WO2025124502A1 - Nav1.8 inhibitor compound, salt thereof, polymorph thereof, and use thereof - Google Patents

Abstract

The present invention relates to a Nav1.8 inhibitor compound, a salt thereof, a polymorph thereof, and the use thereof. The present invention provides a salt of a compound of formula (I), a compound of formula (I) and a crystal form of a salt thereof, which have good medicinal properties. The structure of the formula (I) is as follows:

Description

A Nav1.8 inhibitor compound and its salt, polymorph and use

This application requires the applicant to:

The priority benefit of the prior application, patent application number 202311723384.5, entitled “A Nav1.8 inhibitor compound and its salt, polymorph and use”, filed with the State Intellectual Property Office of China on December 13, 2023;

The priority benefit of the prior application, patent application number 202411777862.5, entitled “A Nav1.8 inhibitor compound and its salt, polymorph and use”, filed with the State Intellectual Property Office of China on December 4, 2024;

The entirety of said prior application is incorporated into the present application by reference.

Technical Field

The present invention belongs to the field of medicine and relates to a Nav1.8 inhibitor compound and its salt, polymorph, and their preparation methods and applications.

Background Art

Pain is "an unpleasant feeling and emotional sensation, accompanied by actual or potential tissue damage, and it is a subjective feeling". Pain can serve as a warning signal to alert the body to potential dangers and has an indispensable protective effect on the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, strong or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the living body. According to statistics, about one-fifth of the world's people suffer from moderate to severe chronic pain. The global analgesic market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023. Among them, acute, moderate and severe pain will grow steadily at a compound annual growth rate of 2.5% in the future, and the chronic pain market will grow at a compound annual growth rate of about 18%. Chronic pain is the main driving force for the continued growth of the global pain market in the next decade.

Pain originates from nociceptors in the peripheral nervous system. This is a free nerve ending widely distributed in the skin, muscles, joints and visceral tissues throughout the body. It can convert the thermal, mechanical or chemical stimulation it senses into nerve impulses (action potentials) and transmit them to the cell body part located in the dorsal root ganglion (DRG) via afferent nerve fibers, and finally to the higher nerve center, causing pain. The generation and conduction of action potentials in neurons depends on voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane is depolarized, the sodium ion channels are activated, the channels open, causing sodium ions to flow in, further depolarizing the cell membrane, and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity helps to treat and relieve pain.

Human sodium ions are a type of transmembrane ion channel protein, consisting of an α subunit with a molecular weight of 260kD and a β subunit with a molecular weight of 30-40kD. According to the different α subunits, it can be divided into 9 subtypes, namely Nav1.1~Nav1.9. Nav1.5, Nav1.8 and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Nav1.5 is mainly present in myocardial cells, and Nav1.8 and Nav1.9 are present in the peripheral nervous system. Among them, Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, and is a highly selective target for pain treatment.

The gene encoding Nav1.8 is SCN10A, which is located in the human chromosome 3p21-22 region and mainly encodes the α subunit. Studies have found that the homology of human and rat Nav1.8 genes is as high as 93%. Nav1.8 is mainly present in trigeminal ganglion neurons and DRG neurons, and has the electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the rise of action potential is mainly composed of Nav1.8 current. In the model of neuropathic pain, nerve injury will increase the expression level of Nav1.8 in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression. After carrageenan was injected into the rat paw, the expression of Nav1.8 in DRG neurons increased. Nav1.8 knockout mice cannot show normal visceral inflammatory pain. When the human Nav1.8 gene produces a gain-of-function mutation, it will cause peripheral neuropathy. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new type of analgesic therapy, which can be used to treat various types of pain, such as inflammatory pain, neuralgia, postoperative pain and cancer pain.

The major drawback of some known Nav's inhibitors is that their therapeutic window is poor, which may be the result of their lack of isotype selectivity. Since Nav1.8 is mainly limited to neurons that perceive pain, selective Nav1.8 blockers are unlikely to induce adverse reactions common to non-selective Nav's blockers. Therefore, the art still needs to develop new Nav1.8 selective inhibitors, preferably Nav channel inhibitors with better selectivity, more effective, increased metabolic stability, increased solubility and fewer side effects to Nav1.8.

Chinese patent application CN202310743287.6 discloses the structure of the compound of formula I:

The compound of formula I can effectively antagonize the activity of Nav1.8 receptors and has broad application prospects in the preparation of drugs for treating diseases related to Nav1.8. Therefore, further research on the compound of formula I and its salt form and crystal form is of great significance for the development of effective therapeutic drugs.

Summary of the invention

In order to solve the problems existing in the prior art, on the one hand, the present invention provides a crystalline form of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula I is as follows:

In some embodiments, the present invention provides a free crystalline form A of the compound of formula I, wherein the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 17.79°, 18.13°, 20.52°, 21.63°, and 25.97°; further, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° also has diffraction peaks at one or more of the following: 12.85°, 16.20°, 24.46°, and 25.00°; further, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 12.85°, 16.20°, 17.79°, 18.13°, 20.52°, 21.63°, and 24.46°. Furthermore, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° is 5.78°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 20.52°, 21.63°, 24.46°, 25.00°, 25.97°. There are diffraction peaks at 25.97°, 27.33°, 27.77°, 28.83°, 29.03°, 30.33°, 30.62°, 34.25°, and 34.64°; further, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° is 5.78°, 10.77°, 11.56°, 12.85°, 16.20°、17.39°、17.79°、18.13°、20.52°、21.63°、22.01°、24.46°、25.00°、25.56°、25.97°、27.33°、27.77°、28.83°、29.03°、30.33°、30.62°、31.77°、33.33°、3 The diffraction peaks are at 4.25°, 34.64°, 35.19°, 36.01°, and 38.66°; further, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° is 5.78°, 8.10°, 9.06°, 10.77°, 11.56°, 12.85°, 16.20°, 17.39°, 17 .79°, 18.13°, 18.45°, 18.93°, 19.55°, 20.52°, 21.63°, 22.01°, 23.20°, 23.89°, 24.46°, 25.00°, 25.56°, 25.97°, 26.39°, 27.33°, 27.77°, 28.83°, 29.03°, 29. There are diffraction peaks at 60°, 30.33°, 30.62°, 31.14°, 31.77°, 32.23°, 33.33°, 33.77°, 34.25°, 34.64°, 35.19°, 36.01°, 38.66°, and 32.86°; further, the free crystalline form A has an XRPD spectrum substantially as shown in Figure 1-1.

In some embodiments, the free crystalline Form A has one, two or three of the following characteristics:

(1) The TGA curve of free form A shows a weight loss of approximately 0.38±1% at 150.0±3°C;

(2) The DSC curve of the free form A has an endothermic peak starting point at 169.5±3℃;

(3) The DSC curve of free form A has an endothermic peak at 171.0±3℃.

In some embodiments, the DSC graph of the free crystalline form A is shown in Figure 1-2; the TGA graph of the free crystalline form A is shown in Figure 1-3.

According to an embodiment of the present invention, the free-state crystalline form A is an anhydrous crystalline form.

In some embodiments, the present invention provides a free crystalline form B of the compound of formula I, wherein the free crystalline form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 11.64°, 12.60°, 17.46°, 20.93°, 25.16°, and 26.56°; further, the free crystalline form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 11.64°, 12.60°, 17.46°, 20.93°, 25.16°, and 26.56°. The X-ray powder diffraction spectrum of the free crystalline form B also has diffraction peaks at one or more of the following positions: 5.80°, 29.25°, 28.22°, 28.51°, and 35.32°; further, the X-ray powder diffraction spectrum of the free crystalline form B represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 5.80°, 11.64°, 12.60°, 17.46°, 20.93°, 22.19°, 25.16 The free form B has diffraction peaks at 5.80°, 11.64°, 12.60°, 16.09°, 17.46°, 18.37°, 20.9 There are diffraction peaks at 3°, 22.19°, 23.03°, 23.82°, 25.16°, 26.56°, 28.22°, 28.51°, 29.25°, 29.79°, 32.20°, 33.23°, 34.42°, 35.32°, and 38.52°; further, the free form B has an XRPD spectrum substantially as shown in Figure 2-1.

In some embodiments, the free crystalline Form B has one, two or three of the following characteristics:

(1) The TGA curve of free form B shows a weight loss of approximately 0.23±1% at 150.0±3°C;

(2) The DSC curve of the free form B has an endothermic peak starting point at 165.8±3℃;

(3) The DSC curve of free form B has an endothermic peak at 168.47±3℃.

In some embodiments, the DSC graph of the free crystalline form B is shown in Figure 2-2; the TGA graph of the free crystalline form B is shown in Figure 2-3.

According to an embodiment of the present invention, the free-state crystalline form B is an anhydrous crystalline form.

On the other hand, the present invention provides a method for preparing the free crystalline form A of the compound of formula I, which comprises the following methods:

Method 1: Place the first sample bottle containing the compound of formula I in an open position in a second sample bottle containing a solvent, seal the second sample bottle, and let it stand at room temperature; the solvent does not cover the mouth of the first sample bottle;

The solvent is selected from one or more of ethanol, acetone, methyl tert-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, n-heptane, and toluene;

Method 2: Place the first sample bottle containing the solution of the compound of formula I in the second sample bottle containing the anti-solvent, seal the second sample bottle, and let it stand at room temperature; the anti-solvent does not cover the mouth of the first sample bottle;

The solvent in the solution of the compound of formula I is selected from one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and N,N-dimethylformamide;

The anti-solvent is selected from one or more of n-heptane, methyl tert-butyl ether, and water;

Method 3: Add a solvent to the compound of formula I at room temperature, stir magnetically, and collect the solid;

The solvent is selected from one or more of water, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, toluene, N,N-dimethylformamide, and N-methylpyrrolidone;

Method 4: Add solvent to the compound of formula I at 50°C, stir magnetically, and collect the solid;

The solvent is selected from one or more of water, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, toluene, N,N-dimethylformamide, and N-methylpyrrolidone;

Method 5: Add the compound of formula I into organic solvent I, filter after dissolving, and evaporate at room temperature:

Preferably, the organic solvent I is selected from one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, dichloromethane and acetonitrile;

Method 6: Completely dissolve the compound of formula I in a good solvent, filter, and dropwise add an antisolvent to the clear solution until solid precipitates;

The good solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone, N,N-dimethylacetamide, ethanol, and isopropyl acetate;

The anti-solvent is selected from one or more of water, toluene, methyl tert-butyl ether, and n-heptane;

In some embodiments, when the anti-solvent is selected from water, the good solvent is selected from one of dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, and N,N-dimethylacetamide; when the anti-solvent is selected from methyl tert-butyl ether, the good solvent is selected from dichloromethane; when the anti-solvent is selected from n-heptane, the good solvent is selected from methyl ethyl ketone or ethanol.

Method 7: Dissolve the compound of formula I completely in a good solvent, filter, and add the clear solution to an anti-solvent;

The good solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, ethyl acetate, 1,4-dioxane, methyl ethyl ketone, and tetrahydrofuran;

The anti-solvent is selected from one or more of water, n-heptane, methyl tert-butyl ether, and toluene;

In some embodiments, when the anti-solvent is selected from water, the good solvent is selected from dimethyl sulfoxide or N,N-dimethylformamide; when the anti-solvent is selected from methyl tert-butyl ether, the good solvent is selected from 1,4-dioxane or methyl ethyl ketone; when the anti-solvent is selected from n-heptane, the good solvent is selected from ethyl acetate; when the anti-solvent is selected from toluene, the good solvent is selected from methyl ethyl ketone or tetrahydrofuran.

Method 8: Add the compound of formula I into organic solvent I at 50°C, filter after dissolving, stir magnetically, and cool at room temperature;

Preferably, the organic solvent I is selected from one or more of methanol, ethanol, isopropyl acetate, acetonitrile, ethyl acetate, and acetone;

Method 9: Add the compound of formula I into a mortar or add the compound of formula I and a solvent into a mortar and grind;

Preferably, the solvent is selected from one or more of water, methyl tert-butyl ether and n-heptane.

On the other hand, the present invention provides a method for preparing the free crystalline form B of the compound of formula I, which comprises the following methods:

Method 1: Dissolve the compound of formula I completely in a good solvent, filter, and add an antisolvent dropwise to the clear solution until solid precipitates;

The good solvent is selected from one or two of tetrahydrofuran and N,N-dimethylacetamide, and the anti-solvent is selected from n-heptane.

The anti-solvent is selected from one or more of water, toluene, methyl tert-butyl ether and n-heptane.

Method 2: completely dissolve the compound of formula I in a good solvent, filter, and add the clear solution into an anti-solvent;

The good solvent is selected from one or two of dichloromethane and 1,4-dioxane; the anti-solvent is selected from n-heptane.

Method 3: Add the compound of formula I into isopropanol at 40-60° C. (eg 50° C.), dissolve, filter, stir, and cool at room temperature.

Method 4: Completely dissolve the compound of formula I in tetrahydrofuran, filter, add n-heptane to the clear solution with stirring until solid precipitates, then add free form B seed crystals and stir.

According to an embodiment of the present invention, the free-state crystal form B seed can be prepared by one of the methods one, two, three, and four.

On the other hand, the present invention provides a pharmaceutically acceptable salt of the compound of formula I, wherein the pharmaceutically acceptable salt is selected from the salts formed by the compound of formula I and an acid or base. In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is selected from the salts formed by the compound of formula I and the following acids or bases: hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, L-malic acid, succinic acid, p-toluenesulfonic acid, methanesulfonic acid, sodium hydroxide, and arginine.

When the compound of formula I forms a salt with an acid or a base, the molar ratio of the acid or the base to the compound of formula I can be 5:1 to 1:5, for example, 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is selected from the maleate salt of the compound of formula I; in some embodiments, in the maleate salt, the molar ratio of the compound of formula I to maleic acid is 1:1.

In some embodiments, the pharmaceutically acceptable salt of the compound of formula I is selected from the sodium salt of the compound of formula I; in some embodiments, in the sodium salt, the molar ratio of the compound of formula I to sodium is 1:1.

In another aspect, the present invention provides a crystalline form of a pharmaceutically acceptable salt of the compound of formula I.

In some embodiments, the present invention provides a maleate salt form A of a compound of formula I, wherein the maleate salt form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° and has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, and 18.44°; further, the maleate salt form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° and has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.96°, 25.62°, and 26.78°; further, the maleate salt form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° and has diffraction peaks at 2θ±0.2°. The figure has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.96°, 21.61°, 25.29°, 25.62°, and 26.78°; further, the X-ray powder diffraction spectrum of the maleate salt form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.45°, 20.96°, 21.61°, 25.29°, 25.62°, 26.19°, and 26.78°; further, the X-ray powder diffraction spectrum of the maleate salt form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.45°, 20.96°, 21.61°, 25.29°, 25.62°, 26.19°, and 26.78° The X-ray powder diffraction spectrum of the maleate salt form A has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, 27.41°, 28.47°, 28.96°, 30.05°, 31.25°, 31.61°, and 33.91°; further, the X-ray powder diffraction spectrum of the maleate salt form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 10.65°, 13.78°, 16.31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, .31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, 27.41°, 28.47°, 28.96°, 30.05, 30.74°, 31.25°, 31.61°, 32.70°, 33.13°, 33.91°, 34.49°, 35.22°, 36.21°, and 38.48°; further, the maleate salt form A has an XRPD spectrum substantially as shown in Figure 3-1;

In some embodiments, the maleate salt form A has one or two of the following characteristics:

(1) The TGA curve of the maleate salt form A shows a weight loss of 0.5-3% at 120±3°C, preferably 0.5, 1.0, 1.5, 2.0, 2.5, 3.0%, for example 1.41%;

(2) The maleate salt form A has an endothermic peak at 139.1±3°C.

In some embodiments, the TGA/DSC graph of the maleate salt form A is substantially as shown in FIG. 3-2 ; the ¹ H NMR graph of the maleate salt form A is substantially as shown in FIG. 3-3 .

In some embodiments, the present invention provides a sodium salt crystalline form A of the compound of formula I, wherein the sodium salt crystalline form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 16.70°, 17.02°, 21.23°, 22.33°, 24.39°, 25.50°, and 25.89° having diffraction peaks; further, the sodium salt crystalline form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, and 29.73° having diffraction peaks; further, the sodium salt crystalline form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at There are diffraction peaks at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, 29.73°, and 30.76°; further, the X-ray powder diffraction spectrum of the sodium salt form A expressed at a diffraction angle of 2θ±0.2° is at 4.85°, 9.70°, , 12.13°, 13.55°, 14.20°, 14.55, 1670°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 29.73°, and 30.76° have diffraction peaks; In the step, the X-ray powder diffraction spectrum of the sodium salt form A represented by a diffraction angle of 2θ±0.2° is 4.85°, 9.70°, 12.13°, 13.55°, 14.20°, 14.55, 16.70°, 17.02°, 17.67°, 18.51°, 20.27°, 21.23°, 22.33°, 23.35° , 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 29.73°, 30.76°, 31.43°, 31.88°, 32.46°, and 39.71°; further, the X-ray powder diffraction spectrum of the sodium salt form A represented by a diffraction angle of 2θ±0.2° is at 4.85 °, 9.70°, 12.13°, 13.55°, 14.20°, 14.55°, 16.70°, 17.02°, 17.67°, 18.51°, 20.27°, 21.23°, 22.33°, 23.35°, 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28. There are diffraction peaks at 44°, 28.87°, 29.73°, 30.76°, 31.43°, 31.88°, 32.46°, 32.98°, 34.06°, 35.13°, 35.68°, 36.33°, 38.30°, and 39.71°; further, the sodium salt form A has an XRPD spectrum substantially as shown in Figure 4-1.

In some embodiments, the sodium salt form A has one or two of the following characteristics:

(1) The TGA curve of the sodium salt form A shows a weight loss of 1.0-5.0% at 150±3°C, preferably 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0%, for example 2.75%;

(2) The sodium salt form A has two endothermic peaks at 191.0±3°C and 215.0±3°C.

In some embodiments, the TGA/DSC graph of the sodium salt crystalline form A is substantially as shown in FIG. 4-2 ; the ¹ H NMR graph of the sodium salt crystalline form A is substantially as shown in FIG. 4-3 .

On the other hand, the present invention provides a method for preparing a pharmaceutically acceptable salt (including a crystalline form of the salt) of the compound of formula I, comprising mixing the compound of formula I with a suitable acid or base to obtain the pharmaceutically acceptable salt.

In some embodiments, when the pharmaceutically acceptable salt of the compound of formula I is a maleate or sodium salt, the preparation method comprises the following steps: mixing the compound of formula I with an equimolar amount of maleic acid or sodium hydroxide, stirring in an organic solvent A, and separating to obtain a solid. In some embodiments, the stirring time is 1-5 days, for example, 3 days, and the stirring temperature is room temperature; the organic solvent A is selected from one or more of isopropanol, ethyl acetate, and 2-methyltetrahydrofuran. In some embodiments, the compound of formula I is mixed with maleic acid or sodium hydroxide, a suspension is obtained in an organic solvent A, and the suspension is stirred;

In some embodiments, when the pharmaceutically acceptable salt of the compound of formula I is maleate crystalline form A, the preparation method comprises the following steps: mixing the compound of formula I with an equimolar amount of maleic acid, obtaining a suspension in an organic solvent A, suspending and stirring, and separating to obtain a solid. In some embodiments, the suspension and stirring time is 1-5 days, for example, 3 days, and the suspension and stirring temperature is room temperature; the organic solvent A is selected from ethyl acetate.

In some embodiments, when the pharmaceutically acceptable salt of the compound of formula I is sodium salt crystal form A, the preparation method comprises the following steps: mixing the compound of formula I with an equimolar amount of sodium hydroxide, obtaining a suspension in an organic solvent A, suspending and stirring, and separating to obtain a solid. In some embodiments, the suspension and stirring time is 1-5 days, for example, 3 days, and the suspension and stirring temperature is room temperature; the organic solvent A is selected from one or more of isopropanol, ethyl acetate, and 2-methyltetrahydrofuran.

In another aspect, the present invention provides a pharmaceutical composition comprising one or more of the free crystalline forms of the compound of formula I as described above (e.g., free crystalline form A, free crystalline form B), and the pharmaceutically acceptable salts of the compound of formula I as described above (including their crystalline forms).

In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient or carrier.

In another aspect, the present invention provides a pharmaceutical composition, comprising substance A and a pharmaceutically acceptable carrier, wherein substance A is a free crystalline form of a compound of formula I or a crystalline form of a pharmaceutically acceptable salt of a compound of formula I as described in any one of the above items; preferably, substance A is free crystalline form A of a compound of formula I, free crystalline form B of a compound of formula I, maleate crystalline form A, or sodium salt crystalline form A.

In another aspect, the present invention provides the use of the free crystalline form of the compound of formula I (e.g., free crystalline form A, free crystalline form B), a pharmaceutically acceptable salt of the compound of formula I (including its crystalline form) or the pharmaceutical composition in the preparation of a drug for treating and/or preventing voltage-gated sodium channel-related diseases.

According to an embodiment of the present invention, the voltage-gated sodium ion channel-related disease is a Nav1.8-related disease.

According to an embodiment of the present invention, the free crystalline form of the compound of formula I (e.g., free crystalline form A, free crystalline form B), a pharmaceutically acceptable salt of the compound of formula I (including its crystalline form) or the pharmaceutical composition described in the present invention can provide patients in need with better and more effective clinical treatment drugs or regimens.

The present invention also provides a method for treating and/or preventing diseases related to Nav1.8, which comprises administering to a patient a therapeutically effective dose of a crystalline form of the compound of formula I as described above, a pharmaceutically acceptable salt of the compound of formula I as described above, a crystalline form of the salt as described above, or a pharmaceutical composition as described above; preferably, a pharmaceutical preparation comprising a free crystalline form of the compound of formula I as described above (e.g., free crystalline form A, free acid crystalline form B), a pharmaceutically acceptable salt of the compound of formula I (including its crystalline form, such as maleate crystalline form A, sodium salt crystalline form A) or the pharmaceutical composition.

According to an embodiment of the present invention, the Nav1.8-related diseases include: pain.

Preferably, the pain includes: acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

Definitions and Explanations of Terms

The various terms and phrases used in the present invention have general meanings known to those skilled in the art. Even so, the present invention still hopes to provide a more detailed description and explanation of these terms and phrases herein. If the mentioned terms and phrases are inconsistent with the known meanings, the meanings expressed in the present invention shall prevail.

Unless otherwise stated, the numerical ranges recorded in this specification and claims are equivalent to recording at least each specific integer value therein. For example, two or more represent 2, 3, 4, 5, 6, 7, 8, 9, 10 or more. When certain numerical ranges are defined or understood as "numbers", they should be understood to record the two endpoints of the range, each integer within the range, and each decimal within the range. For example, "a number from 0 to 10" should be understood to record not only each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least the sum of each integer therein and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, respectively.

When the description and claims record "about" a certain value, it includes the value itself, as well as the values within the range of the value acceptable in the art, such as the values within the range of ±15% of the value, the values within the range of ±10%, the values within the range of ±5%, etc. For example, about 10 represents: values within the range of 10±1.5, that is, values within the range of 8.5 to 11.5; values within the range of 10±1.0, that is, values within the range of 9.0 to 11.0; and values within the range of 10±0.5, that is, values within the range of 9.5 to 10.5.

The "2θ or 2θ angle" mentioned in the present disclosure refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ is ±0.20 (preferably ±0.10) (including the case where the numbers exceeding 2 decimal places are rounded off).

The salts and polymorphs of the compound of formula I of the present invention may be used in combination with other active ingredients as long as it does not cause other adverse effects such as allergic reactions.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

The term "therapeutically effective dose" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following: (1) preventing disease: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the pathology or symptoms of the disease; (2) inhibiting disease: for example, inhibiting the disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms); (3) alleviating disease: for example, alleviating the disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and/or symptoms).

The term "pharmaceutically acceptable" means that the formulation components or active ingredients have no undue adverse effect on health for the general purpose of treatment.

The term "pharmaceutically acceptable excipient or carrier" means one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers, wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc. The pharmaceutical composition can be specially formulated in solid or liquid form for oral administration, for parenteral injection or for rectal administration. The pharmaceutical composition can be formulated into a variety of dosage forms for easy administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions), injectable preparations (such as injectable solutions or suspensions, or injectable dry powders that can be used immediately after adding a pharmaceutical solvent before injection).

When used for the above-mentioned treatment and/or prevention purposes, the total daily dosage of the salts, polymorphs and pharmaceutical compositions of the compounds of formula I of the present invention shall be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dosage level shall be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the administration time, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concurrently with the specific compound used; and similar factors known in the medical field. For example, it is practiced in the art to start the dosage of the compound from a level lower than that required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained.

The term "free state" refers to a form of a compound that has not been further salted, such as the compound of Formula I itself herein. It will be understood by those skilled in the art that when the "free state" forms a salt with a certain acid, the "free state" can be understood as the "free base" corresponding to the salt formed by the acid. That is, "free base" and "free state" have equivalent meanings, and similarly, "free acid" can also have equivalent meanings to "free state" (when the free state forms a salt with a base).

Beneficial Effects

The present invention provides salts of compounds of formula I, and crystal forms of compounds of formula I and their salts, which have good pharmaceutical properties.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1-1 is an XRPD diagram of free form A of the compound of formula I;

Figure 1-2 is a DSC diagram of the free form A of the compound of formula I;

Figure 1-3 is a TGA diagram of the free form A of the compound of formula I;

Figure 2-1 is an XRPD diagram of free form B of the compound of formula I;

Figure 2-2 is a DSC diagram of the free form B of the compound of formula I;

Figure 2-3 is a TGA diagram of the free form B of the compound of formula I;

Figure 3-1 XRPD diagram of maleate salt form A

Figure 3-2 TGA/DSC graph of maleate crystal form A

Figure 3-3 ¹ H NMR graph of maleate salt form A

Figure 4-1 XRPD diagram of sodium salt form A

Figure 4-2 TGA/DSC diagram of sodium salt form A

Figure 4-3 ¹ H NMR spectrum of sodium salt form A

Figure 5 Dynamic solubility curve at 37℃

Figure 6-1 XRPD overlay of solubility samples of free form A in H ₂ O

Figure 6-2 XRPD overlay of solubility samples of free form A in SGF

Figure 6-3 XRPD overlay of solubility samples of free form A in FaSSIF

Figure 6 XRPD overlay of solubility samples of free form A in FeSSIF

Figure 7-1 DVS diagram of free crystal form A

Figure 7-2 XRPD overlay of free form A before and after DVS test

Figure 7-3 DVS diagram of maleate crystal form A

Figure 7-4 XRPD overlay of maleate crystal form A before and after DVS test

Figure 8-1 XRPD overlay of the stability evaluation sample of free form A

Figure 8-2 XRPD overlay of maleate crystal form A stability evaluation sample

DETAILED DESCRIPTION

The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

The instrument and detection method adopted by the present invention are as follows:

1. X-ray powder diffraction (XRPD)

The XRPD pattern was collected on an X-ray powder diffraction analyzer produced by Bruker and PANalytacal, and the scanning parameters are shown in Tables A-1a and A-1b below, respectively.

Table A-1a XRPD test parameters

Table A-1b XRPD test parameters

2. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC)

2.1 TGA and DSC images were collected on a TA Q500 thermogravimetric analyzer and a TA Q2000 differential scanning calorimeter, respectively. The test parameters are listed in Table A-2a below.

Table A-2a DSC and TGA test parameters

2.2 TGA and DSC graphs were collected on a TA 5500 thermogravimetric analyzer and a TA 2500 differential scanning calorimeter, respectively. The test parameters are listed in Table A-2b below.

Table A-2b TGA and DSC test parameters

3. Dynamic moisture adsorption (DVS)

Dynamic moisture sorption (DVS) curves were collected on the DVS IntrInsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was calibrated using the deliquescent points of LiCl, Mg(NO ₃ ) ₂ and KCl. The DVS test parameters are listed in Table A-3.

Table A-3 DVS test parameters

4. Liquid Nuclear Magnetics ( ^1H NMR)

Liquid-state NMR spectra were collected on a Bruker 400M NMR spectra using DMSO- _d6 as solvent.

5. Ultra-high performance liquid chromatography and ion chromatography (UPLC/IC)

In the experiment, the purity test, dynamic solubility and stability test were performed by Waters H-Class ultra high performance liquid chromatograph, and the ion salt formation molar ratio test was performed by ion chromatography. The analysis conditions are shown in Table A-4 and Table A-5.

Table A-4 HPLC test conditions

Table A-5 Ion chromatography test conditions

6. Preparation of Biosolvent

Preparation of simulated gastric fluid (SGF)

Weigh 100 mg NaCl and 50 mg Trinaton X-100 into a 50-mL volumetric flask and add purified water to dissolve. Add 816 μL 1 M hydrochloric acid and adjust the pH to 1.8 with 1 M hydrochloric acid or 1 M NaOH solution. Add purified water to volume.

Preparation of fasting-simulated intestinal fluid (FaSSIF)

Weigh 340 mg of anhydrous NaH ₂ PO ₄ and 620 mg of NaCl into a 100-mL volumetric flask. Add purified water to dissolve, then add 55.44 μL of 50% NaOH solution, and adjust the pH to 6.5 with 1M hydrochloric acid or 1M NaOH solution. Add purified water to make up to volume. Then weigh 110 mg of SIF powder into a 50-mL volumetric flask, dissolve with the above solution and make up to volume.

Preparation of simulated fed intestinal fluid (FeSSIF)

Take 0.82 mL of glacial acetic acid and 1.18 g of NaCl into a 100-mL volumetric flask, add purified water to dissolve, then add 528 μL of 50% NaOH solution, adjust the pH to 5.0 with 1 M hydrochloric acid or 1 M NaOH solution, and add purified water to make up to volume. Then weigh 560 mg of SIF powder into a 50-mL volumetric flask, dissolve with the above solution and make up to volume.

VII. The reagents used in the present invention are shown in Table A-6 below

Table A-6 Comparison table of Chinese and English names of solvents used in the test

Example 1: Preparation of Compounds of Formula I

5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyrimidine 1-oxide

The synthetic route of the compound of formula I is as follows:

Step 1: Synthesis of 4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid

At room temperature, 4,5-dichloro-2-fluorobenzoic acid (1.0 g, 4.78 mmol), cesium carbonate (4.68 g, 14.35 mmol) and 4-(trifluoromethoxy)phenol (8 mL) were added to a 20 mL microwave tube, which was sealed and reacted at 150°C for 1 hour. After cooling to room temperature, water (10 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL×3). The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and dried, and the crude product was purified by column chromatography (SiO ₂ ; PE:EA=10:1) to obtain 4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid (3) (1.0 g; yield 56.9%).

Step 2: Synthesis of 4,5-dichloro-N-(pyrimidin-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide

4,5-Dichloro-2-(4-(trifluoromethoxy)phenoxy)benzoic acid (1.0 g, 2.72 mmol), 5-aminopyrimidine (310.88 mg, 3.27 mmol) and HATU (2.07 g, 5.45 mmol) were added to DMF (10 mL), and then DIPEA (1.06 g, 8.17 mmol) was added. After the addition was complete, the reaction solution was reacted at room temperature for 16 hours. LC-MS showed that the reaction was complete. NH ₄ Cl solution (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL×3). The organic phases were combined, washed with water (20 mL×2) and saturated brine (10 mL), respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and dried by spin drying. The crude product was separated by normal phase silica gel column chromatography (SiO ₂ ; EtOAc/PE＝1:1) to give 4,5-dichloro-N-(pyrimidin-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (1.10 g; yield 90.9%).

Step 3: 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyrimidine 1-oxide (compound of formula I)

At room temperature, 4,5-dichloro-N-(pyrimidin-5-yl)-2-(4-(trifluoromethoxy)phenoxy)benzamide (1.0 g, 2.09 mmol) was weighed into DCM (10 mL), and then m-CPBA (849.89 mg, 4.19 mmol; 85%) was slowly added. The reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane (20 mL), and then washed with saturated sodium bicarbonate aqueous solution (15 mL×2). The organic phase was dried over Na ₂ SO ₄ , concentrated, and sent to high pressure liquid chromatography (ammonia-acetonitrile) to obtain 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)pyrimidine 1-oxide (86.6 mg, yield 8.38%).

¹ H NMR (400MHz, DMSO): δ8.85-8.84(m,2H),8.43-8.42(m,1H),8.04(s,1H),7.45(s,1H),7.40-7.37(m,2H),7.20-7.18(m,2H).

LC-MS,M/Z(ESI):458.1[MH] ^- .

Example 2: Preparation of crystal form by gas-solid diffusion method

Weigh about 40 mg of the compound of formula I and put it into a 2 mL transparent sample bottle, add the solvent system (3 mL) in Table 1-1 to the 20 mL sample bottle, place the 2 mL transparent sample bottle open in the 20 mL sample bottle, seal the 20 mL sample bottle and let it stand at room temperature, and filter to obtain a solid sample. After vacuum drying at room temperature, the sample was subjected to XRPD testing. The results show that free form A was obtained under the solvent system in Table 1-1.

Table 1-1: Crystal screening results of gas-solid diffusion method

Example 3: Preparation of crystal form by gas-liquid diffusion method

Weigh about 40 mg of the compound of formula I and put them into 2 mL transparent sample bottles respectively. Add a small amount of good solvents in Table 2 to the 2 mL sample bottles at room temperature, shake to fully dissolve the samples, and filter the obtained solution into another 2 mL transparent sample bottle with a 0.22 μm filter membrane. Take another 20 mL sample bottle and add 4 mL of the corresponding anti-solvent in Table 2 thereto. Place the 2 mL transparent sample bottle containing the clear solution after filtration into the 20 mL sample bottle with an open mouth. Seal the 20 mL sample bottle and let it stand at room temperature to precipitate solids. After vacuum drying at room temperature, perform XRPD test on the sample. The results show that free crystalline form A is obtained under the solvent system of Table 1-2. When the good solvent is DMSO and the anti-solvent is H ₂ O, a mixture of free crystalline forms A and B is obtained.

Table 1-2: Crystal screening results of gas-liquid diffusion method

Example 4: Preparation of crystal form by room temperature suspension method

Weigh about 50 mg of the compound of formula I and put them into 2 mL transparent sample bottles respectively, add 0.1-0.5 mL of the solvent in Table 3 to the sample bottles at room temperature, stir magnetically for about two weeks, and filter to obtain a solid sample. After vacuum drying at room temperature, the solid sample was subjected to XRPD test. The results show that free crystalline form A was obtained under the solvent system of Table 1-3. The free crystalline form A obtained in the solvent EtOH was selected for XRPD, TGA, and DSC tests, and its XRPD spectrum is shown in Figure 1-1, and the XRPD diffraction peak data is shown in Table 1-4; the DSC graph is shown in Figure 1-2, and the TGA graph is shown in Figure 1-3.

Table 1-3: Room temperature suspension method crystal screening results

Table 1-4: XRPD diffraction peak data of free form A

Example 5: Preparation of crystal form by 50°C suspension method

Weigh approximately 50 mg of the compound of formula I into a 2 mL transparent sample bottle, add 0.1-0.5 mL of the solvent in Table 1-5 to the sample bottle at 50°C, stir magnetically for about one week, and filter to obtain a solid sample. After vacuum drying at room temperature, the sample was subjected to XRPD testing. The results show that free crystalline form A was obtained in the solvent system in Table 1-5.

Table 1-5: Screening results of 50℃ suspension crystals

Example 6: Preparation of crystal form by slow evaporation method

Weigh approximately 40 mg of the compound of formula I into a 2 mL transparent sample bottle, add 2-7 mL of the solvent in Table 1-6 to the sample bottle, filter the resulting solution with a 0.22 μm filter membrane, and slowly volatilize the filtered clear solution at room temperature to obtain a solid. After vacuum drying at room temperature, the sample was subjected to XRPD testing. The results show that free crystalline form A was obtained under the solvent system in Table 1-6. When the solvent is 1,4-dioxane, a mixture of free crystalline form B and a small amount of free crystalline form A was obtained.

Table 1-6: Slow evaporation method crystal screening results

Example 7: Preparation of Crystalline Form by Anti-Solvent Method

Weigh approximately 40 mg of the compound of formula I into a 2 mL transparent sample bottle, dissolve the sample with a small amount of good solvent at room temperature, and filter the resulting solution with a 0.22 μm filter membrane. Then slowly add 2-4 times the anti-solvent to the filtered clear solution until solids precipitate, and filter to obtain a solid sample. After vacuum drying at room temperature, the sample was subjected to XRPD testing. The results show that free crystalline form A and free crystalline form B were obtained under the solvent system of Table 1-7.

Table 1-7: Anti-solvent method crystal screening results

Example 8: Preparation of Crystalline Form by Anti-Anti-Solvent Method

Weigh approximately 40 mg of the compound of formula I into a 2 mL transparent sample bottle, dissolve the sample with a small amount of good solvent at room temperature, and filter the resulting solution with a 0.22 μm filter membrane. Then quickly add the filtered clear solution to 2-4 times the anti-solvent, precipitate the solid, and filter to obtain a solid sample. After vacuum drying at room temperature, the sample was subjected to XRPD testing. The results show that free crystalline form A and free crystalline form B were obtained under the solvent system of Table 1-8. When the good solvent is 1,4-dioxane and the anti-solvent is H ₂ O, a mixture of free crystalline form B and a small amount of free crystalline form A was obtained.

Table 1-8: Anti-antisolvent method crystal screening results

Example 9: Preparation of crystal form by cooling method

Weigh approximately 40 mg of the compound of formula I into a 2 mL transparent sample bottle, dissolve the sample with a small amount of solvent at 50°C, and filter the resulting solution with a 0.22 μm filter membrane. The filtered clear solution was slowly cooled at room temperature under magnetic stirring to precipitate a solid, and a solid sample was obtained by filtration. After vacuum drying at room temperature, the sample was subjected to XRPD testing. The results showed that free crystalline form A and free crystalline form B were obtained under the solvent system of Table 1-9.

Table 1-9: Cooling method crystal screening results

Example 10: Preparation of crystal form by grinding method

About 40 mg of the compound of formula I was weighed in a mortar and ground for about 10 minutes under different conditions. After the ground solid was dried under vacuum at room temperature, the sample was subjected to XRPD testing. The results showed that under the solvent system of Table 1-10, a large amount of amorphous free-state crystalline form A was obtained.

Table 1-10: Crystal screening results by grinding method

Example 11: Preparation of Free Form B

The preparation process of free crystal form B is as follows:

Weigh 500 mg of the compound of formula I into a round-bottom flask. Add 6.25 mL of THF to the round-bottom flask at room temperature, dissolve the sample by ultrasound, and filter the resulting solution into another 100 mL round-bottom flask with a 0.22 μm filter membrane. Slowly add 18.75 mL of heptane to the filtered clear solution under magnetic stirring. A white solid precipitates in the solution, and then add about 5 mg of seed crystals of free form B (obtained by the anti-solvent method THF/heptane in Example 7) and continue stirring. After stirring at room temperature for about three hours, filter and obtain a white solid. After vacuum drying at room temperature, perform XRPD, TGA, and DSC tests. The XRPD spectrum of free form B is shown in Figure 2-1, and the XRPD diffraction peak data is shown in Table 1-12; the DSC graph is shown in Figure 2-2, and the TGA graph is shown in Figure 2-3.

Table 1-11: Characterization of free crystal form B

Table 1-12: XRPD diffraction peak data of free form B of Example 11

Example 12 Salt type screening

Starting with the free form A sample, 13 ligands (acid-base feed ratio of 1:1) and 3 solvents were selected to set up a total of 39 salt screening tests. The specific steps of the screening test are as follows: weigh about 20 mg of the free form A sample and an equimolar amount of the corresponding ligand into an HPLC vial, add 0.5 mL of solvent to mix to obtain a suspension, and the liquid acid is diluted with the corresponding solvent before mixing with the starting sample. After stirring at room temperature for about 3 days, the solid is separated by centrifugation and vacuum dried at 50°C. The XRPD characterization results of the obtained solid show (Table 2-1) that a total of 2 salt form samples were obtained in the salt screening test, namely maleate form A and sodium salt form A. The screened salt samples were characterized by TGA/DSC, and the salt formation molar ratio was determined by ¹ H NMR and HPLC/IC. The salt characterization results are summarized in Table 2-2.

Table 2-1 Summary of salt type screening test results

*: The molar ratio of the ligand to the free state was 1:1; ^# : The sample was observed to turn orange-red.
^a : The sample was clarified after stirring at room temperature and then stirred at 5°C; ^b : The sample was clarified after stirring at 5°C and then 1.0 mL of n-heptane was added to induce crystallization; ^c : The sample became gel after adding n-heptane to induce crystallization and then the temperature cycle was performed from 50°C to 5°C; ^d : The sample was clarified after adding n-heptane to induce crystallization and then stirred at 5°C; ^e : The sample remained clarified after stirring at 5°C and then volatilized at room temperature.

Table 2-2 Summary of the characterization results of the salt types obtained by screening

^# : calculated by ¹ H NMR or HPLC/IC; ND: not detected.

12.1 Maleate Crystalline Form A

Maleate Form A is obtained by slurrying a free Form A sample and an equimolar amount of maleic acid in EtOAc at room temperature for 3 days, centrifuging and vacuum drying the solid sample at 50°C. The XRPD and TGA/DSC results of the maleate Form A sample are shown in Figures 3-1 and 3-2, respectively. The TGA results show that the sample has a weight loss of 1.41% when heated to 120°C, and the DSC results show that an endothermic signal is observed at 139.1°C (starting point temperature). The ¹ H NMR results are shown in Figure 3-3. The molar ratio of maleic acid to the compound of formula I in the sample is 1:1, and no residual EtOAc solvent is found. The XRPD diffraction peak data of maleate Form A are shown in Table 2-3.

Table 2-3 XRPD diffraction peak data of maleate crystal form A

12.2 Preparation of Sodium Salt Form A

Sodium salt form A is obtained by slurrying a free form A sample and an equimolar amount of sodium hydroxide in 2-MeTHF at room temperature for 3 days, centrifuging and separating the solid sample, and vacuum drying at 50°C. The XRPD and TGA/DSC results of the sodium salt form A sample are listed in Figures 4-1 and 4-2, respectively. The TGA results show that the sample has a 2.75% weight loss when heated to 150°C, and the DSC results show that the sample has two endothermic peaks at 191.0°C and 215.0°C (peak temperature). The ¹ H NMR results are shown in Figure 4-3, and no 2-MeTHF solvent residue was found in the sample. HPLC/IC results show that the molar ratio of Na ⁺ to the compound of formula I in sodium salt form A is 1:1. The XRPD diffraction peak data of sodium salt form A are shown in Table 2-4 below.

Table 2-4 XRPD diffraction peak data of sodium salt form A

Example 13 Evaluation Test

13.1 Dynamic Solubility

The solid feed concentration was 10 mg/mL (in free form) and the mixture was mixed by rotation at 37°C. The solubility of each sample in H ₂ O, SGF, FaSSIF and FeSSIF was measured at different time points (1, 2, 4 and 24 hours). After sampling at each time point, the samples were centrifuged (10000 rpm) and filtered (0.45 μm PTFE). The HPLC concentration and pH value of the filtrate were measured, and the solid samples after centrifugation were tested by XRPD. The solubility test results are summarized in Table 2-5, and the solubility curve is shown in Figure 5. The XRPD results show that the free form A does not change its crystalline form after the dynamic solubility test (Figure 6-1 to Figure 6-4).

Table 2-5 Summary of 37℃ dynamic solubility test results

S: solubility (mg/mL).

13.2. Hygroscopicity

The hygroscopicity of free crystalline form A and maleate crystalline form A was evaluated by dynamic moisture sorption instrument (DVS). The percentage change in mass of the samples was collected when the humidity changed (0% RH-95% RH) under a constant temperature of 25°C. The DVS test results and the XRPD results of the samples before and after the DVS test are shown in Figures 7-1 to 7-4. The results show that the moisture adsorption of free crystalline form A and maleate crystalline form A at 25°C/80% RH are 0.1698% and 0.224%, respectively. The crystal form of all samples remained unchanged after the DVS test, especially the free crystalline form A has almost no hygroscopicity.

13.3 Solid-state stability

The free form A and the maleate form A were placed at 80°C/closed for one day and at 25°C/60%RH and 40°C/75%RH for one week, respectively, and the physical and chemical stability of the samples was tested by XRPD and HPLC. The purity data are listed in Table 2-6, and the XRPD results are listed in Figures 8-1 and 8-2. The results show that no obvious purity changes were observed for all samples, and the crystal form remained unchanged.

Table 2-6 Summary of solid state stability evaluation

Test Example 1: Detection of the inhibitory activity of compounds on Nav1.8 ion channels

All reagents except NaOH and KOH for acid-base titration were purchased from Sigma (St. Louis, MO). The final concentrations of the test compounds were prepared on the day and dissolved in the extracellular solution. The extracellular solution (mM) was: NaCl, 137 mM; KCl, 4 mM; CaCl ₂ , 1.8 mM; MgCl ₂ , 1 mM; HEPES, 10 mM; glucose, 10 mM; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 1 μM TTX. The intracellular solution (mM) was: aspartic acid, 140 mM; magnesium chloride, 2; ethylene glycol tetraacetic acid (EGTA), 11 mM; N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10 mM. The pH was adjusted to 7.4 with cesium hydroxide.

The test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9 mM. On the day of the test, it was dissolved in the extracellular fluid to the required concentration. Electrophysiological experimental steps:

Transfer the cells to the perfusion tank and perfuse with extracellular solution. The intracellular solution was thawed on the day of the experiment. The electrodes were pulled with PC-10 (Narishige, Japan). Whole-cell patch clamp recording was performed, and the noise was filtered at one-fifth of the sampling frequency. 1/4 of the length of the electrode tube was added to the electrode, and the electrode was installed on the probe. Set the required Protocol, adjust the interface to Membrane test, and adjust the Stage to Bath. Apply positive pressure to the electrode, touch the tip of the electrode to the cell, adjust the three-way valve of the vacuum device to the three-way state, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Adjust the Stage to Patch, control the leak within -200pA, and continue to apply negative pressure to rupture the cell membrane and form a current path. Open the vacuum filter and the extracellular solution valve for perfusion, observe the cell current, and start adding drugs when the cell current is stable (the current curves of at least 3 sweeps overlap). Add medicine from low concentration to high concentration. The adding time for each concentration should be no less than 2 minutes and wait until the current is stable before changing the concentration.

The test article is administered by perfusion using a perfusion system that uses its own gravity. During the initial recording period, the peak current amplitude is observed for at least 1 minute until it stabilizes. During this period, the CV% of all peak current amplitudes should be less than 10% to exclude the ups and downs of the initial current. The average of the peak current amplitudes recorded in the last 10 times during the initial recording period is used as the current peak of the negative control. After the initial current stabilizes, the test sample is administered from a low concentration until the peak current recorded in 10 times stabilizes again or after continuous administration for 5 minutes, the peak current after administration is "unchanged" from that before administration. We define the following two situations as "stable" or "unchanged": 1) if the absolute average of the peak current for 10 consecutive scans exceeds 200pA and the CV value is less than 10%, 2) or the average of the peak current for 10 consecutive scans is between 200pA and 50pA and the CV value is less than 30%. Then the next higher concentration is administered for testing.

The peak current average of the last 10 scans for each concentration is used as the peak current for data analysis. If a steady state cannot be reached within 5 minutes, the peak current average of the last 10 scans at this time is used as the peak current for data analysis. At the same time, the cell should be discarded and no longer used for detection of higher concentrations. At least two cells are tested for each concentration of the compound.

Voltage pulse procedure:

The cells were clamped at -80 mV and then depolarized to 10 mV with a 10 ms square wave to obtain NaV1.8 current. This procedure was repeated every 5 seconds. The maximum current induced by the square wave was measured, and after it stabilized, the test compound was perfused. When the response stabilized, the intensity of the blockade was calculated.

Data processing and fitting

Data collection and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Current stability refers to the current changing within a limited range over time. The inhibitory activity (IC 50 ) of the drug on the Nav1.8 ion channel is calculated by plotting the dose-effect relationship between the drug's gradient dilution series concentration and the stable current value generated by its action on HEK293/ _Nav1.8 .

Table B-1: Inhibitory activity of compounds on Nav1.8 ion channels

The test results show that the compound of the present invention has strong inhibitory activity on Nav1.8 ion channel.

Test Example 2: Pharmacokinetics test in mice

For the pharmacokinetic test in mice, three male ICR mice were fasted overnight and given 10 mg/kg by oral gavage. Blood was collected before administration and at 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration. The blood samples were centrifuged at 8000 rpm and 4°C for 6 minutes, and the plasma was collected and stored at -20°C. The plasma at each time point was taken, mixed with 3-5 times the amount of acetonitrile solution containing the internal standard, vortexed for 1 minute, centrifuged at 13000 rpm and 4°C for 10 minutes, the supernatant was taken, mixed with 3 times the amount of water, and an appropriate amount of the mixed solution was taken for LC-MS/MS analysis. The main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.

Table B-2: Results of pharmacokinetic tests of compounds in mice

The test results show that the compound of the present invention has good pharmacokinetic characteristics.

Test Example 3: Rat spinal nerve ligation neuropathic pain model

Male SD rats weighing 180-220g were placed in a prone position on the operating table after anesthesia. An opening was made along the spine near the hip bone of the animal to separate the fascia and muscles. The L5 transverse process was carefully bitten off with forceps, the L5 nerve was separated with a glass needle, and the L5 nerve was ligated with a 5-0 ligature. The muscles and skin were sutured and disinfected with iodine. After 14 days of modeling, the animals were divided into different groups, with 10 in each group, and different compounds were orally gavaged. The mechanical pain threshold of the animals was detected with Von-Frey fibers at different time points after administration. For specific dosage and detection time, please see Table B-3 below.

Mechanical pain threshold detection method: The test animal is continuously stimulated with Von-Frey fibers to make the fibers bend, and the animal's paw retraction reaction is observed. The test animals are stimulated one by one in the order of the fiber weight from small to large, and each fiber weight is stimulated 5 times in a row. If the positive reaction is less than 3 times, repeat the above operation with a larger fiber. When the positive reaction occurs 3 times or more for the first time, the fiber is the pain threshold of the animal (each animal is tested 3 times and the average value is taken). Fiber weight: 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0; the cut-off value is 15.0g.

Table B-3: Effects of compounds on pain threshold in rats with spinal nerve ligation


One-way ANOVA, ***P<0.001, **P<0.01, *P<0.05
NA: No test is scheduled at this time

The test results show that the compound of the present invention can significantly improve the reduction of the mechanical pain threshold of animals caused by spinal nerve ligation modeling in rats and has excellent analgesic effect.

Test Example 4: Rat Incisional Pain Model

Male SD rats weighing 200-250g were anesthetized and fixed in a prone position. The soles of their hind limbs were flattened upwards, and the toes were fixed with surgical tape and disinfected. A scalpel was used to cut the skin fascia from 0.5cm behind the heel of the animal's foot to the toe tip, and a longitudinal incision of about 1cm was made. After lifting the short flexor digitorum with surgical curved forceps, a longitudinal incision was made on the belly of the muscle with a scalpel without completely cutting the muscle. The skin was sutured and disinfected. On the second day of modeling, the animals were divided into different groups, with 8 rats in each group, and different compounds were orally gavaged. The mechanical pain threshold of the animals was detected with Von-Frey fibers at different time points after administration. For specific grouping dosage and detection time, please see Table B-4 below.

Mechanical pain threshold detection method: The test animal is continuously stimulated with Von-Frey fibers to make the fibers bend, and the animal's paw retraction reaction is observed. The test animals are stimulated one by one in the order of the fiber weight from small to large, and each fiber weight is stimulated 5 times in a row. If the positive reaction is less than 3 times, repeat the above operation with a larger fiber. When the positive reaction occurs 3 times or more for the first time, the fiber is the pain threshold of the animal (each animal is tested 3 times and the average value is taken). Fiber weight: 0.6, 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 15.0; the cut-off value is 15.0g.

Table B-4: Effects of compounds on pain threshold in rats with incisional pain model

One-way ANOVA, vs Vehicle group, ***P<0.001

The test results show that the compound of the present invention can significantly improve the reduction of the mechanical pain threshold of animals caused by the incision pain modeling in rats and has excellent analgesic effect.

Claims (10)

A crystalline form of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the structure of the compound of formula I is as follows:
The crystal form according to claim 1, wherein the crystal form is the free crystal form A of the compound of formula I, and the free crystal form A has diffraction peaks at 17.79°, 18.13°, 20.52°, 21.63°, and 25.97° in an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2°; Preferably, the X-ray powder diffraction spectrum of the free crystalline form A expressed at a diffraction angle of 2θ±0.2° also has diffraction peaks at one or more of the following locations: 12.85°, 16.20°, 24.46°, 25.00°; Preferably, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 12.85°, 16.20°, 17.79°, 18.13°, 20.52°, 21.63°, 24.46°, 25.00°, and 25.97°; Preferably, the free crystalline form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 5.78°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 20.52°, 21.63°, 24.46°, 25.00°, 25.97°, 27.33°, 27.77°, 28.83°, 29.03°, 30.33°, 30.62°, 34.25°, and 34.64°; Preferably, the free crystalline form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 5.78°, 10.77°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 20.52°, 21.63°, 22.01°, 24.46°, 25.00°, 25.56°, 25.97°, 27.33°, 27.77°, 28.83°, 29.03°, 30.33°, 30.62°, 31.77°, 33.33°, 34.25°, 34.64°, 35.19°, 36.01°, and 38.66°; Preferably, the X-ray powder diffraction spectrum of the free crystalline form A represented by a diffraction angle of 2θ±0.2° is 5.78°, 8.10°, 9.06°, 10.77°, 11.56°, 12.85°, 16.20°, 17.39°, 17.79°, 18.13°, 18.45°, 18.93°, 19.55°, 20.52°, 21.63°, 22.01°, 23.20°, 23.89°, 24. There are diffraction peaks at 46°, 25.00°, 25.56°, 25.97°, 26.39°, 27.33°, 27.77°, 28.83°, 29.03°, 29.60°, 30.33°, 30.62°, 31.14°, 31.77°, 32.23°, 33.33°, 33.77°, 34.25°, 34.64°, 35.19°, 36.01°, 38.66°, and 32.86°; Preferably, the free crystalline form A has an XRPD spectrum substantially as shown in FIG1-1; Preferably, the free crystalline form A is anhydrous crystalline form; Preferably, the free crystalline form A has one, two or three of the following characteristics: (1) The TGA curve of free form A shows a weight loss of approximately 0.38±1% at 150.0±3°C; (2) The DSC curve of the free form A has an endothermic peak starting point at 169.5±3℃; (3) The DSC curve of free form A has an endothermic peak at 171.0±3℃; Preferably, the DSC graph of the free crystalline form A is substantially as shown in Figure 1-2; Preferably, the TGA graph of the free crystalline form A is substantially as shown in Figures 1-3. The crystal form according to claim 1, wherein the crystal form is a free crystal form B of the compound of formula I, and the free crystal form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 11.64°, 12.60°, 17.46°, 20.93°, 25.16°, and 26.56°; Preferably, the X-ray powder diffraction spectrum of the free crystalline form B expressed at a diffraction angle of 2θ±0.2° also has diffraction peaks at one or more of the following locations: 5.80°, 29.25°, 28.22°, 28.51°, 35.32°; Preferably, the free crystalline form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 5.80°, 11.64°, 12.60°, 17.46°, 20.93°, 22.19°, 25.16°, 26.56°, 28.22°, 28.51°, 29.25°, 33.23°, 35.32°, and 38.52°; Preferably, the free crystalline form B has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 5.80°, 11.64°, 12.60°, 16.09°, 17.46°, 18.37°, 20.93°, 22.19°, 23.03°, 23.82°, 25.16°, 26.56°, 28.22°, 28.51°, 29.25°, 29.79°, 32.20°, 33.23°, 34.42°, 35.32°, and 38.52°; Preferably, the free crystalline form B has an XRPD spectrum substantially as shown in FIG2-1; Preferably, the free-state crystalline form B is an anhydrous crystalline form; Preferably, the free crystalline form B has one, two or three of the following characteristics: (1) The TGA curve of free form B shows a weight loss of approximately 0.23±1% at 150.0±3°C; (2) The DSC curve of the free form B has an endothermic peak starting point at 165.8±3℃; (3) The DSC curve of free form B has an endothermic peak at 168.47±3℃; Preferably, the DSC graph of the free crystalline form B is substantially as shown in Figure 2-2; Preferably, the TGA graph of the free crystalline form B is substantially as shown in Figure 2-3. The method for preparing the free crystalline form A of the compound of formula I according to claim 2, wherein any one of the following methods is selected: Method 1: Place the first sample bottle containing the compound of formula I in a second sample bottle containing a solvent, seal the second sample bottle, and let it stand at room temperature; the solvent does not cover the mouth of the first sample bottle; The solvent is selected from one or more of ethanol, acetone, methyl tert-butyl ether, ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile, n-heptane, and toluene; Method 2: Place the first sample bottle containing the solution of the compound of formula I in the second sample bottle containing the anti-solvent, seal the second sample bottle, and let it stand at room temperature; the anti-solvent does not cover the mouth of the first sample bottle; The solvent in the solution of the compound of formula I is selected from one or more of dichloromethane, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and N,N-dimethylformamide; The anti-solvent is selected from one or more of n-heptane, methyl tert-butyl ether, and water; Method 3: Add a solvent to the compound of formula I at room temperature, stir magnetically, and collect the solid; The solvent is selected from one or more of water, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, toluene, N,N-dimethylformamide, and N-methylpyrrolidone; Method 4: Add solvent to the compound of formula I at 50°C, stir magnetically, and collect solid; The solvent is selected from one or more of water, ethanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, acetone, methyl ethyl ketone, dimethyl sulfoxide, acetonitrile, toluene, N,N-dimethylformamide, and N-methylpyrrolidone; Method 5: Add the compound of formula I into organic solvent I, filter after dissolving, and evaporate at room temperature: Preferably, the organic solvent I is selected from one or more of methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, acetone, methyl ethyl ketone, dichloromethane and acetonitrile; Method 6: Dissolve the compound of formula I completely in a good solvent, filter, and dropwise add an antisolvent to the clear solution until solid precipitates; The good solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, tetrahydrofuran, methyl ethyl ketone, N-methylpyrrolidone, N,N-dimethylacetamide, ethanol, and isopropyl acetate; The anti-solvent is selected from one or more of water, toluene, methyl tert-butyl ether, and n-heptane; Preferably, when the anti-solvent is selected from water, the good solvent is selected from one of dimethyl sulfoxide, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, and N,N-dimethylacetamide; when the anti-solvent is selected from methyl tert-butyl ether, the good solvent is selected from dichloromethane; when the anti-solvent is selected from n-heptane, the good solvent is selected from methyl ethyl ketone or ethanol; Method 7: Dissolve the compound of formula I completely in a good solvent, filter, and add the clear solution to an anti-solvent; The good solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, ethyl acetate, 1,4-dioxane, methyl ethyl ketone, and tetrahydrofuran; The anti-solvent is selected from one or more of water, n-heptane, methyl tert-butyl ether, and toluene; Method 8: Add the compound of formula I into organic solvent I at 50°C, filter after dissolution, stir magnetically, and cool at room temperature; Preferably, the organic solvent I is selected from one or more of methanol, ethanol, isopropyl acetate, acetonitrile, ethyl acetate, and acetone; Method 9: Add the compound of formula I into a mortar or add the compound of formula I and a solvent into a mortar and grind; Preferably, the solvent is selected from one or more of water, methyl tert-butyl ether and n-heptane. The method for preparing the free crystalline form B of the compound of formula I according to claim 3 comprises the following methods: Method 1: Dissolve the compound of formula I completely in a good solvent, filter, and add an anti-solvent dropwise to the clear solution until solid precipitates; The good solvent is selected from one or two of tetrahydrofuran and N,N-dimethylacetamide, and the anti-solvent is selected from n-heptane; The anti-solvent is selected from one or more of water, toluene, methyl tert-butyl ether, and n-heptane; Method 2: completely dissolve the compound of formula I in a good solvent, filter, and add the clear solution into an anti-solvent; The good solvent is selected from one or two of dichloromethane and 1,4-dioxane; the anti-solvent is selected from n-heptane; Method 3: Add the compound of formula I to isopropanol at 40-60°C (e.g. 50°C), filter after dissolving, stir, and cool at room temperature; Method 4: Completely dissolve the compound of formula I in tetrahydrofuran, filter, add n-heptane to the clear solution with stirring until solid precipitates, then add free form B seed crystals and stir. A pharmaceutically acceptable salt of a compound of formula I, wherein the structure of the compound of formula I is as follows:
The pharmaceutically acceptable salt is selected from the salts of the compound of formula I and acid or base; Preferably, the pharmaceutically acceptable salt of the compound of formula I is selected from the salts formed by the compound of formula I and the following acids or bases: hydrochloric acid, sulfuric acid, maleic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, L-malic acid, succinic acid, p-toluenesulfonic acid, methanesulfonic acid, sodium hydroxide, arginine; Preferably, the pharmaceutically acceptable salt of the compound of formula I is selected from the maleate salt of the compound of formula I; in the maleate salt, the molar ratio of the compound of formula I to maleic acid is 1:1; Preferably, the pharmaceutically acceptable salt of the compound of formula I is selected from the sodium salt of the compound of formula I; in the sodium salt, the molar ratio of the compound of formula I to sodium is 1:1. The pharmaceutically acceptable salt of the compound of formula I according to claim 6, wherein the salt is a crystalline form; Preferably, the crystalline form is maleate crystalline form A, and the X-ray powder diffraction spectrum of the maleate crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, and 18.44°; further, the X-ray powder diffraction spectrum of the maleate crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.96°, 25.62°, and 26.78°; further, the X-ray powder diffraction spectrum of the maleate crystalline form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.96°, 25.62°, and 26.78°. 3.78°, 16.31°, 17.07°, 18.44°, 20.96°, 21.61°, 25.29°, 25.62°, and 26.78°; further, the maleate salt form A has a diffraction peak at 8.39°, 13.78°, 16.31°, 17.07°, 18.44°, 20.45°, 20.96°, 21.61°, 25.29°, 25.62°, 26.19°, and 26.78° in an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2°; further, the maleate salt form A has a diffraction peak at 8. The maleate salt form A has diffraction peaks at 8.39°, 10.65°, 13.78°, 16.31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, 27.41°, 28.47°, 28.96°, 30.05°, 31.25°, 31.61°, and 33.91°; further, the maleate salt form A has an X-ray powder diffraction spectrum represented by a diffraction angle of 2θ±0.2° at 8.39°, 10.65°, 13.78°, 16.31°, 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, , 17.07°, 18.44°, 19.01°, 20.45°, 20.96°, 21.61°, 22.65°, 23.19°, 24.62°, 25.29°, 25.62°, 26.19°, 26.78°, 27.03°, 27.41°, 28.47°, 28.96°, 30.05, 30.74°, 31.25°, 31.61°, 32.70°, 33.13°, 33.91°, 34.49°, 35.22°, 36.21°, and 38.48°; further, the maleate salt form A has an XRPD spectrum substantially as shown in FIG. 3-1; Preferably, the maleate salt form A has one or two of the following characteristics: (1) The TGA curve of the maleate salt form A shows a weight loss of 0.5-3% at 120±3°C, preferably 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, for example 1.41%; (2) The maleate salt form A has an endothermic peak at 139.1±3°C; Preferably, the TGA/DSC graph of the maleate salt form A is substantially as shown in FIG3-2; the ¹ H NMR graph of the maleate salt form A is substantially as shown in FIG3-3; Or the crystal form is sodium salt crystal form A of the compound of formula I, and the X-ray powder diffraction spectrum of the sodium salt crystal form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 16.70°, 17.02°, 21.23°, 22.33°, 24.39°, 25.50°, and 25.89°; further, the X-ray powder diffraction spectrum of the sodium salt crystal form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 16.70°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, and 29.73°; further, the X-ray powder diffraction spectrum of the sodium salt crystal form A represented by a diffraction angle of 2θ±0.2° has diffraction peaks at 16.70°, , 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, 29.73°, and 30.76°; further, the X-ray powder diffraction spectrum of the sodium salt form A represented by a diffraction angle of 2θ±0.2° is 4.85°, 9.70°, 12.1 There are diffraction peaks at 3°, 13.55°, 14.20°, 14.55, 1670°, 17.02°, 17.67°, 18.51°, 21.23°, 22.33°, 24.39°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 29.73°, and 30.76°; further, The X-ray powder diffraction spectrum of the sodium salt form A represented by a diffraction angle of 2θ±0.2° is 4.85°, 9.70°, 12.13°, 13.55°, 14.20°, 14.55, 16.70°, 17.02°, 17.67°, 18.51°, 20.27°, 21.23°, 22.33°, 23.35°, 24. .39°, 25.50°, 25.89°, 26.72°, 27.74°, 28.44°, 29.73°, 30.76°, 31.43°, 31.88°, 32.46°, and 39.71°; further, the X-ray powder diffraction spectrum of the sodium salt form A represented by a diffraction angle of 2θ±0.2° is 4.85°, 9.70°、12.13°、13.55°、14.20°、14.55°、16.70°、17.02°、17.67°、18.51°、20.27°、21.23°、22.33°、23.35°、24.39°、25.50°、25.89°、26.72°、27.74°、28.4 There are diffraction peaks at 4°, 28.87°, 29.73°, 30.76°, 31.43°, 31.88°, 32.46°, 32.98°, 34.06°, 35.13°, 35.68°, 36.33°, 38.30°, and 39.71°; further, the sodium salt form A has an XRPD spectrum substantially as shown in Figure 4-1; Preferably, the sodium salt crystalline form A has one or two of the following characteristics: (1) The TGA curve of the sodium salt form A shows a weight loss of 1.0-5.0% at 150±3°C, preferably 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, for example 2.75%; (2) The sodium salt form A has two endothermic peaks at 191.0±3°C and 215.0±3°C; Preferably, the TGA/DSC graph of the sodium salt crystal form A is substantially as shown in FIG. 4-2 ; the ¹ H NMR graph of the sodium salt crystal form A is substantially as shown in FIG. 4-3 . A method for preparing a pharmaceutically acceptable salt of a compound of formula I as claimed in claim 6, comprising mixing a compound of formula I with a suitable acid or base to obtain the pharmaceutically acceptable salt; Preferably, when the pharmaceutically acceptable salt of the compound of formula I is a maleate or sodium salt, the preparation method comprises the following steps: mixing the compound of formula I and maleic acid or sodium hydroxide, stirring in an organic solvent A, and separating to obtain a solid; preferably, the stirring time is 1-5 days, and the stirring temperature is room temperature; the organic solvent A is selected from one or more of isopropanol, ethyl acetate, and 2-methyltetrahydrofuran; preferably, mixing the compound of formula I and maleic acid or sodium hydroxide, obtaining a suspension in an organic solvent A, and suspending and stirring; Preferably, when the pharmaceutically acceptable salt of the compound of formula I is maleate crystalline form A, the preparation method comprises the following steps: mixing the compound of formula I and an equimolar amount of maleic acid to obtain a suspension in an organic solvent A, suspending and stirring, and separating to obtain a solid; preferably, the suspension stirring time is 1-5 days, and the suspension stirring temperature is room temperature; the organic solvent A is selected from ethyl acetate; Preferably, when the pharmaceutically acceptable salt of the compound of formula I is sodium salt form A, the preparation method comprises the following steps: mixing the compound of formula I and an equimolar amount of sodium hydroxide to obtain a suspension in an organic solvent A, suspending and stirring, and separating to obtain a solid; in some embodiments, the suspension and stirring time is 1-5 days, for example, 3 days, and the suspension and stirring temperature is room temperature; the organic solvent A is selected from one or more of isopropanol, ethyl acetate, and 2-methyltetrahydrofuran. A pharmaceutical composition, wherein the pharmaceutical composition comprises a crystalline form of the compound of formula I according to any one of claims 1 to 3, 6 to 7, a pharmaceutically acceptable salt thereof, or one or more crystalline forms of a pharmaceutically acceptable salt thereof; Preferably, the crystalline form of the compound of formula I is a free crystalline form of the compound of formula I; Preferably, the crystalline form of the compound of formula I is the free crystalline form A of the compound of formula I; Preferably, the crystalline form of the compound of formula I is the free crystalline form B of the compound of formula I; Preferably, the crystalline form of the pharmaceutically acceptable salt of the compound of formula I is maleate crystalline form A or sodium salt crystalline form A. Use of a crystalline form of the compound of formula I according to any one of claims 1 to 3, 6 to 7, or a pharmaceutically acceptable salt thereof, or a crystalline form of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 9 in the preparation of a drug; Preferably, the drug is used to treat and/or prevent voltage-gated sodium channel-related diseases; Preferably, the voltage-gated sodium channel-related disease is a Nav1.8-related disease; Preferably, the Nav1.8-related diseases include: pain; Preferably, the pain includes: acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.