.219, and 33.298. In some embodiments, the II crystal form of the potassium salt of the compound shown in formula (I) has characteristic peaks at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915, 22.860, 26.219, 33.298, and 38.093. In some embodiments, the potassium salt II crystal form of the compound shown in formula (I) exhibits characteristic peaks at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915, 22.860, 26.219, 27.808, 31.943, 33.298, 38.093, and 40.734. In some embodiments, the X-ray powder diffraction pattern of the potassium salt II crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 6 As shown.

[0033] This disclosure further provides a method for preparing the potassium salt of the compound shown in formula (I) in crystal form I or II, comprising: a) mixing the compound shown in formula (I), isopropanol, and potassium hydroxide solution, and b) precipitating the mixture.

[0034] In some embodiments, the volume (μl) of isopropanol, the solvent of this disclosure, used may be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method of this disclosure further includes filtration, washing, or drying steps.

[0035] This disclosure provides the III crystal form of the potassium salt of the compound shown in formula (I), with X-ray powder diffraction patterns expressed as diffraction angles of 2θ, showing characteristic peaks at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948, and 27.600. In some embodiments, the III crystal form of the potassium salt of the compound shown in formula (I) has characteristic peaks at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948, 26.462, 27.600, 30.872, and 34.296. In some embodiments, the potassium salt III crystal form of the compound shown in formula (I) exhibits characteristic peaks at 7.457, 11.223, 13.603, 15.042, 16.970, 19.420, 20.485, 23.948, 25.061, 26.462, 27.600, 30.872, and 34.296. In some embodiments, the X-ray powder diffraction pattern of the potassium salt III crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 7 As shown.

[0036] This disclosure further provides a method for preparing the potassium salt III crystal form of the compound shown in formula (I), comprising: 1) mixing the compound shown in formula (I), at least one solvent selected from ethanol and tetrahydrofuran, with a potassium hydroxide solution, and 2) precipitating the precipitate.

[0037] In some embodiments, the volume (μl) of the solvent used in this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method described in this disclosure further includes filtration, washing, or drying steps.

[0038] This disclosure provides the A-phase of the amine salt of the compound shown in formula (I), and its X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.324, 11.597, 14.903, 15.445, 17.259, 23.498, and 24.596. In some embodiments, the A-phase of the amine salt of the compound shown in formula (I) has characteristic peaks at 8.324, 11.597, 12.156, 14.903, 15.445, 17.259, 23.498, 24.596, 28.342, and 31.287. In some embodiments, the A crystal form of the amine salt of the compound shown in formula (I) has characteristic peaks at 8.324, 11.597, 12.156, 13.808, 14.903, 15.445, 17.259, 19.073, 21.251, 23.498, 24.596, 28.342, and 31.287. In some embodiments, the X-ray powder diffraction pattern of the A crystal form of the amine salt of the compound shown in formula (I), expressed as a diffraction angle 2θ, is as follows: Figure 8 As shown.

[0039] This disclosure further provides a method for preparing the A crystal form of the amine salt of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I), isopropanol and ammonia, and b) slurrying and crystallizing.

[0040] In some embodiments, the volume (μl) of isopropanol, the solvent of this disclosure, used may be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method of this disclosure further includes filtration, washing, or drying steps.

[0041] This disclosure provides the B-crystal form of the amine salt of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, showing characteristic peaks at 5.263, 10.629, 16.619, 20.208, 21.472, 24.052, and 29.047. In some embodiments, the B-crystal form of the amine salt of the compound shown in formula (I) has characteristic peaks at 5.263, 8.132, 10.629, 16.619, 18.848, 20.208, 21.472, 24.052, 29.047, and 29.644. In some embodiments, the B crystal form of the amine salt of the compound shown in formula (I) exhibits characteristic peaks at 5.263, 8.132, 10.629, 11.886, 16.619, 17.221, 18.848, 20.208, 21.472, 24.052, 27.121, 29.047, and 29.644. In some embodiments, the X-ray powder diffraction pattern of the B crystal form of the amine salt of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 9 As shown.

[0042] This disclosure further provides a method for preparing the B crystal form of the amine salt of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I), isopropanol and ammonia, and b) cooling to crystallize.

[0043] In some embodiments, the volume (μl) of the solvent used in this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method described in this disclosure further includes filtration, washing, or drying steps.

[0044] This disclosure provides the α-crystal form of the calcium salt of the compound shown in formula (I), with X-ray powder diffraction patterns expressed as diffraction angles 2θ, showing characteristic peaks at 8.455, 9.436, 13.657, 18.106, 28.892, 29.878, and 34.073. In some embodiments, the α-crystal form of the calcium salt of the compound shown in formula (I) has characteristic peaks at 8.455, 9.436, 13.657, 16.433, 18.106, 20.756, 26.620, 28.892, 29.878, and 34.073. In some embodiments, the α-crystal form of the calcium salt of the compound shown in formula (I) exhibits characteristic peaks at 8.455, 9.436, 13.657, 16.433, 17.105, 18.106, 20.756, 23.017, 26.620, 27.653, 28.892, 29.878, and 34.073. In some embodiments, the X-ray powder diffraction pattern of the α-crystal form of the calcium salt of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is shown below. Figure 10 As shown.

[0045] This disclosure further provides a method for preparing the calcium salt of the compound shown in formula (I) in crystal form a, comprising: a) mixing the compound shown in formula (I), ethanol and calcium hydroxide solution, heating, and b) precipitating out.

[0046] In some embodiments, the volume (μl) of ethanol used as the solvent of this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method of this disclosure further includes filtration, washing, or drying steps.

[0047] This disclosure further provides the A-phase of the lysine salt of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, exhibiting characteristic peaks at 8.493, 17.127, 18.633, 21.196, 23.020, 25.226, and 25.795. In some embodiments, the A-phase of the lysine salt of the compound shown in formula (I) exhibits characteristic peaks at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020, 23.926, 25.226, 25.795, and 30.365. In some embodiments, the A-phase of the lysine salt of the compound shown in formula (I) exhibits characteristic peaks at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020, 23.926, 24.450, 25.226, 25.795, 30.365, and 34.619. In some embodiments, the X-ray powder diffraction pattern of the A-phase of the lysine salt of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is shown below. Figure 11 As shown.

[0048] This disclosure further provides a method for preparing the A crystal form of the lysine salt of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I), acetone and a lysine solution, heating, and b) precipitating out.

[0049] In some embodiments, the volume (μl) of acetone used as the solvent of this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method of this disclosure further includes filtration, washing, or drying steps.

[0050] This disclosure further provides the A-phase of the arginine salt of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle 2θ, exhibiting characteristic peaks at 7.780, 10.847, 15.726, 18.634, 20.265, 21.618, and 26.485. In some embodiments, the A-phase of the arginine salt of the compound shown in formula (I) exhibits characteristic peaks at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265, 21.618, 23.794, 25.589, and 26.485. In some embodiments, the A-phase of the arginine salt of the compound shown in formula (I) exhibits characteristic peaks at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265, 21.618, 22.911, 23.794, 25.589, 26.485, 29.631, and 37.910. In some embodiments, the X-ray powder diffraction pattern of the A-phase of the arginine salt of the compound shown in formula (I), expressed as a diffraction angle 2θ, is shown below. Figure 12 As shown.

[0051] This disclosure further provides a method for preparing the A crystal form of the arginine salt of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I), acetone and an aqueous solution of arginine, and b) stirring to induce crystallization.

[0052] In some embodiments, the volume (μl) of acetone used as the solvent of this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method of this disclosure further includes filtration, washing, or drying steps.

[0053] This disclosure further provides the B-crystal form of the arginine salt of the compound shown in formula (I), with an X-ray powder diffraction pattern expressed as a diffraction angle of 2θ, exhibiting characteristic peaks at 8.097, 15.541, 19.256, 22.111, 24.679, 27.124, and 33.605. In some embodiments, the B-crystal form of the arginine salt of the compound shown in formula (I) exhibits characteristic peaks at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111, 24.679, 27.124, 33.605, and 43.535. In some embodiments, the B crystal form of the arginine salt of the compound shown in formula (I) exhibits characteristic peaks at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111, 24.679, 27.124, 29.546, 31.433, 33.155, 33.605, 34.490, and 43.535. In some embodiments, the X-ray powder diffraction pattern of the B crystal form of the arginine salt of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is shown below. Figure 13 As shown.

[0054] This disclosure further provides a method for preparing the B crystal form of the arginine salt of the compound shown in formula (I), comprising: a) mixing the compound shown in formula (I), acetone and arginine, b) heating and cooling to crystallize.

[0055] In some embodiments, the volume (μl) of the solvent used in this disclosure can be 1-200 times the mass (mg) of the compound of Formula I, and in non-limiting embodiments, it can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, or 200. In some embodiments, the preparation method described in this disclosure further includes filtration, washing, or drying steps.

[0056] This disclosure also provides pharmaceutical compositions prepared from the crystal form of the pharmaceutically acceptable salt described in (I) above.

[0057] This disclosure also provides a pharmaceutical composition comprising the crystal form of the aforementioned pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

[0058] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form of the aforementioned pharmaceutically acceptable salt with a pharmaceutically acceptable carrier, diluent, or excipient.

[0059] This disclosure also provides the use of the aforementioned pharmaceutically acceptable salt crystal form, or the aforementioned composition, or the composition prepared by the aforementioned method, in the preparation of a medicament for inhibiting a subject's voltage-gated sodium channel, preferably, wherein the voltage-gated sodium channel is Na V 1.8.

[0060] This disclosure also provides the crystal form of the aforementioned pharmaceutically acceptable salt, or the aforementioned composition, or the composition prepared by the aforementioned method, in preparation for the treatment and / or relief of pain and pain-related diseases, multiple sclerosis, and Shamajor epidemiology. Figure 3 Use in medications for Schizophrenia syndrome, incontinence, or arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

[0061] The determination of the stoichiometry between the compound of formula (I) and the base molecule described in this disclosure is subject to a certain degree of error. Generally, ±10% is within a reasonable error range. The error may vary to a certain extent depending on the context in which it is used, but this variation shall not exceed ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, and preferably ±5%.

[0062] The "2θ or 2θ angle" mentioned in this disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ for each characteristic peak is ±0.20 (including the case where the number has more than one decimal place after rounding), and can be -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.

[0063] The precipitation methods described in this disclosure include, but are not limited to, stirring, volatilization, pulping, and sedimentation.

[0064] According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in the "Guiding Principles on Hygroscopicity of Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia,

[0065] Deliquescence: Absorbs sufficient moisture to form a liquid;

[0066] Extremely hygroscopic: the weight gain due to hygroscopic absorption is not less than 15%;

[0067] It has hygroscopic properties: the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;

[0068] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%;

[0069] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0070] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0071] The drying temperature described in this disclosure is generally 25℃~100℃, preferably 40℃~70℃, and can be dried under normal pressure or reduced pressure.

[0072] "Pharmaceutical composition" means a mixture containing one or more compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0073] The crystal forms described in this disclosure include, but are not limited to, solvates of the meglumine salt of the compound shown in formula (I), wherein the solvents include, but are not limited to, tetrahydrofuran / ethanol, DMSO, ethanol, acetonitrile, acetone, methyl tert-butyl ether, and toluene. The crystal forms described in this disclosure include, but are not limited to, solvates of the ethanolamine salt of the compound shown in formula (I), wherein the solvents include, but are not limited to, ethanol. The crystal forms described in this disclosure include, but are not limited to, solvates of the sodium salt of the compound shown in formula (I), wherein the solvents include, but are not limited to, isopropanol and EtOH / THF. The crystal forms described in this disclosure include, but are not limited to, solvates of the potassium salt of the compound shown in formula (I), wherein the solvents include, but are not limited to, isopropanol. The crystal forms described in this disclosure include, but are not limited to, solvates of the amine salt of the compound shown in formula (I), wherein the solvents include, but are not limited to, isopropanol. The crystal forms described in this disclosure include, but are not limited to, solvates of the calcium salt of the compound shown in formula (I), wherein the solvents include, but are not limited to, ethanol. The crystal forms described in this disclosure include, but are not limited to, solvates of the lysine of the compound shown in formula (I), wherein the solvents include, but are not limited to, acetone. The crystal forms described in this disclosure include, but are not limited to, solvates of the arginine of the compound shown in formula (I), wherein the solvents include, but are not limited to, acetone.

[0074] The "solvents" described in this disclosure include, but are not limited to, complexes formed by combining a compound of formula I with a solvent. Attached Figure Description

[0075] Figure 1 XRPD pattern of the amorphous crystals of the compound diglucamine salt shown in formula (I).

[0076] Figure 2 XRPD pattern of ethanolamine salt A crystal form of compound (I).

[0077] Figure 3 XRPD pattern of sodium salt a of the compound shown in formula (I).

[0078] Figure 4 XRPD pattern of sodium salt b of the compound shown in formula (I).

[0079] Figure 5 XRPD pattern of potassium salt I crystal form of compound shown in formula (I).

[0080] Figure 6 XRPD pattern of potassium salt II crystal form of compound shown in formula (I).

[0081] Figure 7 XRPD pattern of potassium salt III crystal form of compound shown in formula (I).

[0082] Figure 8 XRPD pattern of amine salt A of compound shown in formula (I).

[0083] Figure 9 XRPD pattern of amine salt B crystal form of compound (I).

[0084] Figure 10 XRPD pattern of calcium salt a crystal form of the compound shown in formula (I).

[0085] Figure 11 XRPD pattern of lysine salt A crystal form of compound (I).

[0086] Figure 12 XRPD pattern of arginine salt A crystal form of compound (I).

[0087] Figure 13 XRPD pattern of arginine salt B crystal form of compound (I). Detailed Implementation

[0088] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in this disclosure are only used to illustrate the technical solutions in this disclosure and are not intended to limit the substance and scope of this disclosure.

[0089] The reagents used in this invention are commercially available.

[0090] The testing conditions of the instruments used in the experiments of this invention:

[0091] 1. Differential Scanning Calorimeter (DSC)

[0092] Instrument Model: Mettler Toledo DSC 3+STARe System

[0093] Purging gas: nitrogen; Nitrogen purging rate: 50 mL / min

[0094] Heating rate: 10.0℃ / min

[0095] Temperature range: 25-350℃

[0096] 2. X-ray Powder Diffraction (XRPD)

[0097] Instrument Model: BRUKER D8 Discover A25 X-ray Powder Diffractometer

[0098] Rays: Monochromatic Cu-Kα rays (λ = 1.5406)

[0099] Scanning mode: θ / 2θ, scanning range (2θ range): 3~50°

[0100] Voltage: 40kV, Current: 40mA

[0101] 3. Thermogravimetric Analysis (TGA)

[0102] Instrument model: Mettler Toledo TGA2

[0103] Purging gas: nitrogen; Nitrogen purging rate: 50 mL / min

[0104] Heating rate: 10.0℃ / min

[0105] Temperature range: 25-350℃

[0106] 4. DVS is a dynamic moisture adsorption method.

[0107] The assay was performed using a Surface Measurement Systems advantage 2 at 25°C, with humidity ranging from 50% to 95% to 0% to 95% to 50% RH in 10% increments. The judgment criterion was a mass change of dM / dT of less than 0.002% for each gradient. The TMAX was 360 min, and the cycle was repeated twice. 5. The average kinase inhibition rate and IC50 value were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0108] 6. In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system used for purifying the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system. Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used for TLC. The silica gel plates used in TLC had a diameter of 0.15 mm to 0.2 mm, and the diameter used for separating and purifying the products was 0.4 mm to 0.5 mm. Silica gel column chromatography generally used Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0109] 7. The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm).

[0110] The NMR measurements were performed using a Bruker AVANCE NEO 500M spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0111] MS measurements were performed using an Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS). Other instruments used included: a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector); and a THERMOUltimate3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0112] 8. The known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0113] 9. HPLC determination was performed using an Agilent 1260DAD high-performance liquid chromatograph (ACE Excel C18 150×4.6mm column) and a Thermo Dionex Ultimate 3000 high-performance liquid chromatograph (Waters Xbridge C18 150×4.6mm column).

[0114] Example 1: Preparation of Compound I

[0115] Step 1: Compound of Formula III

[0116]

[0117] Compound IV (1.5 g, 3.26 mmol, 1.0 eq) was mixed with 10 mL of formaldehyde aqueous solution, stirred, heated, and filtered to give 1.5 g of a white solid. Ms (ESI): m / z 491.00 [M+1]+. ¹H-NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.26–7.30 (m, 2H), 7.16–7.14 (d, 1H), 7.01 (s, 1H), 6.88–6.83 (m, 1H), 6.72–6.88 (m, 1H), 5.29–5.27 (d, 2H).

[0118] Step 2: Compound of Formula II

[0119]

[0120] Compound III (1 g, 2.04 mmol, 1.0 eq) was added to anhydrous THF (10 mL) and stirred. The mixture was purged with nitrogen and cooled. A 1.0 M solution of sodium bis(trimethylsilyl)amino(NaHMDS) / (tetrahydrofuran) THF (3.05 mL, 3.05 mmol, 1.5 eq) was added, followed by dropwise addition of a 2 mL solution of tetrabenzyl pyrophosphate (1.09 g, 2.04 mmol, 1.0 eq) in THF. After the addition was complete, the mixture was stirred at room temperature. The reaction mixture was diluted with ethyl acetate (EA), followed by dropwise addition of 0.5 M NaOH aqueous solution. The mixture was separated, the organic phases were combined, dried, filtered, and concentrated to dryness to obtain a crude, pale yellow oily product. Purification yielded 1.25 g, 81.69% yield, Ms(ESI): m / z 750.95[M+1]+. 1H-NMR(400MHz,DMSO-d6)δ11.19(s,1H),8.07(s,1H),7.98(s,1H),7.34-7.31(m,12H), 7.17-7.14(d,1H),7.01(s,1H),6.89-6.85(m,1H),5.83-5.81(d,2H),5.05-5.03(d,4H).

[0121] Step 3: Compound (I)

[0122]

[0123] Trifluoroacetic acid (TFA) (10.34 mL, 139.14 mmol, 95.0 eq) was added to the starting compound II (1.10 g, 1.46 mmol, 1.0 eq), and the reaction was stirred. The mixture was concentrated to dryness to obtain a crude product. Purification yielded 0.77 g of a white solid, yield: 92.11%, Ms (ESI): m / z 570.90 [M+1]+. ¹H-NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.33 (s, 1H), 7.39–7.26 (m, 1H), 7.15–7.13 (d, 1H), 7.01 (s, 1H), 6.87–6.83 (m, 1H), 5.63–5.61 (d, 2H).

[0124] Test Example 1: Compound I of Formula I on Na V 1.8 Determination of inhibitory activity

[0125] The purpose of the experiment was to investigate the effect of compound I on Na in in vitro experiments. V 1.8 Influence of ion channels, Na V 1.8 Ion channels are stably expressed in HEK293 cells. In Na+... V1.8 After the current stabilizes, compare the Na before and after the application of the compound. V 1.8 The magnitude of the current can be used to obtain the reaction of the compound with Na. V 1.8 The effect of ion channels.

[0126] 1. Experimental Materials and Instruments

[0127] 1) Patch clamp amplifier: PC-505B (WARNER instruments) / MultiClamp700A (Axon instruments)

[0128] 2) Digital-to-analog converters: Digidata 1440A (Axon CNS) / Digidata 1550A (Axon Instruments)

[0129] 3) Microcontroller: MP-225 (SUTTER instrument)

[0130] 4) Inverted microscope: TL4 (Olympus)

[0131] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[0132] 6) Microelectrode glass capillary: B12024F (Wuhan Microprobe Scientific Instruments Co., Ltd.)

[0133] 7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

[0134] 8)TTX AF3014 (Affix Scientific)

[0135] 2 Experimental Procedure

[0136] 2.1 Test Compounds

[0137] Compound I and VX-150 (prepared according to the method in WO2015089361).

[0138] 2.1 Compound Preparation

[0139] Except for NaOH and KOH used in acid-base titrations, all compounds used to prepare intracellular and extracellular fluids were purchased from Sigma (St. Louis, MO). The extracellular fluid (mM) composition was: NaCl, 137; KCl, 4; CaCl2, 1.8; MgCl2, 1.8. 2,1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration). Intracellular solution (mM) was Aspartic acid, 140; MgCl2, 2; EGTA, 11; HEPES, 10; pH 7.2 (CsOH titration). All test and control compound solutions contained 1 μM TTX.

[0140] The test compound was stored at a concentration of 9 mM and dissolved in dimethyl sulfoxide (DMSO). It was then dissolved in extracellular fluid on the day of testing to prepare the required concentration.

[0141] 2.2 Manual Patch Clamp Test Procedure

[0142] 1) After the compound is prepared into a solution of a specified concentration, add the solution to each pipe in order of increasing concentration and label each pipe.

[0143] 2) Transfer the cells to the perfusion tank, apply positive pressure to the electrode, and bring the electrode tip into contact with the cell. Adjust the three-way valve of the suction device to the three-way position, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Continue to apply negative pressure to rupture the cell membrane and form a current pathway.

[0144] 3) After the cell membrane rupture current stabilizes, perform perfusion at different concentrations sequentially. If the current stabilizes for at least one minute, proceed to the next concentration. The perfusion time for each concentration should not exceed five minutes.

[0145] 4) Clean the perfusion tank. Rinse with the drug solution from high to low concentration, rinsing for 20 seconds for each concentration. Finally, rinse with extracellular fluid for 1 minute.

[0146] 2.3 Test Voltage Equation (resting) and Results

[0147] The cells were clamped at -80 mV and then depolarized to 10 mV using a square wave for 10 milliseconds to obtain Na. V 1.8 Current. This procedure is repeated every 5 seconds. The maximum current induced by the square wave is detected, and after it stabilizes, the test compound is perfused. Once the reaction stabilizes, the blocking strength is calculated.

[0148] 3. Data Analysis

[0149] The data will be stored in a computer system for analysis. Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA), and administrators will review the analysis results. Current stability refers to the current changing within a finite range over time. The magnitude of the current after stabilization is used to calculate the effect of compounds at that solubility.

[0150] The inhibitory activity of the compound (I) of the present disclosure against Nav1.8 was measured in the above test to determine IC 50 value of 2.80 nM, and that of VX-150 is 17.71 nM.

[0151] Test Example 2: In Vivo Pharmacokinetic Study in Rats

[0152] 1. Summary

[0153] Using CD rats as test animals, the LC / MS / MS method was applied to determine the drug concentration in plasma at different time points after intravenous administration of the compound of the present disclosure. The pharmacokinetic behavior of the compound of the present disclosure in mice was studied, and its pharmacokinetic characteristics were evaluated.

[0154] 2. Test Protocol

[0155] 2.1 Test Drugs

[0156] Compound of Formula I: Formulated with sodium chloride injection;

[0157] Compound of Formula IV: Formulated with 1% DMSO + 5% HS15 + 94% normal saline.

[0158] 2.2 Test Animals

[0159] SD rats, half male and half female, weighing 190-230 g, were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., with production license number SCXK (Shanghai) 2018-0004 and certificate number 20180004038484.

[0160] 2.3 Administration

[0161] A total of 2 groups of rats were set up, 6 rats in each group, half male and half female. Fasting for no less than 12 h before administration, with free access to drinking water, and unified feeding 4 h after administration. The specific arrangement is shown in the following table:

[0162] Table 2

[0163]

[0164] 3. Operation

[0165] Sample Collection and Processing:

[0166] 0.2 ml of blood was collected from the retrobulbar venous plexus before administration and at 5 min, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 7.0 h, 10 h, 24 h and 48 h after administration. After sampling, the blood was placed in an EDTA-K2 anticoagulant tube containing 10 μL of 100 mM BNPP, centrifuged at 11000 rpm for 5 min (4°C), plasma was separated within 30 min, and stored at -70°C for testing.

[0167] The concentrations of compounds of formula I and IV in rat plasma at different time points after drug administration were determined by LC-MS / MS. Pharmacokinetic parameters in rats after drug administration were calculated using a non-compartmental model with Phoenix WinNonlin 7.0 software (Pharsight Pharmaceuticals, USA).

[0168] Peak time T max Peak concentration C max All values ​​are actual measurements.

[0169] Area under the curve (AUC) during drug administration 0-t Value: Calculated using the trapezoidal rule; AUC 0-∞ =AUC 0-t +C t / k e C t k represents the blood drug concentration at the last measurable time point. e To eliminate the rate constant;

[0170] Elimination half-life t 1 / 2 =0.693 / k e ;

[0171] Mean residence time MRT = AUMC / AUC;

[0172] Sweep rate CL = D / AUC 0-∞ (D represents the dosage);

[0173] Steady-state distributed volume V ss =CL×MRT.

[0174] 4. Pharmacokinetic Parameter Results

[0175] Table 3

[0176]

[0177] in conclusion:

[0178] After intravenous injection of compound I into SD rats, compound I was not detected in plasma (below the lower limit of quantitation 7.50 ng / mL). The plasma concentration of compound IV peaked at the first sampling point (5 min) after administration, suggesting that compound I can be rapidly converted into the parent drug compound IV in vivo after administration.

[0179] At equimolar doses, the peak concentration (Ci) of compound IV in the compound I administration group 5min ) represents the peak concentration (C) of compound IV in the dosing group. 5min The 38.3% exposure rate is speculated to be related to the fact that after intravenous administration, compound I can be rapidly distributed to tissues and then converted into compound IV; the exposure AUC 0-twhich is 77% of that of the compound of Formula IV administration group; the plasma clearance rate CL and steady-state volume of distribution V ss are 1.40 times and 1.77 times those of the compound of Formula IV administration group, respectively.

[0180] Test Example 3: Pharmacokinetic Study in Beagle Dogs

[0181] 1. Summary

[0182] Using Beagle dogs as test animals, the LC / MS / MS method was applied to determine the drug concentration in plasma at different time points after intravenous injection of the compound of the present disclosure. The pharmacokinetic behavior of the compound of the present disclosure in Beagle dogs was studied, and its pharmacokinetic characteristics were evaluated.

[0183] 2. Test Protocol

[0184] 2.1 Test Drugs

[0185] Compound of Formula I: prepared with sodium chloride injection;

[0186] Compound of Formula IV: prepared with 2% DMSO + 10% HS15 (polyethylene glycol (PEG) 12-hydroxystearate) + 88% normal saline.

[0187] 2.2 Test Animals

[0188] Beagle dogs, half male and half female, weighing about 9-11 kg, purchased from Jiangsu Yadong Laboratory Animal Research Institute Co., Ltd., with production license number SCXK(Shanghai) 2016-0009 and certificate number 202020255.

[0189] 2.3 Drug Administration

[0190] 6 Beagle dogs, half male and half female, were fasted for no less than 12 h before administration with free access to water. Four hours after administration, the dogs were fed uniformly. The washout period was 1 week.

[0191] Table 4 Schedule of Pharmacokinetic Test in Beagle Dogs

[0192]

[0193] 3. Operation

[0194] 1 ml of blood was collected from the limb veins before administration and at 5 min, 15 min, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 7.0 h, 10 h, 24 h and 48 h after administration. After sampling, the blood was placed into an EDTA-K2 anticoagulant tube containing 50 μL of 100 mM BNPP, centrifuged at 3500 rpm for 10 min (4°C), plasma was separated within 1 h, and stored at -70°C to be tested.

[0195] The concentrations of compounds of formula I and IV in plasma at different time points after administration to beagle dogs were determined by LC-MS / MS. Pharmacokinetic parameters after administration to beagle dogs were calculated using a non-compartmental model with Phoenix WinNonlin 7.0 software (Pharsight Pharmaceuticals, USA).

[0196] Peak time T max Peak concentration C max All values ​​are actual measurements.

[0197] Area under the curve (AUC) during drug administration 0-t Value: Calculated using the trapezoidal rule; AUC 0-∞ =AUC 0-t +C t / k e C t k represents the blood drug concentration at the last measurable time point. e To eliminate the rate constant;

[0198] Elimination half-life t 1 / 2 =0.693 / k e ;

[0199] Mean residence time MRT = AUMC / AUC;

[0200] Sweep rate CL = D / AUC 0-∞ (D represents the dosage);

[0201] Steady-state distributed volume V ss =CL×MRT.

[0202] 4. Pharmacokinetic Parameter Results

[0203] Table 5

[0204]

[0205] Following intravenous administration of compound I to beagles, compound I was not detected in plasma (below the lower limit of quantitation 7.50 ng / mL). The plasma concentration of compound IV peaked at the first sampling point (5 min) after administration, suggesting that compound I can be rapidly converted into the parent compound IV in vivo after administration.

[0206] At equimolar doses, the peak concentration (Ci) of compound IV after injection of compound I in beagle dogs 5min ) represents the peak concentration (C) of compound IV in the dosing group. 5min 100.4% of ); AUC 0-t The efficacy rate was 96.3% in the group treated with compound IV. The plasma clearance rate (CL) and steady-state volume of distribution (V) of compound IV were also observed. ss and half-life t1 / 2 No significant differences were observed between the two groups.

[0207] Example 2: Preparation of the amorphous form of the diglucamine salt of the compound shown in formula (I)

[0208] 100 mg of the compound shown in formula (I) was dissolved in 3 mL of a 1:1 tetrahydrofuran (THF) / ethanol (EtOH) solution at 50 °C. 0.1 mL of a 684 mg / mL meglumine aqueous solution was added, and the mixture was allowed to react upon cooling to precipitate. 3 mL of pre-cooled isopropanol was added, and the precipitate was collected. The solid was then centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD spectrum is shown below. Figure 1 As shown.

[0209] The nuclear magnetic resonance (HNMR) analysis of the obtained product showed that the content of meglumine was 43.2%, indicating that the molar ratio of the compound in the salt to meglumine was approximately 1:2.

[0210] Example 3: Preparation of the amorphous form of the diglucamine salt of the compound shown in formula (I)

[0211] 100 mg of the compound shown in formula (I) was dissolved in 3 mL of THF / EtOH (1:1) at 50 °C. 0.1 mL of a 684 mg / mL meglumine aqueous solution was added, and the mixture was allowed to react upon cooling to precipitate. 3 mL of pre-cooled EtOH was added, and the precipitate was collected. The solid was then centrifuged and dried under vacuum. X-ray powder diffraction analysis revealed that the product was amorphous.

[0212] Example 4: Preparation of the amorphous form of the diglucamine salt of the compound shown in formula (I)

[0213] 100 mg of the compound shown in formula (I) was dissolved in 0.5 mL of DMSO, and then 0.1 mL of a 684 mg / mL meglumine aqueous solution was added. The reaction was carried out at 50 °C, cooled to room temperature, and the reaction solution was added dropwise to 10 mL of pre-cooled EtOH, resulting in precipitation. The solid was then centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was amorphous.

[0214] Example 5: Preparation of the amorphous form of the diglucamine salt of the compound shown in formula (I)

[0215] 10.0 mg of the compound shown in formula (I) and 7.8 mg of meglumine were added to 0.2 mL of ethanol, and the mixture was heated to 50 °C, stirred at room temperature, and then centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was amorphous.

[0216] Example 6: Preparation of the amorphous form of the diglucamine salt of the compound shown in formula (I)

[0217] 10.0 mg of the compound shown in formula (I) and 7.8 mg of meglumine were mixed with 0.2 mL of acetone and heated to 50 °C. The mixture was stirred at room temperature and then centrifuged to dry under vacuum. X-ray powder diffraction analysis showed that the product was amorphous.

[0218] Example 7: Preparation of the amorphous form of the diglucamine salt of the compound shown in formula (I)

[0219] 10.0 mg of the compound shown in formula (I) and 7.8 mg of meglumine were mixed with 0.2 mL of acetonitrile, heated to 50 °C, stirred at room temperature, and then centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was amorphous.

[0220] Example 8: Preparation of the amorphous monoglucamine salt of the compound shown in formula (I)

[0221] 10.4 mg of the compound shown in formula (I) and 3.9 mg of meglumine were added, along with 0.2 mL of methyl tert-butyl ether. The mixture was heated to 50 °C, cooled, and then centrifuged to dry the solid under vacuum. X-ray powder diffraction analysis showed that the product was amorphous.

[0222] The nuclear magnetic resonance (HNMR) analysis of the obtained product showed that the content of meglumine was 26.6%, indicating that the molar ratio of the compound in the salt to meglumine was approximately 1:1.

[0223] Example 9: Preparation of the amorphous monoglucamine salt of the compound shown in formula (I)

[0224] 10.3 mg of the compound shown in formula (I) and 3.9 mg of meglumine were added to 0.3 mL of toluene, heated to 50 °C, cooled, and centrifuged to dry the solid under vacuum. X-ray powder diffraction analysis showed that the product was amorphous.

[0225] Example 10: Preparation of the A crystal form of the ethanolamine salt of the compound shown in formula (I)

[0226] 11.2 mg of the compound shown in formula (I) was dissolved in 0.2 mL of ethanol and 19.3 μL of a 1 mol / L aqueous solution of ethanolamine. The solution was heated to precipitate, and the solid was centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was of crystal form A, and the XRPD spectrum is shown below. Figure 2 As shown in Table 1, the positions of its characteristic peaks are as follows. The DSC spectrum shows an endothermic peak at 105.27℃. The TGA spectrum shows a weight loss of 6.64% at 25-110℃ and 6.36% at 110-255℃. Nuclear magnetic resonance (HNMR) analysis of the obtained product indicates that the salt ratio of the compound to ethanolamine in this salt is approximately 1:1.1.

[0227] Table 1

[0228]

[0229]

[0230] Example 11: Preparation of the sodium salt a crystal form of the compound shown in formula (I)

[0231] 10.35 mg of the compound shown in formula (I) was added to 0.2 mL of isopropanol at room temperature, followed by 19.3 μL of a 1 mol / L sodium hydroxide aqueous solution. The mixture was heated to 45 °C, cooled to room temperature, and slurried. 0.1 mL of isopropanol was added to precipitate the product, which was then centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was in α-crystal form. The XRPD spectrum is shown below. Figure 3 As shown in Table 2, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 57.49℃, 97.49℃, 162.79℃, and 241.94℃, and exothermic peaks at 197.83℃. The TGA spectrum shows a weight loss of 5.47% between 25-105℃ and 3.49% between 105-190℃.

[0232] Table 2

[0233]

[0234] Example 12: Preparation of the sodium salt b crystal form of the compound shown in formula (I)

[0235] 10.1 mg of the compound shown in formula (I) was heated with 0.2 mL of EtOH / THF (1:1), followed by the addition of 19.3 μL of a 1 mol / L sodium hydroxide aqueous solution, resulting in precipitation. The precipitate was then centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was in the b-crystal form, and the XRPD spectrum is shown below. Figure 4 As shown in Table 3, the positions of its characteristic peaks are as follows. Ion chromatography analysis of the obtained product showed that the salt ratio of the compound to sodium ions in this salt was approximately 1:1.

[0236] Table 3

[0237]

[0238] Example 13: Preparation of the potassium salt I crystal form of the compound shown in formula (I)

[0239] 10.1 mg of the compound shown in formula (I) was added to 0.2 mL of isopropanol, followed by 19.3 μL of a 1 mol / L potassium hydroxide aqueous solution. The mixture was heated to 45 °C, cooled to room temperature, slurried for 3 days, centrifuged, and then vacuum dried. X-ray powder diffraction analysis showed that the product was crystal form I, and the XRPD spectrum is shown below. Figure 5 As shown in Table 4, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 80.79℃, 166.10℃, and 241.89℃, and exothermic peaks at 203.52℃. The TGA spectrum shows a weight loss of 9.15% between 25-130℃ and 5.25% between 130-235℃.

[0240] Table 4

[0241]

[0242]

[0243] Example 14: Preparation of the potassium salt II crystal form of the compound shown in formula (I)

[0244] 49.72 mg of the compound shown in formula (I) was added to 1.0 mL of isopropanol, followed by 49.7 μL of 1 mol / L potassium hydroxide aqueous solution. The mixture was heated to 45 °C, cooled to room temperature, slurried for one day, centrifuged, and then vacuum dried. X-ray powder diffraction analysis showed that the product was in crystal form II. The XRPD spectrum is shown below. Figure 6 As shown in Table 5, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 68.80℃, 167.05℃, and 240.18℃, and exothermic peaks at 197.03℃. The TGA spectrum shows a weight loss of 3.94% between 25-140℃ and 4.63% between 140-235℃.

[0245] Table 5

[0246]

[0247] Example 15: Preparation of the potassium salt III crystal form of the compound shown in formula (I)

[0248] 10 mg of the compound shown in formula (I) was dissolved in 0.3 mL of ethanol / tetrahydrofuran at 50 °C. After cooling to room temperature, 19.3 μL of 1 M potassium hydroxide aqueous solution was added, followed by further cooling to allow precipitation. The precipitate was then centrifuged and dried to obtain a solid. X-ray powder diffraction analysis showed that the product was in crystal form III, and the XRPD spectrum is shown below. Figure 7 The characteristic peak positions are shown in Table 6. DSC spectra show endothermic peaks at 72.31℃, 186.68℃, and 244.60℃, and exothermic peaks at 202.45℃. TGA spectra show a weight loss of 2.64% between 25-145℃ and 4.31% between 145-230℃. Ion chromatography analysis of the obtained product showed that the salt ratio of the compound to potassium ions in this salt was approximately 1:0.9.

[0249] Table 6

[0250]

[0251] Example 16: Preparation of the A crystal form of the amine salt of the compound shown in formula (I)

[0252] 10.3 mg of the compound shown in formula (I) was added to 0.2 mL of isopropanol, followed by 19.3 μL of a 1 mol / L ammonia solution. The mixture was heated to 45 °C and stirred at room temperature for 3 days. A white solid precipitated out, which was then centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was of crystal form A. The XRPD spectrum is shown below. Figure 8 As shown in Table 7, the positions of its characteristic peaks are as follows. The DSC spectrum shows endothermic peaks at 76.96℃ and 138.8℃. The TGA spectrum shows a weight loss of 13.27% between 25-240℃. Ion chromatography analysis of the obtained product indicates that the salt ratio of the compound to the amine in this salt is approximately 1:1.

[0253] Table 7

[0254]

[0255]

[0256] Example 17: Preparation of the amine salt B crystal form of the compound shown in formula (I)

[0257] 202.9 mg of the compound shown in formula (I) was added to 4 ml of isopropanol, followed by 385.4 μL of 1 M ammonia aqueous solution. The mixture was then subjected to temperature fluctuations (50 °C - 5 °C), centrifuged, and dried under vacuum. X-ray powder diffraction analysis showed that the product was of crystal form B. The XRPD spectrum is shown below. Figure 9 As shown in Table 8, the positions of its characteristic peaks are as follows. The DSC spectrum shows an endothermic peak at 173.34℃ and an exothermic peak at 188.10℃. The TGA spectrum shows a weight loss of 5.00% between 25-230℃. Ion chromatography analysis of the obtained product indicates that the salt ratio of the compound to the amine in this salt is approximately 1:0.8.

[0258] Table 8

[0259]

[0260] Example 18: Preparation of the calcium salt a crystal form of the compound shown in formula (I)

[0261] 10.1 mg of the compound shown in formula (I) was mixed with 1.6 mg of calcium hydroxide and 0.2 mL of ethanol, and heated to 45 °C. A white suspension precipitated out, and the solid was centrifuged and dried under vacuum. X-ray powder diffraction analysis showed that the product was in α-crystal form, and the XRPD spectrum is shown below. Figure 10 As shown in Table 9, the positions of its characteristic peaks are as follows. The DSC spectrum shows that the endothermic peak has a peak value of 204.14℃. The TGA spectrum shows that the weight loss is 2.15% from 25-170℃ and 3.50% from 170-235℃.

[0262] Table 9

[0263]

[0264] Example 19: Preparation of the lysine salt A crystal form of the compound shown in formula (I)

[0265] 10.4 mg of the compound shown in formula (I) was added to 0.2 mL of acetone, followed by 19.3 μL of a 1 mol / L lysine aqueous solution. The mixture was heated to precipitate, and then dried. X-ray powder diffraction analysis showed that the product was in crystal form A, and the XRPD spectrum is shown below. Figure 11 As shown in Table 10, the positions of its characteristic peaks are as follows. The DSC spectrum shows that the endothermic peaks have peak values ​​of 175.18℃ and 193.83℃, and the exothermic peak has a peak value of 179.36℃. The TGA spectrum shows a weight loss of 11.50% between 25 and 170℃.

[0266] Table 10

[0267]

[0268] Example 20: Preparation of the arginine salt A crystal form of the compound shown in formula (I)

[0269] 10.1 mg of the compound shown in formula (I) was added to 0.2 mL of acetone, followed by 19.3 μL of a 1 mol / L arginine aqueous solution. The mixture was heated and stirred for 3 days until a solid precipitated. The solid was then centrifuged and dried. X-ray powder diffraction analysis showed that the product was in crystal form A. The XRPD spectrum is shown below. Figure 12 As shown in Table 11, the characteristic peak positions are as follows. The DSC spectrum shows endothermic peaks at 72℃, 86.16℃, 155.82℃, and 181.49℃. The TGA spectrum shows a weight loss of 6.70% between 25-140℃ and 8.00% between 140-240℃. Nuclear magnetic resonance (HNMR) analysis of the obtained product indicates that the salt ratio of the compound to arginine in this salt is approximately 1:1.

[0270] Table 11

[0271]

[0272]

[0273] Example 21: Preparation of the arginine salt B crystal form of the compound shown in formula (I)

[0274] 200.7 mg of the compound shown in formula (I) and 70.1 mg of arginine were added to 2 ml of acetone and 100 μL of pure water. The mixture was heated (50°C - 5°C) until a solid precipitated. The solid was then centrifuged and dried. X-ray powder diffraction analysis showed that the product was of crystal form B. The XRPD spectrum is shown below. Figure 13As shown in Table 12, the positions of its characteristic peaks are as follows. The DSC spectrum shows an endothermic peak at 118.02℃. The TGA spectrum shows a weight loss of 5.63% from 25-145℃. Nuclear magnetic resonance (HNMR) analysis of the obtained product indicates that the salt ratio of the compound to arginine in this salt is approximately 1:1.

[0275] Table 12

[0276]

[0277]

[0278] Example 22: Preparation of the amorphous arginine salt of the compound shown in formula (I)

[0279] 10 mg of the compound shown in formula (I) was mixed with 3.5 mg of arginine and 0.2 mL of ethanol. The mixture was heated to 45 °C, cooled to room temperature with stirring, centrifuged, and dried to obtain the product. X-ray powder diffraction analysis showed that the product was amorphous. Nuclear magnetic resonance (HNMR) analysis of the obtained product showed that the salt ratio of the compound to arginine in this salt was approximately 1:1.

[0280] Example 23: Preparation of the amorphous lysine salt of the compound shown in formula (I)

[0281] 10 mg of the compound shown in formula (I) was mixed with 6 mg of lysine and 0.2 mL of isopropyl acetate. The mixture was heated to 45 °C, cooled to room temperature, stirred, centrifuged, and dried to obtain the product. X-ray powder diffraction analysis showed that the product was amorphous. Nuclear magnetic resonance (HNMR) analysis of the obtained product showed that the salt ratio of the compound to lysine in the salt was approximately 1:0.9.

[0282] Example 24: Solubility and stability tests of different salts

[0283] I. Solubility

[0284] The solubility of the compound represented by formula (I) and its different salts in phosphate buffer solution was determined by HPLC, as shown in the table below:

[0285] Free state A crystal form 0.39 0.51 0.84 1.50 0.13 0.28

[0286] Potassium salt III crystal form 0.13 0.33 0.15 1.84 1.88 0.01 Sodium salt b crystal form 0.03 0.01 2.18 ＞10.2 ＞4.6 0.02 Calcium salt a crystal form 0.23 0.01 0.07 0.01 0.02 0.05 Ethanolamine salt A crystal form 0.02 0.04 / 0.48 23-30.7 0.32 Amine salt A crystal form 0.11 0.11 5.44 11.70 6.73 0.27 Amine salt B crystal form 1.23 0.19 0.33 0.54 0.66 0.20 Arginine salt A crystal form 2.83 0.39 ＞28 ＞24.5 0.19 1.92 Arginine salt B crystal form 0.27 0.26 25-50 ＞50 1.29 0.36 Arginine salt amorphous 0.83 0.37 1.95 ＞148 ＞37.5 1.23 Lysine salt amorphous 0.41 0.33 0.90 2.22 9.01 0.20

[0287] The results showed that, compared with other salts of Formula I, the diglucamine salt has a significant advantage in solubility.

[0288] II. Stability:

[0289] The solid-state stability of the compounds shown in Formula 1 and their salts is shown in the table below:

[0290]

[0291]

[0292] The results showed that at room temperature, meglumine salt was more stable than sodium salt.

[0293] Example 25: Amorphous stability study of the diglucamine salt of the compound shown in Formula I

[0294] The diglucamine salt of the compound shown in Formula I was left open and its stability was investigated under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions. The sampling period was 30 days, and the results are shown in the table below.

[0295] Table 13

[0296]

[0297] Experiments on influencing factors show that the amorphous form of the compound diglucamine salt shown in Formula I has good physical stability after one month under conditions of light, high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%); except for high temperature (60℃) and light, it has good chemical stability under other conditions.

[0298] Example 26: Long-term / accelerated stability study of the amorphous diglucamine salt of the compound shown in Formula I

[0299] The diglucamine salt of the compound shown in Formula I was amorphous, and its stability was investigated under conditions of -20℃, 4℃, 25℃ and 60%RH, 40℃ and 75%RH, respectively. The results are shown in the table below:

[0300] Table 14

[0301]

[0302] Long-term / accelerated stability tests show that the amorphous diglucamine salt of the compound described in Formula I has good physical stability after 3 months of storage under long-term / accelerated stability conditions and remains amorphous; except for accelerated conditions, it has good chemical stability after 3 months of storage at -20℃, 4℃ and under long-term conditions.

[0303] Example 27: Hygroscopicity study of different salt crystal forms of the compound shown in Formula I

[0304] Using Surface Measurement Systems Advantage 2, at 25℃ and humidity starting at 50%, the humidity range was investigated from 0% to 95% in 10% increments. The criteria for judgment were a mass change of dM / dT of less than 0.002% and a TMAX of less than 360 min for each gradient, with two cycles. The hygroscopicity of different salt crystal forms of the compound shown in Formula I was investigated, and the experimental results are shown in the table below:

[0305]

[0306] Under normal storage conditions (25°C, RH 60%), the water absorption of potassium salt III crystal form, amine salt B crystal form, arginine salt B crystal form, and ethanolamine salt A crystal form is approximately 2.80%, 1.25%, 0.20%, and 7.49%, respectively; under accelerated testing conditions (RH 70%), the water absorption is approximately 2.91%, 1.78%, 0.27%, and 8.58%, respectively; and under extreme conditions (RH 90%), the water absorption is approximately 3.37%, 9.90%, 0.60%, and 13.95%, respectively.

[0307] Example 28: Stability study of different salt forms of the compound shown in Formula I

[0308] Different salts of the compound shown in Formula I were laid out in the open to investigate their stability under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 92.5%) conditions. The sampling period was 30 days. The experimental results are shown in the table below:

[0309]

[0310]

[0311]

[0312]

[0313] Experimental results table: The potassium salt III crystal form of the compound shown in Formula I is basically physically and chemically stable under the influencing factors; the arginine salt B crystal form and the amine salt B crystal form have good physical stability; the arginine salt A crystal form and the ethanolamine salt A crystal form transform under high humidity conditions, and have good physical stability under other conditions; except for high temperature 60℃ and light irradiation, the arginine salt B and A crystal forms, the amine salt B crystal form, and the ethanolamine salt A crystal form have good chemical stability under other conditions.

[0314] Experimental Example 29: Long-term / accelerated stability of different salt forms of the compound shown in Formula I

[0315] The stability of different salt crystal forms of the compound shown in Formula I was investigated by placing samples at 4℃, 25℃ and 60%RH, and 40℃ and 75%RH, respectively, for a period of 2 months. The experimental results are shown in the table below:

[0316]

[0317]

[0318] The results showed that, except for arginine salt A and ethanolamine salt A crystal forms which had slightly lower physical stability, the other crystal forms exhibited good physical stability. Except for a decrease in purity under accelerated conditions, potassium salt III, amine salt A, amine salt B, arginine salt A, arginine salt B, and ethanolamine salt A crystal forms showed good chemical stability under other conditions.

Claims

1. A pharmaceutically acceptable salt of the compound shown in formula (I), wherein the pharmaceutically acceptable salt is selected from meglumine salts, ethanolamine salts, sodium salts, potassium salts, ammonium salts, calcium salts, lysine salts, and arginine salts. 。 2. The medicinal salt according to claim 1, characterized in that, The chemical ratio of the compound shown in formula (I) to the base molecule or cation is 1:0.5 to 1:

3.

3. The medicinal salt according to claim 2, characterized in that, The chemical ratio of the compound shown in formula (I) to the base molecule or cation is 1:0.5, 1:1, 1:2 or 1:

3.

4. The medicinal salt according to claim 3, characterized in that, The chemical ratio of the compound shown in formula (I) to the base molecule or cation is 1:1 or 1:

2.

5. The pharmaceutically acceptable salt according to any one of claims 1-4, wherein the pharmaceutically acceptable salt is a diglucamine salt.

6. A method for preparing the pharmaceutically acceptable salt according to any one of claims 1-5, comprising: The step of the compound in formula (1) forming a salt with a base.

7. The method according to claim 6, characterized in that, The solvent used in the salt formation reaction is selected from at least one of methanol, 2-butanone, ethyl acetate, 1,4-dioxane, methyl isobutyl ketone, methyl tert-butyl ether, dichloromethane, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene, and water.

8. A pharmaceutical composition prepared from the pharmaceutically acceptable salt according to any one of claims 1-5.

9. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 1-5, or a pharmaceutically acceptable salt prepared by the method of claim 6 or 7, and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

10. A method for preparing a pharmaceutical composition, comprising the step of mixing a pharmaceutically acceptable salt according to any one of claims 1-5, or a pharmaceutically acceptable salt prepared by the method of claim 6 or 7, with a pharmaceutically acceptable carrier, diluent, or excipient.

11. Use of the pharmaceutically acceptable salt of any one of claims 1-5, or the pharmaceutically acceptable salt prepared by the method of claim 6 or 7, or the composition of claim 8 or 9, or the composition prepared by the method of claim 10, in the preparation of a medicament for inhibiting subject voltage-gated sodium channels.

12. The use according to claim 11, wherein the voltage-gated sodium channel is Na V 1.

8.

13. Use of the pharmaceutically acceptable salt of any one of claims 1-5, or the pharmaceutically acceptable salt prepared by the method of claim 6 or 7, or the composition of claim 8 or 9, or the composition prepared by the method of claim 10, in the preparation of a medicament for treating and / or alleviating pain and pain-related diseases, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, or arrhythmia.

14. The use according to claim 13, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

15. The A crystal form of the ethanolamine salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726, and 27.

000.

16. The A crystal form of the ethanolamine salt of the compound of formula (I) according to claim 15, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726, 24.375, 25.060, 27.000, and 27.

847.

17. The A crystal form of the ethanolamine salt of the compound of formula (I) according to claim 15, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 9.857, 13.767, 14.953, 16.243, 16.932, 19.965, 22.654, 23.726, 24.375, 25.060, 26.102, 27.000, and 27.

847.

18. The A crystal form of the ethanolamine salt of the compound of formula (I) according to claim 15, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 2.

19. The α-crystal form of the sodium salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.242, 7.497, 9.934, 12.281, 18.354, 20.784, and 23.

654.

20. The a-crystal form of the sodium salt of the compound of formula (I) according to claim 19, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002, 17.442, 18.354, 20.784, and 23.

654.

21. The sodium salt of the compound of formula (I) according to claim 19, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002, 16.533, 17.442, 18.354, 20.168, 20.784, 22.996, and 23.

654.

22. The sodium salt of the compound of formula (I) according to claim 19, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 3.

23. The b-crystal form of the sodium salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.105, 9.016, 15.193, 16.945, 21.259, 25.301, and 28.

642.

24. The b-crystal form of the sodium salt of the compound of formula (I) according to claim 23, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 8.105, 9.016, 14.259, 15.193, 16.945, 21.259, 24.629, 25.301, 27.428, and 28.

642.

25. The b-crystal form of the sodium salt of the compound of formula (I) according to claim 23, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.105, 9.016, 11.816, 14.259, 15.193, 16.945, 21.259, 24.629, 25.301, 27.428, 28.642, and 30.

771.

26. The b-crystal form of the sodium salt of the compound of formula (I) according to claim 23, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 4.

27. The I crystal form of the potassium salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.910, 11.916, 15.916, 16.931, 22.433, 24.044, and 26.

297.

28. The potassium salt of the compound of formula (I) according to claim 27, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433, 24.044 and 26.297, 32.079 and 39.

038.

29. The potassium salt of the compound of formula (I) according to claim 27, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433, 24.044 and 26.297, 29.594, 30.585, 32.079, 36.429 and 39.

038.

30. The potassium salt of the compound of formula (I) according to claim 27, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 5.

31. The II crystal form of the potassium salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.488, 11.277, 13.394, 15.073, 22.860, 26.219, and 33.

298.

32. The potassium salt of the compound of formula (I) according to claim 31, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915, 22.860, 26.219, 33.298, and 38.

093.

33. The potassium salt of the compound of formula (I) according to claim 31, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915, 22.860, 26.219, 27.808, 31.943, 33.298, 38.093, and 40.

734.

34. The potassium salt of the compound of formula (I) according to claim 31, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 6.

35. The III crystal form of the potassium salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948, and 27.

600.

36. The potassium salt of the compound of formula (I) according to claim 35, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948, 26.462, 27.600, 30.872, and 34.

296.

37. The potassium salt of the compound of formula (I) according to claim 35, in crystal form III, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.457, 11.223, 13.603, 15.042, 16.970, 19.420, 20.485, 23.948, 25.061, 26.462, 27.600, 30.872, and 34.

296.

38. The potassium salt of the compound of formula (I) according to claim 35, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 7.

39. The A crystal form of the ammonium salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.324, 11.597, 14.903, 15.445, 17.259, 23.498, and 24.

596.

40. The A crystal form of the ammonium salt of the compound of formula (I) according to claim 39, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 8.324, 11.597, 12.156, 14.903, 15.445, 17.259, 23.498, 24.596, 28.342, and 31.

287.

41. The A crystal form of the ammonium salt of the compound of formula (I) according to claim 39, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.324, 11.597, 12.156, 13.808, 14.903, 15.445, 17.259, 19.073, 21.251, 23.498, 24.596, 28.342, and 31.

287.

42. The A crystal form of the ammonium salt of the compound of formula (I) according to claim 39, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 8.

43. The B crystal form of the ammonium salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.263, 10.629, 16.619, 20.208, 21.472, 24.052, and 29.

047.

44. The B-crystal form of the ammonium salt of the compound of formula (I) according to claim 43, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 5.263, 8.132, 10.629, 16.619, 18.848, 20.208, 21.472, 24.052, 29.047, and 29.

644.

45. The B-crystal form of the ammonium salt of the compound of formula (I) according to claim 43, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 5.263, 8.132, 10.629, 11.886, 16.619, 17.221, 18.848, 20.208, 21.472, 24.052, 27.121, 29.047, and 29.

644.

46. ​​The B crystal form of the ammonium salt of the compound of formula (I) according to claim 43, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 9.

47. The α-crystal form of the calcium salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.455, 9.436, 13.657, 18.106, 28.892, 29.878, and 34.

073.

48. The α-crystal form of the calcium salt of the compound of formula (I) according to claim 47, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 8.455, 9.436, 13.657, 16.433, 18.106, 20.756, 26.620, 28.892, 29.878, and 34.

073.

49. The α-crystal form of the calcium salt of the compound of formula (I) according to claim 47, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.455, 9.436, 13.657, 16.433, 17.105, 18.106, 20.756, 23.017, 26.62, 27.653, 28.892, 29.878, and 34.

073.

50. The α-crystal form of the calcium salt of the compound of formula (I) according to claim 47, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 10.

51. The A crystal form of the lysine salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.493, 17.127, 18.633, 21.196, 23.020, 25.226, and 25.

795.

52. The A crystal form of the lysine salt of the compound of formula (I) according to claim 51, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020, 23.926, 25.226, 25.795, and 30.

365.

53. The A crystal form of the lysine salt of the compound of formula (I) according to claim 51, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020, 23.926, 24.450, 25.226, 25.795, 30.365, and 34.

619.

54. The A crystal form of the lysine salt of the compound of formula (I) according to claim 51, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 11.

55. The A crystal form of the arginine salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.780, 10.847, 15.726, 18.634, 20.265, 21.618, and 26.

485.

56. The A crystal form of the arginine salt of the compound of formula (I) according to claim 55, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265, 21.618, 23.794, 25.589, and 26.

485.

57. The A crystal form of the arginine salt of the compound of formula (I) according to claim 55, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265, 21.618, 22.911, 23.794, 25.589, 26.485, 29.631, and 37.

910.

58. The A crystal form of the arginine salt of the compound of formula (I) according to claim 55, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 12.

59. The B-crystal form of the arginine salt of the compound shown in formula (I), ， Its features are, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.097, 15.541, 19.256, 22.111, 24.679, 27.124, and 33.

605.

60. The B-crystal form of the arginine salt of the compound of formula (I) according to claim 59, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111, 24.679, 27.124, 33.605, and 43.

535.

61. The B-crystal form of the arginine salt of the compound of formula (I) according to claim 59, characterized in that, The X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, shows characteristic peaks at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111, 24.679, 27.124, 29.546, 31.433, 33.155, 33.605, 34.490, and 43.

535.

62. The B-crystal form of the arginine salt of the compound of formula (I) according to claim 59, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is shown in Figure 13.

63. The crystal form according to any one of claims 15-62, characterized in that, The error range of the 2θ angle is ±0.

20.

64. A pharmaceutical composition prepared from the crystal form according to any one of claims 15-63.

65. A pharmaceutical composition comprising the crystal form of any one of claims 15-63 and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

66. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form described in any one of 15-63 with a pharmaceutically acceptable carrier, diluent or excipient.

67. Use of the crystal form according to any one of claims 15-63, or the composition according to claim 64 or 65, or the composition prepared by the method of claim 66, in the preparation of a medicament for inhibiting subject voltage-gated sodium channels.

68. The use according to claim 67, wherein the voltage-gated sodium channel is Na V 1.

8.

69. Use of the crystal form according to any one of claims 15-63, or the composition according to claim 64 or 65, or the composition prepared by the method of claim 66 in the preparation of a medicament for treating and / or alleviating pain and pain-related diseases, multiple sclerosis, Sharma-Tutankhamun syndrome, incontinence, or arrhythmia.

70. The use according to claim 69, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

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