WO2022179624A1

WO2022179624A1 - Pharmaceutically acceptable salt of selective nav inhibitor and crystalline form thereof, and preparation method therefor

Info

Publication number: WO2022179624A1
Application number: PCT/CN2022/078026
Authority: WO
Inventors: 祝令建; 洪敏�; 郑澄; 黄建; 马亚辉; 杨俊然; 杜振兴; 王捷
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2021-02-26
Filing date: 2022-02-25
Publication date: 2022-09-01
Also published as: CN116964065A; TW202302118A

Abstract

Provided are a pharmaceutically acceptable salt of a selective NaV inhibitor and a crystalline form thereof, and a preparation method therefor. Specifically, provided are a meglumine salt, an ethanolamine salt, a potassium salt, an amine salt, a sodium salt, a calcium salt, a lysine salt and an arginine salt of a compound as represented by a formula (I), a preparation method therefor, and a crystalline form thereof.

Description

a selective Na Pharmaceutically acceptable salts, crystalline forms of V inhibitors and methods for their preparation

This application claims the priority of Chinese patent application 202110216129.6 with the filing date of 2021/2/26. This application cites the full text of the above Chinese patent application.

technical field

The present disclosure relates to a pharmaceutically acceptable salt, a crystalline form and a preparation method of a selective Nav1.8 inhibitor prodrug, and specifically, provides compounds represented by formula (I) meglumine salt, ethanolamine salt, potassium salt, Amine salts, sodium salts, calcium salts, lysine salts and arginine salts, crystalline forms and methods of preparation.

Background technique

Pain is a common clinical symptom that originates from nociceptors in the peripheral nervous system. This receptor is widely distributed in skin, muscles, joints, and visceral tissues throughout the body and converts thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) that are transmitted by afferent nerve fibers to their dorsal root ganglia (dorsal root ganglia). ganglia, DRG), which is ultimately transmitted to higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons in turn depend on voltage-gated sodium channels (Na _V ) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated, the channel opens, and the sodium ion flows inward, which further depolarizes the cell membrane, resulting in the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity is helpful for the treatment and relief of pain.

The local anesthetic lidocaine relieves pain by inhibiting Na _V. Nonselective Na _V inhibitors, such as lamotrigine, lacosamide, and mexiletine, have been successfully used to treat chronic pain. Due to the lack of subtype selectivity of Na _V inhibitors used in the clinic and their ability to inhibit sodium ion channels in the heart and central nervous system, the therapeutic window is narrow and the scope of application is limited. Na _V 1.8 is mainly distributed in the peripheral nervous system, and selective inhibition of Na _V 1.8 can effectively reduce side effects. Therefore, it is necessary to develop Na _V 1.8 inhibitors with higher activity, better selectivity, better pharmacokinetic properties and fewer side effects. The applicant's patent application WO2020140959 provides a selective Na _V 1.8 inhibitor whose chemical name is 5-chloro-2-(4-fluoro-2-(methoxy-d ₃ )phenoxy)-N -(6-oxo-1,6-dihydropyridazin-4-yl)-4-(trifluoromethyl)benzamide (formula A), it has been found that the compound has good pharmaceutical activity. PCT/CN2021/113504 provides a selective Na _V 1.8 inhibitor, the structure of which is a compound represented by formula (I),

SUMMARY OF THE INVENTION

The present disclosure provides a pharmaceutically acceptable salt of the compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from meglumine salt, ethanolamine salt, sodium salt, calcium salt, amine salt, potassium salt, lysine salt salts and arginine salts.

In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) to the base molecule or cation is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3 , most preferably 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) and meglumine is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) and ethanolamine is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) to the sodium ion is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) and potassium ion is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) to the ammonia molecule is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) to calcium ions is 1:1. In certain embodiments, the stoichiometric ratio of the compound represented by formula (I) to lysine is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) to arginine is 1:1 or 1:2.

The present disclosure also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by formula (I), comprising the step of forming a salt of the compound represented by formula (1) with a base. In certain embodiments, the solvent used in the salt-forming reaction is selected from methanol, 2-butanone, ethyl acetate, 1,4-dioxane, methyl isobutyl ketone, methyl tert-butyl ether , at least one of dichloromethane, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene and water. In certain embodiments, the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of volatilizing the solvent or stirring for crystallization, filtering, drying, and the like.

The present disclosure provides a pharmaceutical composition prepared from the aforementioned pharmaceutically acceptable salt.

The present 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.

The present disclosure provides a preparation method of a pharmaceutical composition, comprising mixing the aforementioned pharmaceutically acceptable salt, or the pharmaceutically acceptable salt of the compound of formula (I) prepared by the aforementioned method, with a pharmaceutically acceptable carrier, diluent or excipient. The step of mixing the excipients.

The present disclosure provides a pharmaceutically acceptable salt of the compound of the former formula (I), or a pharmaceutically acceptable salt prepared by the aforementioned method, or the aforementioned composition, or a composition prepared by the aforementioned method. The use in the medicine of voltage-gated sodium channel of the test subject, preferably, the voltage-gated sodium channel is Na _V 1.8.

The present disclosure provides a pharmaceutically acceptable salt of a compound of the former formula (I), or a pharmaceutically acceptable salt prepared by the aforementioned method, or the aforementioned composition, or a composition prepared by the aforementioned method in the preparation of therapeutic and /or use in a medicament for alleviating pain and pain-related diseases, multiple sclerosis, Sharma-Figure 3 syndrome, incontinence or arrhythmia, preferably the pain is selected from chronic pain, acute pain, inflammatory Pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, bowel pain and idiopathic pain.

The present disclosure provides dimeglumine salts of compounds represented by formula (I).

The present disclosure provides the amorphous form of dimeglumine salt of the compound represented by formula (I), and the diffraction angle 2θ of its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-48°.

The present disclosure further provides an amorphous method for preparing the dimeglumine salt of the compound represented by formula (I), method 1, comprising the steps of: a) mixing the compound represented by formula (I) with solvent I, heating, and the solvent Be selected from at least one in tetrahydrofuran, ethanol, DMSO, b) add meglumine solution reaction, cool down, separate out, c) add isopropanol or ethanol, precipitate out; Or method 2, comprises steps: a) formula (I) ), the meglumine is mixed with solvent II, and the solvent II is heated for reaction, and the solvent II is selected from at least one of ethanol, acetone and acetonitrile, and b) is precipitated.

In certain embodiments, the volume (μl) used for solvent I or II described in the present disclosure 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, 200. In certain embodiments, the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.

The present disclosure provides the amorphous form of the compound represented by formula (I), a meglumine salt, the X-ray powder diffraction pattern of which has no obvious characteristic peaks in the diffraction angle 2θ of the powder diffraction pattern in the range of 2-48°.

The present disclosure further provides a method for preparing the amorphous monomeglumine salt of the compound represented by the formula (I), comprising the steps of: a) the compound represented by the formula (I), meglumine and a solvent methyl tert-butyl ether or toluene Mix, b) heat, and precipitate out.

In certain embodiments, the volume (μl) of the solvent described in the present disclosure 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, 200. In certain embodiments, the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.

The present disclosure provides an X-ray powder diffraction pattern of the ethanolamine salt of the compound represented by formula (I), Form A, expressed as a diffraction angle 2θ, characterized at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726, and 27.000 peak. In certain embodiments, Form A of the ethanolamine salt of the compound of 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, and in some In embodiments, Form A of the ethanolamine salt of the compound shown 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 certain embodiments, the X-ray powder diffraction pattern of Form A of the ethanolamine salt of the compound represented by formula (I) in terms of diffraction angle 2θ is shown in FIG. 2 .

The present disclosure further provides a method for preparing Form A of the ethanolamine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), ethanol and ethanolamine, and b) heating and precipitation.

In certain embodiments, the used volume (μl) of the solvent ethanol described in the present disclosure 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, 200. In certain embodiments, the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.

The present disclosure provides an X-ray powder diffraction pattern of the sodium salt of the compound represented by formula (I) in form a, expressed as a diffraction angle 2θ, characterized at 7.242, 7.497, 9.934, 12.281, 18.354, 20.784, and 23.654 peak. In certain embodiments, the crystalline form a of the sodium salt of the compound of 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 certain embodiments, the crystalline form a of the sodium salt of the compound of formula (I) is characterized 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 peak. In certain embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound represented by formula (I) of crystal form a, represented by the diffraction angle 2θ, is shown in FIG. 3 .

The present disclosure further provides a method for preparing crystal form a of the sodium salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), isopropanol and sodium hydroxide solution, and b) precipitating.

In certain embodiments, the volume (μl) of the solvent isopropanol used in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments, it 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, 200. In certain embodiments, the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.

The present disclosure further provides an X-ray powder diffraction pattern of the sodium salt of the compound represented by formula (I) of form b, expressed as a diffraction angle 2θ, characterized at 8.105, 9.016, 15.193, 16.945, 21.259, 25.301 and 28.642 peak. In certain embodiments, crystal form b of the sodium salt of the compound of formula (I) 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. In certain embodiments, the crystalline form b of the sodium salt of the compound of formula (I) has 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 certain embodiments, the X-ray powder diffraction pattern of the sodium salt of the compound represented by formula (I) of crystal form b, expressed as a diffraction angle 2θ, is shown in FIG. 4 .

The present disclosure further provides a method for preparing the b crystal form of the sodium salt of the compound represented by the formula (I), comprising: a) mixing the compound represented by the formula (I), a sodium hydroxide solution and a solvent, and heating, and the solvent is selected from EtOH , at least one of THF, b) precipitation.

The present disclosure also provides an X-ray powder diffraction pattern of Form I of the potassium salt of the compound represented by formula (I), expressed in diffraction angle 2θ, at 7.910, 11.916, 15.916, 16.931, 22.433, 24.044 and 26.297. Characteristic peaks. In certain embodiments, Form I of the potassium salt of the compound of 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 certain embodiments, Form I of the potassium salt of the compound of formula (I) is characterized 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 peak. In certain embodiments, the X-ray powder diffraction pattern of Form I of the potassium salt of the compound represented by formula (I) is shown in FIG. 5 as a diffraction angle 2θ.

The present disclosure provides an X-ray powder diffraction pattern of the potassium salt of the compound represented by formula (I), Form II, characterized by 7.488, 11.277, 13.394, 15.073, 22.860, 26.219, and 33.298, in terms of diffraction angle 2Θ peak. In certain embodiments, Form II of the potassium salt of the compound of 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 certain embodiments, Form II of the potassium salt of the compound of formula (I) is characterized 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 peak. In certain embodiments, the X-ray powder diffraction pattern of Form II of the potassium salt of the compound represented by formula (I) is shown in FIG. 6 as a diffraction angle 2θ.

The present disclosure further provides a method for preparing the I or II crystal form of the potassium salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), isopropanol and potassium hydroxide solution, b) precipitating out .

The present disclosure provides an X-ray powder diffraction pattern of the potassium salt of the compound represented by formula (I), Form III, characterized at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948, and 27.600, as an X-ray powder diffraction pattern at diffraction angles 2 theta peak. In certain embodiments, Form III of the potassium salt of the compound of 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 certain embodiments, Form III of the potassium salt of the compound of formula (I) is characterized 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 peak. In certain embodiments, the X-ray powder diffraction pattern of Form III of the potassium salt of the compound represented by formula (I) in terms of diffraction angle 2Θ is shown in FIG. 7 .

The present disclosure further provides a method for preparing the potassium salt III crystal form of the compound represented by formula (I), comprising: 1) the compound represented by formula (I), at least one solvent in ethanol and tetrahydrofuran, mixed with potassium hydroxide solution, 2) Precipitation.

The present disclosure provides an X-ray powder diffraction pattern of the amine salt of the compound represented by formula (I) of Form A, expressed as a diffraction angle 2Θ, characterized at 8.324, 11.597, 14.903, 15.445, 17.259, 23.498, and 24.596 peak. In certain embodiments, Form A of the amine salt of the compound of 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 certain embodiments, Form A of the amine salt of the compound of formula (I) is characterized 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 peak. In certain embodiments, the X-ray powder diffraction pattern of Form A of the amine salt of the compound represented by formula (I) in terms of diffraction angle 2θ is shown in FIG. 8 .

The present disclosure further provides a method for preparing Form A of the amine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), isopropanol and ammonia water, and b) beating and crystallization.

The present disclosure provides an X-ray powder diffraction pattern of an amine salt of a compound represented by formula (I), Form B, expressed as a diffraction angle 2θ, characterized at 5.263, 10.629, 16.619, 20.208, 21.472, 24.052, and 29.047 peak. In certain embodiments, Form B of the amine salt of the compound of formula (I) has characteristic peaks at 5.263, 8.132, 10.629, 16.619, 18.848, 20.208, 21.472, 24.052, 29.047, 29.644. In certain embodiments, Form B of the amine salt of the compound of formula (I) is characterized 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, 29.644 peak. In certain embodiments, the X-ray powder diffraction pattern of the amine salt of the compound represented by formula (I) of Form B, expressed as a diffraction angle 2θ, is shown in FIG. 9 .

The present disclosure further provides a method for preparing the B crystal form of the amine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), isopropanol and ammonia water, and b) cooling and crystallization.

The present disclosure provides an X-ray powder diffraction pattern of a calcium salt of a compound represented by formula (I), characterized at 8.455, 9.436, 13.657, 18.106, 28.892, 29.878, and 34.073, as an X-ray powder diffraction pattern expressed as a diffraction angle 2θ peak. In certain embodiments, the crystalline form a of the calcium salt of the compound of 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 certain embodiments, the crystalline form a of the calcium salt of the compound of formula (I) is characterized 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 peak. In certain embodiments, the X-ray powder diffraction pattern of the calcium salt form a of the compound represented by formula (I) in terms of diffraction angle 2θ is shown in FIG. 10 .

The present disclosure further provides a method for preparing a crystal form of calcium salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), ethanol and calcium hydroxide solution, heating, and b) precipitating.

The present disclosure further provides the X-ray powder diffraction pattern of Form A of the lysine salt of the compound represented by formula (I), expressed in diffraction angle 2θ, at 8.493, 17.127, 18.633, 21.196, 23.020, 25.226 and 25.795 There are characteristic peaks. In certain embodiments, Form A of the lysine salt of the compound of formula (I) 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. In certain embodiments, Form A of the lysine salt of a compound of formula (I) is characterized 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 peak. In certain embodiments, the X-ray powder diffraction pattern of Form A of the lysine salt of the compound represented by formula (I), represented by the diffraction angle 2θ, is shown in FIG. 11 .

The present disclosure further provides a method for preparing the crystal form A of the lysine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), acetone and lysine solution, heating, and b) precipitating out .

In certain embodiments, the volume (μl) of the solvent acetone used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments 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, 200. In certain embodiments, the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.

The present disclosure further provides an X-ray powder diffraction pattern of Form A of the arginine salt of the compound represented by formula (I), expressed as diffraction angle 2θ, at 7.780, 10.847, 15.726, 18.634, 20.265, 21.618 and 26.485 There are characteristic peaks. In certain embodiments, Form A of the arginine salt of the compound of formula (I) 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. In certain embodiments, Form A of the arginine salt of the compound of formula (I) is 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 There are characteristic peaks. In certain embodiments, the X-ray powder diffraction pattern of the crystal form A of the arginine salt of the compound represented by formula (I) is shown in FIG. 12 as a diffraction angle 2θ.

The present disclosure further provides a method for preparing Form A of the arginine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), acetone and an aqueous arginine solution, and b) stirring and crystallization.

The present disclosure further provides an X-ray powder diffraction pattern of Form B of the arginine salt of the compound represented by formula (I), expressed as diffraction angle 2θ, at 8.097, 15.541, 19.256, 22.111, 24.679, 27.124 and 33.605 There are characteristic peaks. In certain embodiments, Form B of the arginine salt of the compound of formula (I) 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. In certain embodiments, Form B of the arginine salt of the compound of formula (I) is 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 There is a characteristic peak at 43.535. In certain embodiments, the X-ray powder diffraction pattern of the crystal form B of the arginine salt of the compound represented by formula (I) is shown in FIG.

The present disclosure further provides a method for preparing the crystal form B of the arginine salt of the compound represented by the formula (I), comprising: a) mixing the compound represented by the formula (I), acetone and arginine, b) heating, cooling down for crystallization .

The present disclosure also provides pharmaceutical compositions prepared from the crystalline forms of the pharmaceutically acceptable salts described in the aforementioned (I).

The present disclosure also provides a pharmaceutical composition comprising the aforementioned crystalline form of the pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier, diluent or excipient.

The present disclosure also provides a preparation method of a pharmaceutical composition, comprising the step of mixing the aforementioned crystalline form of the pharmaceutically acceptable salt with a pharmaceutically acceptable carrier, diluent or excipient.

The present disclosure also provides the use of the crystalline form of the aforementioned pharmaceutically acceptable salt, or the aforementioned composition, or the composition prepared by the aforementioned method in the preparation of a medicament for inhibiting voltage-gated sodium channels in a subject, preferably, The voltage-gated sodium channel is Na _V 1.8.

The present disclosure also provides the crystalline forms of the aforementioned pharmaceutically acceptable salts, or the aforementioned compositions, or the compositions prepared by the aforementioned methods in preparation for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, summer- Use in the medicament of Horse-Figure 3 syndrome, incontinence or arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain Pain, bowel pain and idiopathic pain.

There is a certain error in the determination of the stoichiometric ratio between the compound of formula (I) and the base molecule described in the present disclosure. Generally speaking, plus or minus 10% is within a reasonable error range. There is a certain degree of error variation with the context in which it is used, which does not vary by more than plus or minus 10%, plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, Plus or minus 4%, plus or minus 3%, plus or minus 2%, plus or minus 1%, preferably plus or minus 5%.

The “2θ or 2θ angle” mentioned in this disclosure refers to the diffraction angle, and θ is the Bragg angle, in degrees or degrees; the error range of each characteristic peak 2θ is ±0.20 (including rounded numbers with more than 1 decimal place). case), 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.

The precipitation methods described in the present disclosure include, but are not limited to, stirring, volatilization, beating, and precipitation.

According to the description of hygroscopic characteristics and the definition of hygroscopic weight gain in "9103 Guiding Principles of Drug Hygroscopicity" in the 2015 edition of the Chinese Pharmacopoeia,

Deliquescence: Absorbs sufficient water to form a liquid;

Extremely hygroscopic: the weight gain of moisture is not less than 15%;

Moisture: Moisture gain is less than 15% but not less than 2%;

Slightly hygroscopic: wet weight gain is less than 2% but not less than 0.2%;

No or almost no hygroscopicity: hygroscopic weight gain is less than 0.2%.

"Differential Scanning Calorimetry or DSC" as used in this disclosure refers to the measurement of the temperature difference, heat flow difference between a sample and a reference during the heating or constant temperature of the sample to characterize all physical changes related to thermal effects and Chemical changes to obtain phase transition information of the sample.

The drying temperature mentioned in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and can be dried under normal pressure or under reduced pressure.

"Pharmaceutical composition" means a mixture containing one or more compounds of formula (I) described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, together with other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

The crystal forms described in the present disclosure include but are not limited to the solvate of the compound meglumine salt of formula (I), and the solvents include but are not limited to tetrahydrofuran/ethanol, DMSO, ethanol, acetonitrile, acetone, methyl tertiary Butyl ether, toluene. The crystal form described in the present disclosure includes but is not limited to the solvate of the ethanolamine salt of the compound represented by formula (I), and the solvent includes but is not limited to ethanol. The crystal form described in the present disclosure includes but is not limited to the solvate of the sodium salt of the compound represented by formula (I), and the solvent includes but is not limited to isopropanol, EtOH/THF. The crystal form described in the present disclosure includes but is not limited to the solvate of the potassium salt of the compound represented by formula (I), and the solvent includes but not limited to isopropanol, EtOH/THF. The crystal form described in the present disclosure includes, but is not limited to, the solvate of the amine salt of the compound represented by formula (I), and the solvent includes but is not limited to isopropanol. The crystal forms described in the present disclosure include, but are not limited to, the solvate of the calcium salt of the compound represented by formula (I), and the solvent includes, but is not limited to, ethanol. The crystal form described in the present disclosure includes, but is not limited to, a solvate of lysine of the compound represented by formula (I), and the solvent includes but is not limited to acetone. The crystal form described in the present disclosure includes, but is not limited to, a solvate of the compound represented by formula (I), arginine, and the solvent includes, but is not limited to, acetone.

"Solvates" as used in this disclosure include, but are not limited to, complexes formed by combining a compound of formula I with a solvent.

Description of drawings

Fig. 1: XRPD pattern of amorphous crystal of dimeglumine salt of compound represented by formula (I).

Figure 2: XRPD pattern of the ethanolamine salt form A of the compound represented by formula (I).

Figure 3: XRPD pattern of the sodium salt form a of the compound represented by formula (I).

Figure 4: XRPD pattern of the sodium salt form b of the compound represented by formula (I).

Figure 5: The XRPD pattern of the potassium salt of the compound represented by the formula (I) in crystal form I.

Figure 6: XRPD pattern of the potassium salt form II of the compound represented by formula (I).

Figure 7: XRPD pattern of the potassium salt III crystal form of the compound represented by formula (I).

Figure 8: XRPD pattern of amine salt form A of the compound represented by formula (I).

Figure 9: XRPD pattern of the amine salt form B of the compound represented by formula (I).

Figure 10: XRPD pattern of the calcium salt form a of the compound represented by formula (I).

Figure 11: XRPD pattern of the lysine salt form A of the compound represented by formula (I).

Figure 12: The XRPD pattern of the crystalline form A of arginine salt of the compound represented by formula (I).

Figure 13: XRPD pattern of the crystalline form B of arginine salt of the compound represented by formula (I).

Detailed ways

The present disclosure will be explained in more detail below with reference to the embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure, but do not limit the essence and scope of the present disclosure.

The reagents used in the present invention are commercially available.

The test conditions of the instrument used in the experiment in the present invention:

1. Differential Scanning Calorimeter (DSC)

Instrument model: Mettler Toledo DSC 3+STARe System

Purge gas: nitrogen; nitrogen purge rate: 50mL/min

Heating rate: 10.0℃/min

Temperature range: 25-350℃

2. X-ray Powder Diffraction (XRPD)

Instrument model: BRUKER D8 Discover A25 X-ray powder diffractometer

Ray: Monochromatic Cu-Kα ray (λ=1.5406)

Scanning method: θ/2θ, scanning range (2θ range): 3～50°

Voltage: 40kV, Current: 40mA

3. Thermogravimetric Analysis (TGA)

Instrument model: Mettler Toledo TGA2

Purge gas: nitrogen; nitrogen purge rate: 50mL/min

Heating rate: 10.0℃/min

Temperature range: 25-350℃

4. DVS is dynamic moisture adsorption

The detection adopts Surface Measurement Systems advantage 2, at 25°C, the humidity is from 50%-95%-0%-95%-50%RH, the step is 10%, and the judgment standard is that each gradient mass change dM/dT is less than 0.002% , TMAX360min, cycle twice. 5. The average inhibition rate and IC50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).

6. The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent system of the column chromatography adopted for the purification compound and the developing agent system of thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system. The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm. Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

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

NMR was measured with Bruker AVANCE NEO 500M, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS) .

The MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC/MS instrument (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS). waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector). THERMO Ultimate3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)

8. The known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc. ), Darui Chemicals and other companies.

9. The determination of HPLC uses Agilent 1260DAD high performance liquid chromatograph (ACE Excel C18 150×4.6mm chromatographic column) and Thermo Dionex Ultimate 3000 high pressure liquid chromatograph (Waters Xbridge C18 150×4.6mm chromatographic column).

Example 1: Preparation of compounds of formula I

Step 1: Compound of Formula III

The compound of formula IV (1.5g, 3.26mmol, 1.0eq) was added with aqueous formaldehyde solution (10mL) and stirred, heated for reaction, and suction filtered to obtain 1.5g of white solid, Ms(ESI): m/z 491.00[M+1]+. 1H-NMR(400MHz,DMSO-d6)δ11.11(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).

The second step: compound of formula II

The compound of formula III (1 g, 2.04 mmol, 1.0 eq) was added to dry THF (10 mL) and stirred. Nitrogen ventilation protection, cooling. 1.0M sodium bis(trimethylsilyl)amide (NaHMDS)/(tetrahydrofuran) THF solution (3.05mL, 3.05mmol, 1.5eq) was added, followed by dropwise addition of tetrabenzyl pyrophosphate (1.09g, 2.04mmol, 1.0 eq) in THF (2 mL), after the addition was complete, the reaction was stirred at room temperature. Ethyl acetate EA was added to the reaction solution to dilute, then 0.5M NaOH aqueous solution was added dropwise, the layers were separated, the organic phases were combined, dried, filtered, and concentrated to dryness to obtain a light yellow oil crude product, which was purified to give 1.25g, the yield was 81.69%, 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).

The third step: compound of formula (I)

Trifluoroacetic acid (TFA) (10.34 mL, 139.14 mmol, 95.0 eq), the starting compound of formula II (1.10 g, 1.46 mmol, 1.0 eq) was added, and the reaction was stirred. Concentrated and dried to obtain crude product. Purification gave a white solid 0.77g, yield: 92.11%, Ms(ESI): m/z 570.90[M+1]+. 1H-NMR(400MHz,DMSO-d6)δ11.17(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).

Test Example 1: Determination of the Inhibitory Activity of Compounds of Formula I on Na _V 1.8

The purpose of the experiment was to investigate the effect of compound formula I on the Na _V 1.8 ion channel in vitro, _which was stably expressed on HEK293 cells. After the Na _V 1.8 current was stable, comparing the magnitude of the Na _V 1.8 current before and after the application of the compound, the effect of the compound on the Na _V 1.8 ion channel could be obtained.

1 Experimental materials and instruments

1) Patch clamp amplifier: patch clamp PC-505B(WARNER instruments)/MultiClamp 700A(Axon instruments)

2) D/A converter: Digidata 1440A(Axon CNS)/Digidata 1550A(Axon instruments)

3) Micro controller: MP-225 (SUTTER instrument)

4) Inverted microscope: TL4 (Olympus)

5) Glass microelectrode drawing instrument: PC-10 (NARISHIGE)

6) Micro-electrode glass capillary: B12024F (Wuhan Micro-Exploration Scientific Instrument Co., Ltd.)

7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)

8) TTX AF3014 (Affix Scientific)

2 Experimental steps

2.1 Test compounds

Compound I and VX-150 (prepared with reference to the method in WO2015089361).

2.1 Compound preparation

Compounds for preparing intracellular and extracellular fluids were purchased from Sigma (St.Louis, MO), except for NaOH and KOH used for acid-base titration. Extracellular fluid (mM) was: NaCl, 137; KCl, 4; _CaCl2 , 1.8; MgCl2 _, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). Intracellular fluid (mM) was Aspartic acid, 140; MgCl2,2; EGTA 11; HEPES, 10; pH 7.2 (CsOH titration). All test compound and control compound solutions contained 1 μM TTX.

Test compounds were stored at 9 mM in dimethyl sulfoxide (DMSO). On the test day, it was redissolved in extracellular fluid to prepare the required concentration.

2.2 Manual patch clamp testing process

1) After the compound is formulated into a solution with a specified concentration, the liquid is added to each pipeline in order from low to high concentration, and each pipeline is marked.

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

3) After the cell transmembrane current is stabilized, perfusion with different concentrations is performed in sequence. If the current is stable for at least one minute, you can switch to the next concentration for perfusion. The perfusion time for each concentration did not exceed five minutes.

4) Clean the perfusion tank. Rinse according to the concentration of the liquid from high to low, and rinse each concentration of liquid for 20s. Finally, rinse with extracellular fluid for 1 min.

2.3 Test voltage equation (resting) and results

Cells were clamped at –80 mV and then depolarized to 10 mV with a square wave lasting 10 ms to obtain Na _V 1.8 currents. This procedure is repeated every 5 seconds. The maximum current induced by the square wave was detected. After it stabilized, the test compound was perfused. When the reaction stabilized, the blocking intensity was calculated.

3. Data Analysis

The data will be stored in a computer system for analysis. Data collection and analysis will use pCLAMP 10 (Molecular Devices, Union City, CA), and management will review the analysis results. Current stabilization refers to the fact that the current varies with time within a limited range. The magnitude of the current after stabilization is used to calculate the effect of the compound's solubility here.

The inhibitory activity of compound (I) of the present disclosure on Nav1.8 was determined by the above test, and the IC ₅₀ value was 2.80 nM, and the VX-150 value was 17.71 nM.

Test Example 2: Pharmacokinetic Study in Rats

1. Abstract

Taking CD rats as test animals, LC/MS/MS method was used to determine the drug concentration in plasma at different times after intravenous injection of the compounds of the present disclosure. The pharmacokinetic behavior of the disclosed compounds in mice was studied, and their pharmacokinetic characteristics were evaluated.

2. Test plan

2.1 Test drug

Compound of formula I: prepared with sodium chloride injection;

Compound of formula IV: formulated with 1% DMSO + 5% HS15 + 94% normal saline.

2.2 Experimental animals

SD rats, half male and half male, weighing 190-230 g, were purchased from Shanghai Jisijie Laboratory Animal Co., Ltd., production license number SCXK (Shanghai) 2018-0004, qualification certificate number 20180004038484.

2.3 Administration

There were 2 groups of rats, 6 rats in each group, half male and half male. Fasting for not less than 12 hours before administration, free drinking water, and uniform food for 4 hours after administration. See the table below for specific arrangements:

Table 2

3. Operation

Sample collection and processing:

Before administration and 5min, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0, 10, 24 and 48h after administration, 0.2ml of blood was collected from the retrobulbar venous plexus, and 10μL of 100mM BNPP in EDTA-K2 was added after sampling In an anticoagulant tube, centrifuge at 11,000 rpm for 5 min (4°C), separate plasma within 30 min, and store at -70°C for testing.

The LC-MS/MS method was used to determine the concentration of the compound of formula I and the compound of formula IV in the plasma of rats at different time points after administration. The non-compartmental model of Phoenix WinNonlin 7.0 software (Pharsight, USA) was used to calculate the pharmacokinetic parameters of rats after administration.

The time to peak _Tmax and the peak concentration _Cmax are all measured values;

AUC _0-t value of the area under the drug-time curve: calculated by trapezoidal method; AUC _0-∞ =AUC _0-t +C _t / _ke , C _t is the blood drug concentration at the last measurable time point, and _ke is elimination rate constant;

elimination half-life t _1/2 =0.693/ _ke ;

Average residence time MRT=AUMC/AUC;

Clearance CL=D/AUC _0-∞ (D is the administered dose);

Steady state volume of distribution V _ss = CL x MRT.

4. Pharmacokinetic parameter results

table 3

in conclusion:

After intravenous injection of the compound of formula I to SD rats, the compound of formula I was not detected in the plasma (below the lower limit of quantification of 7.50 ng/mL), and the plasma concentration of the compound of formula IV reached the peak at the first sampling point (5min) after administration, It is suggested that the compound of formula I can be rapidly converted into the parent compound of formula IV in vivo after administration.

At an equimolar dose, the peak concentration (C _5min ) of the compound of formula IV in the compound of formula I administration group was 38.3% of the peak concentration (C _5min ) of the compound of formula IV administration group. It is related to rapid distribution into tissues and then converted to the compound of formula IV; exposure AUC _0-t is 77% of the compound of formula IV administration group; plasma clearance CL and steady-state volume of distribution _Vss are the same as those of the compound of formula IV administration group, respectively 1.40 and 1.77 times.

Test Example 3: In Vivo Pharmacokinetic Study of Beagle Dogs

1. Abstract

Taking beagle dogs as test animals, the drug concentrations in plasma at different times after intravenous injection of the compounds of the present disclosure were determined by LC/MS/MS method. To study the pharmacokinetic behavior of the disclosed compounds in mice, and to evaluate their pharmacokinetic characteristics.

2. Test plan

2.1 Test drug

Compound of formula I: prepared with sodium chloride injection;

Compound of formula IV: formulated with 2% DMSO + 10% HS15 (polyethylene glycol (PEG) dodecyl stearate) + 88% normal saline.

2.2 Experimental animals

Beagles, half male and half male, weighing about 9-11 kg, were purchased from Jiangsu Yadong Laboratory Animal Research Institute Co., Ltd., production license number SCXK (Shanghai) 2016-0009, certificate number 202020255.

2.3 Administration

Six beagle dogs, half male and half female, fasted for no less than 12 hours before administration, and had free access to water. 4h after administration, the patients were fed uniformly. The washout period is 1 week.

Table 4 Arrangement of pharmacokinetic test in Beagle dogs

3. Operation

Before administration and 5min, 15min, 0.5, 1.0, 2.0, 4.0, 7.0, 10, 24, and 48h after administration, 1ml of blood was collected from the extremities, and 50μL of 100mM BNPP in EDTA _- K2 anticoagulation was added after sampling. In the tube, centrifuge at 3500 rpm for 10 min (4 °C), separate the plasma within 1 h, and store at -70 °C for testing.

The LC-MS/MS method was used to determine the concentrations of the compounds of formula I and IV in plasma at different time points after administration to beagle dogs. The non-compartmental model of Phoenix WinNonlin 7.0 software (Pharsight, USA) was used to calculate the pharmacokinetic parameters of beagle dogs after administration.

elimination half-life t _1/2 =0.693/ _ke ;

Average residence time MRT=AUMC/AUC;

Clearance CL=D/AUC _0-∞ (D is the administered dose);

Steady state volume of distribution V _ss = CL x MRT.

4. Pharmacokinetic parameter results

table 5

After intravenous injection of the compound of formula I to beagle dogs, the compound of formula I was not detected in the plasma (below the lower limit of quantification of 7.50 ng/mL), and the plasma concentration of the compound of formula IV reached a peak at the first sampling point (5min) after administration, It is suggested that the compound of formula I can be rapidly converted into the parent compound of formula IV in vivo after administration.

Under an equimolar dose, the peak concentration (C _5min ) of the compound of formula IV after injection of the compound of formula I in beagle dogs is 100.4% of the peak concentration (C _5min ) of the compound of formula IV administration group; AUC _0-t is the administration of the compound of formula IV 96.3% of the group. The plasma clearance CL, steady state volume of distribution V _ss and half-life t _1/2 of the compounds of formula IV did not show significant differences between the two groups.

Example 2: Amorphous preparation of dimeglumine salt of compound represented by formula (I)

100 mg of the compound represented by formula (I) was dissolved in 3 mL of 1:1 tetrahydrofuran (THF)/ethanol (EtOH) at 50°C, 0.1 mL of 684 mg/mL meglumine aqueous solution was added to react, the temperature was cooled and precipitated, and pre-cooled isopropyl alcohol was added. 3 mL of propanol was precipitated out, and the solid was centrifuged and dried in vacuo. The product is amorphous as detected by X-ray powder diffraction, and the XRPD spectrum is shown in Figure 1.

The result of nuclear magnetic resonance (HNMR) detection of the obtained product: the content of meglumine is 43.2%, indicating that the molar ratio of the compound and meglumine in the salt is about 1:2.

Example 3: Amorphous preparation of dimeglumine salt of compound represented by formula (I)

100 mg of the compound represented by formula (I) was dissolved in 3 mL of THF/EtOH (1:1) at 50° C., 0.1 mL of 684 mg/mL meglumine aqueous solution was added to react, and the temperature was cooled to separate out. 3 mL of pre-cooled EtOH was added to precipitate out, and the solid was centrifuged and dried in vacuo. The product was amorphous as determined by X-ray powder diffraction.

Example 4: Amorphous preparation of dimglumine salt of compound represented by formula (I)

After 100 mg of the compound shown in formula (I) was dissolved in 0.5 mL of DMSO, 0.1 mL of 684 mg/mL meglumine aqueous solution was added, reacted at 50° C., and then lowered to room temperature. The reaction was dropped into precooled 10 mL of EtOH, and precipitated out. , the centrifuged solid was vacuum dried. The product was amorphous as determined by X-ray powder diffraction.

Example 5: Preparation of the amorphous dimeglumine salt of the compound represented by formula (I)

10.0 mg of the compound represented by formula (I) and 7.8 mg of meglumine were added with 0.2 mL of ethanol, heated at 50° C. for reaction, stirred at room temperature, and centrifuged to dry the solid in vacuum. The product was amorphous as determined by X-ray powder diffraction.

Example 6: Preparation of amorphous dimeglumine salt of compound represented by formula (I)

10.0 mg of the compound represented by formula (I) and 7.8 mg of meglumine were added with 0.2 mL of acetone, heated at 50° C. for reaction, stirred at room temperature, and the solid was centrifuged and dried in vacuo. The product was amorphous as determined by X-ray powder diffraction.

Example 7: Preparation of amorphous dimeglumine salt of compound represented by formula (I)

10.0 mg of the compound represented by formula (I) and 7.8 mg of meglumine were added with 0.2 mL of acetonitrile, heated at 50° C. for reaction, stirred at room temperature, and centrifuged and the solid was vacuum-dried. The product was amorphous as determined by X-ray powder diffraction.

Example 8: Amorphous preparation of monomeglumine salt of compound represented by formula (I)

10.4 mg of the compound represented by formula (I) and 3.9 mg of meglumine were added with 0.2 mL of methyl tert-butyl ether, heated at 50°C for reaction, cooled down, and the solid was centrifuged and dried in vacuo. The product was amorphous as determined by X-ray powder diffraction.

The result of nuclear magnetic resonance (HNMR) detection of the obtained product: the content of meglumine is 26.6%, indicating that the molar ratio of the compound and meglumine in the salt is about 1:1.

Example 9: Amorphous preparation of monomeglumine salt of compound represented by formula (I)

10.3 mg of the compound represented by the formula (I) and 3.9 mg of meglumine were added with 0.3 mL of toluene, heated at 50° C. to react, then cooled down, and the solid was centrifuged and dried in vacuo. The product was amorphous as determined by X-ray powder diffraction.

Example 10: Preparation of ethanolamine salt crystal form A of the compound represented by formula (I)

11.2 mg of the compound represented by formula (I) was added to 0.2 mL of ethanol, and 19.3 μL of 1 mol/L ethanolamine aqueous solution was added to dissolve the clear solution, heated to separate out, and the solid was centrifuged and dried in vacuo. According to the X-ray powder diffraction detection, the product is crystal form A, the XRPD spectrum is shown in Figure 2, and the characteristic peak positions are shown in Table 1. The DSC spectrum shows that the endothermic peak peak is 105.27°C. The TGA spectrum showed that the weight loss was 6.64% at 25-110°C and 6.36% at 110-255°C. According to the nuclear magnetic resonance (HNMR) detection of the obtained product, the salt-forming ratio of the compound and ethanolamine in this salt is about 1:1.1.

Table 1

Example 11: Preparation of sodium salt a crystal form of compound represented by formula (I)

10.35 mg of the compound represented by formula (I) was added with 0.2 mL of isopropanol at room temperature, 19.3 μL of 1 mol/L aqueous sodium hydroxide solution was added, the reaction was heated at 45° C., cooled to room temperature for beating, added with 0.1 mL of isopropanol for precipitation, and the solid was centrifuged. Vacuum dry. According to the X-ray powder diffraction detection, the product is a crystal form, the XRPD spectrum is shown in Figure 3, and the characteristic peak positions are shown in Table 2. The DSC spectrum shows that the endothermic peaks are 57.49°C, 97.49°C, 162.79°C, and 241.94°C, and the exothermic peaks are 197.83°C. The TGA spectrum showed that the weight loss was 5.47% at 25-105°C and 3.49% at 105-190°C.

Table 2

Example 12: Preparation of sodium salt b crystal form of compound represented by formula (I)

10.1 mg of the compound represented by formula (I) was heated with 0.2 mL of EtOH/THF (1:1), and 19.3 μL of 1 mol/L aqueous sodium hydroxide solution was added to precipitate out, and the solid was centrifuged and dried in vacuo. According to X-ray powder diffraction detection, the product is crystal form b, the XRPD spectrum is shown in Figure 4, and the characteristic peak positions are shown in Table 3. The obtained product was detected by ion chromatography, and the salt-forming ratio of compound and sodium ion in the salt was about 1:1.

table 3

Example 13: Preparation of potassium salt crystal form I of the compound represented by formula (I)

10.1 mg of the compound represented by formula (I) was added with 0.2 mL of isopropanol, and 19.3 μL of 1 mol/L potassium hydroxide aqueous solution was added, and the reaction was heated at 45° C., cooled to room temperature, slurried for 3 days, centrifuged, and the solid was vacuum-dried. Through X-ray powder diffraction detection, the product is crystal form I, the XRPD spectrum is shown in Figure 5, and the characteristic peak positions are shown in Table 4. The DSC spectrum shows that the endothermic peaks are 80.79°C, 166.10°C, and 241.89°C, and the exothermic peaks are 203.52°C. The TGA spectrum showed that the weight loss was 9.15% at 25-130°C and 5.25% at 130-235°C.

Table 4

Example 14: Preparation of potassium salt II crystal form of compound represented by formula (I)

49.72 mg of the compound represented by formula (I) was added with 1.0 mL of isopropanol, 49.7 μL of 1 mol/L potassium hydroxide aqueous solution was added, the reaction was heated at 45° C., cooled to room temperature, slurried for 1 day, centrifuged, and the solid was vacuum-dried. The product was detected by X-ray powder diffraction, and the product was crystal form II, the XRPD spectrum was shown in Figure 6, and the characteristic peak positions were shown in Table 5. The DSC spectrum shows that the endothermic peaks are 68.80°C, 167.05°C, and 240.18°C, and the exothermic peak is 197.03°C. The TGA spectrum showed that the weight loss was 3.94% at 25-140°C and 4.63% at 140-235°C.

table 5

Example 15: Preparation of potassium salt III crystal form of compound represented by formula (I)

10 mg of the compound represented by formula (I) was added with 0.3 mL of ethanol/tetrahydrofuran, dissolved at 50° C., cooled to room temperature, and 19.3 μL of 1M potassium hydroxide aqueous solution was added, cooled, precipitated, centrifuged, and dried to obtain a solid. According to X-ray powder diffraction detection, the product is the III crystal form, the XRPD spectrum is shown in Figure 7, and the characteristic peak positions are shown in Table 6. The DSC spectrum shows that the endothermic peaks are 72.31°C, 186.68°C, and 244.60°C, and the exothermic peaks are 202.45°C. The TGA spectrum showed that the weight loss was 2.64% at 25-145°C and 4.31% at 145-230°C. The ion chromatography of the obtained product shows that the salt-forming ratio of the compound and potassium ion in the salt is about 1:0.9.

Table 6

Example 16: Preparation of amine salt A crystal form of compound represented by formula (I)

10.3 mg of the compound represented by formula (I) was added with 0.2 mL of isopropanol, and 19.3 μL of 1 mol/L ammonia solution was added. The reaction was heated at 45° C., and slurried at room temperature for 3 days. The white solid was precipitated, centrifuged, and the solid was vacuum-dried. According to X-ray powder diffraction detection, the product is crystal form A, the XRPD spectrum is shown in Figure 8, and the characteristic peak positions are shown in Table 7. The DSC spectrum showed that the endothermic peaks were 76.96°C and 138.8°C. The TGA spectrum showed that the weight loss was 13.27% at 25-240°C. The ion chromatography of the obtained product showed that the salt-forming ratio of compound and amine in this salt was about 1:1.

Table 7

Example 17: Preparation of amine salt B crystal form of compound represented by formula (I)

202.9 mg of the compound represented by formula (I) was added with 4 ml of isopropanol, 385.4 ul of 1M aqueous ammonia solution was added, the temperature was raised and lowered (50°C-5°C), centrifuged, and the solid was dried in vacuum. X-ray powder diffraction detection shows that the product is crystal form B, the XRPD spectrum is shown in Figure 9, and the characteristic peak positions are shown in Table 8. The DSC spectrum shows that the endothermic peak peak is 173.34 °C, and the exothermic peak peak is 188.10 °C. The TGA spectrum showed that the weight loss was 5.00% at 25-230°C. The ion chromatography of the obtained product shows that the salt-forming ratio of compound and amine in this salt is about 1:0.8.

Table 8

Example 18: Preparation of calcium salt a crystal form of compound represented by formula (I)

10.1 mg of the compound represented by the formula (I) was added with 1.6 mg of calcium hydroxide, 0.2 mL of ethanol was added, and the reaction was heated at 45° C. The white suspended solid was precipitated, and the centrifuged solid was vacuum-dried. According to X-ray powder diffraction detection, the product is a crystal form, the XRPD spectrum is shown in Figure 10, and the characteristic peak positions are shown in Table 9. The DSC spectrum shows that the peak endothermic peak is 204.14°C. The TGA spectrum showed that the weight loss was 2.15% at 25-170°C and 3.50% at 170-235°C.

Table 9

Example 19: Preparation of lysine salt A crystal form of compound represented by formula (I)

10.4 mg of the compound represented by formula (I) was added with 0.2 mL of acetone, and 19.3 uL of 1 mol/L lysine aqueous solution was added, heated, and precipitated and dried. According to X-ray powder diffraction detection, the product is crystal form A, the XRPD spectrum is shown in Figure 11, and the characteristic peak positions are shown in Table 10. The DSC spectrum shows that the endothermic peaks are 175.18°C and 193.83°C, and the exothermic peaks are 179.36°C. The TGA spectrum showed that the weight loss was 11.50% at 25-170°C.

Table 10

Example 20: Preparation of Arginine Salt Form A of the Compound of Formula (I)

Add 0.2 mL of acetone to 10.1 mg of the compound represented by formula (I), add 19.3 uL of 1 mol/L arginine aqueous solution, heat the reaction, stir for 3 days to precipitate a solid, centrifuge, and dry the solid. According to X-ray powder diffraction detection, the product is crystal form A, the XRPD spectrum is shown in Figure 12, and the characteristic peak positions are shown in Table 11. The DSC spectrum shows that the endothermic peaks are at 72°C, 86.16°C, 155.82°C, and 181.49°C. The TGA spectrum showed that the weight loss was 6.70% at 25-140°C and 8.00% at 140-240°C. According to the nuclear magnetic resonance (HNMR) detection of the obtained product, the salt-forming ratio of compound and arginine in this salt is about 1:1.

Table 11

Example 21: Preparation of arginine salt form B of the compound represented by formula (I)

200.7 mg of the compound represented by formula (I) and 70.1 mg of arginine were added to 2 ml of acetone, and 100 ul of pure water was added to raise and lower the temperature (50° C.-5° C.), the solid was precipitated, and the solid was centrifuged and dried. According to X-ray powder diffraction detection, the product is crystal form B, the XRPD spectrum is shown in Figure 13, and the characteristic peak positions are shown in Table 12. The DSC spectrum shows that the endothermic peak peak is 118.02°C. The TGA spectrum showed that the weight loss was 5.63% at 25-145°C. According to the nuclear magnetic resonance (HNMR) detection of the obtained product, the salt-forming ratio of compound and arginine in this salt is about 1:1.

Table 12

Example 22: Preparation of the amorphous arginine salt of the compound represented by formula (I)

10 mg of the compound represented by formula (I) was added with 3.5 mg of arginine, 0.2 mL of ethanol was added, the reaction was heated at 45° C., cooled to room temperature, stirred, centrifuged, and dried to obtain the product. The product was amorphous as determined by X-ray powder diffraction. According to the nuclear magnetic resonance (HNMR) detection of the obtained product, the salt-forming ratio of compound and arginine in this salt is about 1:1.

Example 23: Preparation of the amorphous lysine salt of the compound represented by formula (I)

10 mg of the compound represented by formula (I), 6 mg of lysine, 0.2 mL of isopropyl acetate were added, the reaction was heated at 45° C., cooled to room temperature, stirred, centrifuged, and dried to obtain the product. The product was amorphous as determined by X-ray powder diffraction. According to the nuclear magnetic resonance (HNMR) detection of the obtained product, the salt-forming ratio of compound and lysine in this salt is about 1:0.9.

Example 24: Solubility and Stability Testing of Different Salts

1. Solubility

Adopt HPLC to detect the solubility of the compound shown in formula (I) and its different salt forms in phosphate buffer solution, as shown in the following table:

溶解度(mg/ml)Solubility (mg/ml)	pH 4pH 4	pH 6pH 6	pH 7.4pH 7.4	pH 9pH 9	水water	0.9％NaCl0.9%NaCl
游离态A晶型Free state A crystal form	0.390.39	0.510.51	0.840.84	1.501.50	0.130.13	0.280.28

二葡甲胺盐无定形Dimeglumine Salt Amorphous	0.340.34	＞130>130	＞154>154	＞194>194	＞226>226	＞238>238
钾盐III晶型Potassium salt form III	0.130.13	0.330.33	0.150.15	1.841.84	1.881.88	0.010.01
钠盐b晶型sodium salt form b	0.030.03	0.010.01	2.182.18	＞10.2>10.2	＞4.6>4.6	0.020.02
钙盐a晶型Calcium salt form a	0.230.23	0.010.01	0.070.07	0.010.01	0.020.02	0.050.05
乙醇胺盐A晶型Ethanolamine salt form A	0.020.02	0.040.04	//	0.480.48	23-30.723-30.7	0.320.32
胺盐A晶型Amine salt form A	0.110.11	0.110.11	5.445.44	11.7011.70	6.736.73	0.270.27
胺盐B晶型Amine salt form B	1.231.23	0.190.19	0.330.33	0.540.54	0.660.66	0.200.20
精氨酸盐A晶型Arginine salt form A	2.832.83	0.390.39	＞28>28	＞24.5>24.5	0.190.19	1.921.92
精氨酸盐B晶型Arginine salt form B	0.270.27	0.260.26	25-5025-50	＞50>50	1.291.29	0.360.36
精氨酸盐无定形Arginine salt amorphous	0.830.83	0.370.37	1.951.95	＞148>148	＞37.5>37.5	1.231.23
赖氨酸盐无定形Lysine salt amorphous	0.410.41	0.330.33	0.900.90	2.222.22	9.019.01	0.200.20

The results show that compared with other salts of the compound of formula I, dimeglumine salt has a great advantage in solubility.

2. Stability:

The solid stability of the compound represented by formula 1 and its salt is shown in the following table:

The results showed that the stability of meglumine salt was better than that of sodium salt at room temperature.

Example 25: Amorphous stability study of dimglumine salt of compound represented by formula I

The dimeglumine salt amorphous of the compound shown in formula I was placed in an open mouth, and the stability under the conditions of illumination (4500Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) was investigated respectively. The sampling period is 30 days. The results are shown in the following table.

Table 13

Experiments on influencing factors show that under the conditions of light, high temperature (40 ° C, 60 ° C), and high humidity (RH 75%, RH 92.5%) for 1 month, the amorphous form of the compound dimeglumine salt of formula I has better properties. The physical stability; except for high temperature 60 ℃ and light, the chemical stability is good under other conditions.

Example 26: Amorphous long-term/accelerated stability study of dimeglumine salt of compound represented by formula I

The amorphous dimeglumine salt of the compound represented by formula I was placed under conditions of -20°C, 4°C, 25°C and 60% RH, 40°C and 75% RH to investigate its stability. The results are shown in the following table. :

Table 14

Long-term/accelerated stability experiments show that: the dimeglumine salt of the compound described in formula I is amorphous and has good physical stability for 3 months under long-term/accelerated stability conditions, and is still amorphous; except for accelerated conditions,- Good chemical stability after 3 months at 20°C, 4°C and long-term conditions.

Example 27: Study on the hygroscopicity of different salt crystal forms of the compound represented by formula I

Using Surface Measurement Systems advantage 2, at 25°C, the humidity starts from 50%, the investigated humidity range is 0%-95%, and the step is 10%. The judgment standard is that each gradient mass change dM/dT is less than 0.002%, and TMAX is less than 0.002%. 360min, cycle twice. The hygroscopic properties of different salt crystal forms of the compound shown in formula I were investigated respectively, and the experimental results were as follows:

Under normal storage conditions (25°C, RH 60%), the water absorption of potassium salt form III, amine salt form B, arginine salt form B and ethanolamine salt form A is about 2.80%, 1.25%, and 0.20%, respectively. and 7.49%; in the accelerated test condition (RH70%), the water absorption is about 2.91%, 1.78%, 0.27%, and 8.58%, respectively; in the extreme condition (RH 90%), the water absorption is about 3.37%, 9.90%, 0.60%, respectively % and 13.95%.

Example 28: Stability study of different salt forms of the compound represented by formula I

The different salts of the compounds shown in formula I were placed on an open side, and the stability of the samples under the conditions of illumination (4500Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) was investigated respectively. Sampling The inspection period is 30 days, and the experimental results are shown in the following table:

Table of experimental results: the crystal form of potassium salt III of the compound represented by formula I is basically stable physically and chemically under the conditions of influencing factors; the crystal form of arginine salt and the crystal form of amine salt B have good physical stability, and the crystal form of arginine salt A , Ethanolamine salt crystal form A is crystallized under high humidity conditions, and has good physical stability under other conditions; except for high temperature of 60 ° C and light, arginine salt crystal form B and A crystal form, amine salt B crystal form, ethanolamine salt Form A has good chemical stability under other conditions.

Experimental Example 29: Long-term/Accelerated Stability of Different Salt Forms of Compounds of Formula I

The samples of different salt crystal forms of the compound represented by formula I were placed at 4 ° C, 25 ° C and 60% RH, 40 ° C and 75% RH conditions to investigate their stability. The sampling period was 2 months. The experimental results are as follows: :

The results show that the physical stability of other crystal forms is good except that the arginine salt form A and the ethanolamine salt form A have slightly poor physical stability. Except for the decrease in purity under accelerated conditions, potassium salt form III, amine salt form A, amine salt form B, arginine salt form A, arginine salt form B and ethanolamine salt form A are in other Good chemical stability under conditions.

Claims

The pharmaceutically acceptable salt of the compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from meglumine salt, ethanolamine salt, sodium salt, potassium salt, amine salt, calcium salt, lysine salt and arginine Salt,
The pharmaceutically acceptable salt according to claim 1, wherein the stoichiometric ratio of the compound represented by the formula (I) and the base molecule or cation is 1:0.5～1:3, preferably 1:0.5, 1:3: 1, 1:2 or 1:3, most preferably 1:1 or 1:2.
The pharmaceutically acceptable salt according to claim 1 or 2, which is a dimeglumine salt.
The method for preparing the pharmaceutically acceptable salt of any one of claims 1-3, comprising: the step of forming a salt of the compound of formula (1) with a base.
The method according to claim 4, wherein the solvent used in the salt-forming reaction is selected from methanol, 2-butanone, ethyl acetate, 1,4-dioxane, methyl isobutyl ketone, At least one of methyl tert-butyl ether, dichloromethane, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene and water.
A pharmaceutical composition prepared from the pharmaceutically acceptable salt of any one of claims 1-3.
A pharmaceutical composition, comprising the pharmaceutically acceptable salt of any one of claims 1-3, or the pharmaceutically acceptable salt prepared by the method of claim 4 or 5, and optionally from a pharmaceutically acceptable salt carrier, diluent or excipient.
A preparation method of a pharmaceutical composition, comprising combining the pharmaceutically acceptable salt of any one of claims 1-3, or the pharmaceutically acceptable salt prepared by the method of claim 4 or 5, with a pharmaceutically acceptable salt. A step of admixing an accepted carrier, diluent or excipient.
The pharmaceutically acceptable salt of any one of claims 1-3, or the pharmaceutically acceptable salt prepared by the method of claim 4 or 5, or the composition of claim 6 or 7, or the Use of the composition prepared by the method of claim 8 in the preparation of a drug for inhibiting a voltage-gated sodium channel in a subject, preferably, the voltage-gated sodium channel is Na V 1.8.
The pharmaceutically acceptable salt of any one of claims 1-3, or the pharmaceutically acceptable salt prepared by the method of claim 4 or 5, or the composition of claim 6 or 7, or the Use of the composition prepared by the method according to claim 8 in the preparation of a medicament for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Sharma-Touya 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.
Form A of the ethanolamine salt of the compound represented by the formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726 and 27.000, preferably at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726 , 24.375, 25.060, 27.000 and 27.847 have characteristic peaks, more preferably have 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 The X-ray powder diffraction pattern represented by the angle 2θ is shown in FIG. 2 .
Form a of the sodium salt of the compound represented by formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.242, 7.497, 9.934, 12.281, 18.354, 20.784 and 23.654, preferably at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002 , 17.442, 18.354, 20.784 and 23.654 have characteristic peaks, more preferably have 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, most preferably have characteristic peaks The X-ray powder diffraction pattern represented by the angle 2θ is shown in FIG. 3 .
Form b of the sodium salt of the compound represented by formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.105, 9.016, 15.193, 16.945, 21.259, 25.301 and 28.642, preferably at 8.105, 9.016, 14.259, 15.193, 16.945, 21.259 , 24.629, 25.301, 27.428 and 28.642 have characteristic peaks, more preferably 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 have characteristic peaks, most preferably at diffraction angles The X-ray powder diffraction pattern expressed in angle is shown in FIG. 4 .
Form I of the potassium salt of the compound represented by formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.910, 11.916, 15.916, 16.931, 22.433, 24.044 and 26.297, preferably at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433 , 24.044 and 26.297, 32.079 and 39.038 have characteristic peaks, more preferably have 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 The X-ray powder diffraction pattern represented by the angular 2θ angle is shown in FIG. 5 .
Form II of the potassium salt of the compound represented by formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.488, 11.277, 13.394, 15.073, 22.860, 26.219 and 33.298, preferably at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915 , 22.860, 26.219, 33.298 and 38.093 have characteristic peaks, more preferably have 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 The X-ray powder diffraction pattern represented by the angular 2θ angle is shown in FIG. 6 .
Form III of the potassium salt of the compound represented by formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948 and 27.600, preferably at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948 , 26.462, 27.600, 30.872 and 34.296 have characteristic peaks, more preferably have 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 The X-ray powder diffraction pattern represented by the angle 2θ is shown in FIG. 7 .
Form A of the amine salt of the compound represented by the formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.324, 11.597, 14.903, 15.445, 17.259, 23.498 and 24.596, preferably at 8.324, 11.597, 12.156, 14.903, 15.445, 17.259 , 23.498, 24.596, 28.342 and 31.287 have characteristic peaks, more preferably have 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 The X-ray powder diffraction pattern represented by the angular 2θ angle is shown in FIG. 8 .
Form B of the amine salt of the compound represented by the formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 5.263, 10.629, 16.619, 20.208, 21.472, 24.052 and 29.047, preferably at 5.263, 8.132, 10.629, 16.619, 18.848, 20.208 , 21.472, 24.052, 29.047 and 29.644 have characteristic peaks, more preferably have diffraction 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 The X-ray powder diffraction pattern represented by the angular 2θ angle is shown in FIG. 9 .
Form a of the calcium salt of the compound represented by the formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.455, 9.436, 13.657, 18.106, 28.892, 29.878 and 34.073, preferably at 8.455, 9.436, 13.657, 16.433, 18.106, 20.756 , 26.620, 28.892, 29.878 and 34.073 have characteristic peaks, more preferably have 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 The X-ray powder diffraction pattern represented by the angle 2θ is shown in FIG. 10 .
Form A of the lysine salt of the compound represented by the formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.493, 17.127, 18.633, 21.196, 23.020, 25.226 and 25.795, preferably at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020 , 23.926, 25.226, 25.795 and 30.365 have characteristic peaks, more preferably 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 have characteristic peaks, most preferably at diffraction angles 2θ The X-ray powder diffraction pattern expressed in angle is shown in FIG. 11 .
Form A of the arginine salt of the compound represented by formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.780, 10.847, 15.726, 18.634, 20.265, 21.618 and 26.485, preferably at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265 , 21.618, 23.794, 25.589 and 26.485 have characteristic peaks, more preferably have 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 The X-ray powder diffraction pattern represented by the angle 2θ is shown in FIG. 12 .
Form B of the arginine salt of the compound represented by formula (I),

It is characterized in that the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.097, 15.541, 19.256, 22.111, 24.679, 27.124 and 33.605, preferably at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111 , 24.679, 27.124, 33.605 and 43.535 have characteristic peaks, more preferably have 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, 33.5605, 34.490, most preferably The X-ray powder diffraction pattern in terms of diffraction angle 2θ is shown in FIG. 13 .
The crystal form according to any one of claims 11-22, wherein the 2θ angle error range is ±0.20.
A pharmaceutical composition prepared from the crystal form of the pharmaceutically acceptable salt according to any one of claims 11-23.
A pharmaceutical composition comprising the crystalline form of the pharmaceutically acceptable salt of any one of claims 11-23 and optionally a pharmaceutically acceptable carrier, diluent or excipient.
A preparation method of a pharmaceutical composition, comprising the steps of mixing the crystalline form of the pharmaceutically acceptable salt described in any one of 11-23 with a pharmaceutically acceptable carrier, diluent or excipient.
The crystalline form of the pharmaceutically acceptable salt of any one of claims 11-23, or the composition of claim 24 or 25, or the composition prepared by the method of claim 26 is prepared for inhibiting The use in the medicine of voltage-gated sodium channel of the test subject, preferably, the voltage-gated sodium channel is Na V 1.8.
The crystalline form of the pharmaceutically acceptable salt of any one of claims 11-23, or the composition of claim 24 or 25, or the composition prepared by the method of claim 26 is prepared for use in therapy and/or or use in a medicament for alleviating pain and pain-related diseases, multiple sclerosis, Sharma-Figure 3 syndrome, incontinence or arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain , cancer pain, neuropathic pain, musculoskeletal pain, primary pain, bowel pain and idiopathic pain.