CN118234735A - Solid form of benfotiamine derivatives and preparation method and use thereof - Google Patents

Abstract

The present invention relates to solid forms of the compound ((Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamide) -5- (phosphonooxy) pent-2-en-3-yl) 2-fluorobenzene thiol ester) of formula (I), methods of preparing the solid forms, pharmaceutical compositions comprising the solid forms, and uses of the solid forms for the treatment of diseases.

Description

Solid form of benfotiamine derivatives and preparation method and use thereof Field of the Invention

The present invention relates to a solid form of (Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-5-(phosphonooxy)pent-2-en-3-yl)2-fluorobenzenethiol ester (hereinafter referred to as "the compound of formula (I)"), a method for preparing the solid form, a pharmaceutical composition containing the solid form, and the use of the solid form for treating diseases.

Background of the Invention

Alzheimer’s disease (commonly known as senile dementia, Alzheimer’s disease, AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations. It is the most common senile dementia, mainly manifested by impaired recognition ability and rapid decline of memory function. The main pathophysiological characteristics are the deposition of β-amyloid protein (β-amyloid, Aβ) in the brain to form senile plaques, hyperphosphorylation of tau protein to form neurofibrillary tangles, brain glucose metabolism disorders and neuron/synapse loss. Due to the long course of the disease and the poor self-care ability of patients, it brings serious mental and economic burdens to families and society. However, there are currently no drugs that can prevent or delay the progression of the disease worldwide. The drugs currently sold on the market for the treatment of AD are only symptomatic drugs, which can only control or improve cognitive and functional symptoms for a period of time, and cannot prevent or delay the deterioration of the disease.

Studies have shown that benfotiamine can prevent and treat Alzheimer's disease. CN109111478A discloses a benfotiamine derivative and a preparation method thereof, which has a significantly higher inhibitory effect on Aβ40 and Aβ42 than benfotiamine.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a crystalline form of a compound of formula (I) ((Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-5-(phosphonooxy)pent-2-en-3-yl)2-fluorobenzenethiol ester) as shown below:

The preferred crystal form of the present invention has good stability. After storage under high temperature, high humidity or light conditions, the crystal form remains unchanged, which can meet the pharmaceutical requirements of production, transportation and storage. The production process is stable, controllable and repeatable, and can be adapted to industrial production.

Another aspect of the present invention provides a method for preparing the crystal of the present invention, the method including but not limited to a suspension stirring method, a volatilization method, a cooling method and a gas-liquid permeation method.

Another aspect of the present invention provides a pharmaceutical composition comprising any one or more crystalline forms of the present invention and one or more pharmaceutically acceptable carriers.

Another aspect of the present invention provides the use of the crystalline form of the present invention in the preparation of a medicament for preventing or treating vitamin B1 deficiency and metabolic related disorders, psychiatric diseases and disorders, diabetes related complications and/or neurodegenerative diseases.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a is an X-ray powder diffraction (XRPD) pattern of the amorphous compound of formula (I).

Figure 1b is a thermogravimetric analysis (TGA) diagram of the amorphous compound of formula (I)

FIG. 1c is a differential scanning calorimetry (DSC) diagram of the amorphous form of the compound of formula (I).

Figure 1d is a hygroscopicity analysis (DVS) diagram of the amorphous compound of formula (I).

FIG2a is an X-ray powder diffraction pattern of Form A of the compound of formula (I).

FIG2b is a thermogravimetric analysis diagram of Form A of the compound of formula (I).

FIG2c is a differential scanning calorimetry diagram of Form A of the compound of formula (I).

Figure 2d is a diagram showing the hygroscopicity analysis of Form A of the compound of formula (I).

FIG3a is an X-ray powder diffraction pattern of Form B of the compound of formula (I).

FIG3b is a thermogravimetric analysis diagram of Form B of the compound of formula (I).

FIG3c is a differential scanning calorimetry diagram of Form B of the compound of formula (I).

Figure 3d is a diagram showing the hygroscopicity analysis of Form B of the compound of formula (I).

FIG4a is an X-ray powder diffraction pattern of Form C of the compound of formula (I).

FIG4b is a thermogravimetric analysis diagram of Form C of the compound of formula (I).

FIG4c is a differential scanning calorimetry diagram of Form C of the compound of formula (I).

Figure 4d is a diagram showing the hygroscopicity analysis of Form C of the compound of formula (I).

Figure 5a is an X-ray powder diffraction pattern of Form D of the compound of formula (I) prepared in Example 15.

Figure 5a-1 is an X-ray powder diffraction pattern of Form D of the compound of formula (I) prepared in Example 18.

Figure 5a-2 is an X-ray powder diffraction pattern of Form D of the compound of formula (I) prepared in Examples 18-21.

FIG5b is a thermogravimetric analysis diagram of Form D of the compound of formula (I).

FIG5c is a differential scanning calorimetry diagram of Form D of the compound of formula (I).

Figure 5d is a diagram showing the hygroscopicity analysis of the crystalline form D of the compound of formula (I).

FIG6a is an X-ray powder diffraction pattern of Form E of the compound of formula (I).

FIG6b is a thermogravimetric analysis diagram of Form E of the compound of formula (I).

FIG6c is a differential scanning calorimetry diagram of Form E of the compound of formula (I).

Figure 6d is a diagram showing the hygroscopicity analysis of the crystalline form E of the compound of formula (I).

FIG. 7a is an X-ray powder diffraction pattern of Form F of the compound of formula (I).

FIG. 7b is a thermogravimetric analysis diagram of Form F of the compound of formula (I).

FIG. 7c is a differential scanning calorimetry diagram of Form F of the compound of formula (I).

Figure 7d is a diagram showing the hygroscopicity analysis of Form F of the compound of formula (I).

FIG8a is an X-ray powder diffraction pattern of Form G of the compound of formula (I).

FIG8b is a thermogravimetric analysis diagram of Form G of the compound of formula (I).

FIG8c is a differential scanning calorimetry diagram of Form G of the compound of formula (I).

Figure 8d is a diagram showing the hygroscopicity analysis of Form G of the compound of formula (I).

FIG9a is an X-ray powder diffraction pattern of Form H of the compound of formula (I).

Figure 9b is a three-dimensional structure diagram of the crystalline form H of the compound of formula (I).

FIG10a is an X-ray powder diffraction pattern of Form I of the compound of formula (I).

Figure 10b is a three-dimensional structure diagram of the crystalline form I of the compound of formula (I).

Figure 11a is a comparison of XRPD patterns of the amorphous form of the compound of formula (I) before and after the accelerated 15-day stability test (where a represents the XRPD pattern before the test, and b represents the XRPD pattern after the test).

Figure 11b is an XRPD comparison of the accelerated 15-day stability test of Form A of the compound of formula (I) (where a represents the XRPD pattern before the test begins, and b represents the XRPD pattern after the test ends).

Figure 11c is an XRPD comparison of the accelerated 15-day stability test of the hydrate form B of the compound of formula (I) (where a represents the XRPD pattern before the test begins, and b represents the XRPD pattern after the test ends).

Figure 11d is an XRPD comparison of the accelerated 15-day stability test of Form C of the compound of formula (I) (where a represents the XRPD pattern before the test begins, and b represents the XRPD pattern after the test ends).

Figure 11e is an XRPD comparison of the accelerated 15-day stability test of Form D of the compound of formula (I) (where a represents the XRPD pattern before the test begins, and b represents the XRPD pattern after the test ends).

Figure 11f is an XRPD comparison of the accelerated 15-day stability test of Form E of the compound of formula (I) (where a represents the XRPD pattern before the test begins, and b represents the XRPD pattern after the test ends).

DETAILED DESCRIPTION OF THE INVENTION

definition

Unless otherwise defined below, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology or replacement of equivalent technology that are obvious to those skilled in the art. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

As used herein, the term "about" means that one of ordinary skill in the art considers to be within an acceptable standard error of the stated value, e.g., ±0.05, ±0.1, ±0.2, ±0.3, ±1, ±2, or ±3, etc.

The term "solid form" as used herein includes all solid forms of the compound of formula (I), such as crystalline forms or amorphous forms.

The term "amorphous" as used herein refers to any solid material that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. As described below, amorphous solids produce diffuse XRPD patterns that typically include one or two broad peaks (i.e., peaks with a base width of about 5° 2θ or greater).

[00136] The term "crystalline form" or "crystal" as used herein refers to any solid material that exhibits a three-dimensional ordering, in contrast to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or parameters derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and/or peak intensities (ordinate).

As used herein, the term "2θ" refers to the peak position expressed in degrees based on the experimental setup of an X-ray diffraction experiment, and is typically the unit of the abscissa in a diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires recording the reflected beam at an angle of 2θ. It should be understood that the specific 2θ value for a specific crystalline form mentioned herein is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-Kα (Kα1 1.540598 and Kα2 1.544426) as the radiation source.

As used herein, the term "differential scanning calorimetry (DSC) spectrum" refers to measuring the temperature difference and heat flow difference between a sample and a reference during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain the phase change information of the sample. The DSC spectrum in this application is preferably collected on a TA DSC Q2000 differential scanning calorimeter.

As used herein, the term "substantially the same" for X-ray diffraction peak positions means that representative peak positions and intensity variations are taken into account. For example, one skilled in the art will understand that peak positions (2θ) will show some variation, typically up to 0.1-0.2 degrees, and that the instrument used to measure diffraction will also show some variation. In addition, one skilled in the art will understand that relative peak intensities will show variation between instruments and due to variation in degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be considered as only qualitative measurements. Similarly, as used herein, "substantially the same" for DSC spectra is also intended to encompass variations associated with these analytical techniques known to those skilled in the art. For example, for well-defined peaks, there will typically be variations of up to ±0.2°C in differential scanning calorimetry spectra, and even greater (e.g., up to ±1°C) for broad peaks.

The term "hydrocarbons" as used herein preferably means hydrocarbons having 1 to 10 carbon atoms, including alkanes, halogenated alkanes, alkenes, alkynes and aromatic hydrocarbons, specifically including but not limited to dichloromethane, chloroform (chloroform), n-hexane, n-heptane and toluene.

As used herein, the term "alcohols" preferably means alcohols having 1 to 10 carbon atoms, including but not limited to methanol, ethanol, 1-propanol (n-propanol), 2-propanol (isopropanol), 1-butanol, 2-butanol and tert-butanol.

The term "ethers" as used herein preferably means ethers having 2-6 carbon atoms, including chain ethers and cyclic ethers (such as furans (including tetrahydrofurans) and dioxanes), specifically including but not limited to diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, cyclopentyl methyl ether, anisole and dimethoxyethane.

As used herein, the term "nitriles" preferably means nitriles having 2 to 6 carbon atoms, which include, but are not limited to, acetonitrile and propionitrile.

As used herein, the term "ketone solvent" preferably means a ketone having 2 to 6 carbon atoms, which includes, but is not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone.

As used herein, the term "esters" preferably means esters having 3 to 10 carbon atoms, which include, but are not limited to, ethyl acetate, propyl acetate, isopropyl acetate, ethyl isopropionate, dimethyl carbonate and butyl acetate.

As used herein, numerical ranges (such as "1-10") and subranges thereof (such as "2-10", "2-6", "3-10"), etc., include any number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) in the numerical range.

The prepared salt or its crystalline form can be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration or any other technique for solid recovery under pressure or under reduced pressure. The recovered solid can be optionally dried. "Drying" in the present invention is carried out under reduced pressure (preferably vacuum) until the content of residual solvent is reduced to within the limits given by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The residual solvent content depends on the type of solvent, but does not exceed about 5000ppm, or preferably about 4000ppm, or more preferably about 3000ppm. The drying can be carried out in a tray dryer, a vacuum oven, an air oven, a cone vacuum dryer, a rotary vacuum dryer, a fluidized bed dryer, a rotary flash dryer, a flash dryer, etc. The drying can be carried out at a temperature of less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperature, at atmospheric pressure or reduced pressure (preferably vacuum) for any desired time (such as about 1, 2, 3, 5, 10, 15, 20, 24 hours or overnight) that can achieve the desired result, as long as the quality of the salt does not deteriorate. The drying can be carried out any desired number of times until the desired product quality is achieved. The dried product can optionally undergo a pulverizing operation to produce a desired particle size. Grinding or micronization can be performed before or after drying of the product. Techniques that can be used to reduce particle size include, but are not limited to, ball milling, roller milling and hammer milling, and jet milling.

The term "anhydrous crystalline form" as used herein preferably means a crystalline form containing no water molecules as structural elements.

Crystalline Form A

In one embodiment, the present invention provides Form A of a compound of formula (I), the XRPD pattern of Form A comprising characteristic peaks at diffraction angles (2θ) of about 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 18.5±0.2°, 18.8±0.2°, 25.5±0.2° and 26.2±0.2°.

In one embodiment, the present invention provides Form A of a compound of formula (I), the XRPD pattern of Form A comprising characteristic peaks at diffraction angles (2θ) of about 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 17.0±0.2°, 18.5±0.2°, 18.8±0.2°, 21.9±0.2°, 22.6±0.2°, 25.5±0.2°, 26.2±0.2° and 27.0±0.2°.

In a preferred embodiment, the XRPD pattern of Form A of the compound of formula (I) includes about 11.7±0.2°, 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 13.3±0.2°, 14.8±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 17.5±0.2°, 18.5±0.2°, 18.8±0.2°. , characteristic peaks at diffraction angles (2θ) of 19.6±0.2°, 21.9±0.2°, 22.6±0.2°, 23.0±0.2°, 24.9±0.2°, 25.5±0.2°, 26.2±0.2°, 26.4±0.2°, 27.0±0.2°, 28.8±0.2°, 30.3±0.2°, 32.4±0.2°, 34.8±0.2° and 36.8±0.2°.

In a more preferred embodiment, the XRPD pattern of Form A of the compound of formula (I) comprises characteristic peaks at diffraction angles (2θ) substantially the same as shown in Figure 2a. In a most preferred embodiment, the XRPD pattern of Form A of the compound of formula (I) is substantially the same as shown in Figure 2a.

In a preferred embodiment, the DSC spectrum of the crystalline form A of the compound of formula (I) of the present invention includes endothermic peaks at about 92.6±0.2°C and about 144.0±0.2°C. In a more preferred embodiment, the DSC spectrum of the crystalline form A of the compound of formula (I) of the present invention includes characteristic peaks at temperatures substantially the same as those shown in Figure 2c. In a most preferred embodiment, the DSC spectrum of the crystalline form A of the compound of formula (I) is substantially the same as that shown in Figure 2c.

In a preferred embodiment, in thermogravimetric analysis, Form A of the compound of formula (I) of the present invention has a weight loss of about 8.98% when heated to about 133±2° C. In a more preferred embodiment, the TGA spectrum of Form A of the compound of formula (I) of the present invention is substantially the same as shown in FIG. 2 b.

In a preferred embodiment, the crystalline form A of the compound of formula (I) of the present invention is a solvate formed by the compound of formula (I) and nitromethane.

In some embodiments, the present invention also provides a method for preparing Form A, which is a suspension stirring method, which comprises adding a compound of formula (I) to an organic solvent, stirring at 20-35°C, and then filtering it to obtain Form A.

In a preferred embodiment, the organic solvent is nitromethane, or a mixed solvent of nitromethane and other organic solvents.

The other organic solvents are, for example, alcohols, hydrocarbons, ethers, esters, ketones or halogenated hydrocarbon solvents having 1 to 10 carbon atoms. The alcohol solvents are, for example, isoamyl alcohol or methanol, the hydrocarbon solvents are, for example, n-hexane or n-heptane, the ether solvents are, for example, tetrahydrofuran or ether, the ester solvents are, for example, ethyl acetate or isopropyl acetate, the ketone solvents are, for example, acetone, methyl ethyl ketone or methyl isobutyl ketone, and the halogenated hydrocarbon solvents are, for example, dichloromethane.

Preferably, the organic solvent is nitromethane or a mixed solvent of nitromethane and isoamyl alcohol. More preferably, the volume ratio of nitromethane to isoamyl alcohol in the mixed solvent is 1:1.

Preferably, the stirring is performed at about 25°C.

Preferably, the stirring is continued for about 24 hours.

In some embodiments, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the organic solvent is (10-30):1, preferably about 20:1.

Crystalline Form B

In another embodiment, the present invention provides Form B of the compound of formula (I), the XRPD pattern of Form B comprising characteristic peaks at diffraction angles (2θ) of about 6.2±0.2°, 12.5±0.2°, 16.0±0.2°, 18.8±0.2°, 24.1±0.2°, 24.8±0.2° and 26.5±0.2°.

In a preferred embodiment, the XRPD pattern of Form B of the compound of formula (I) includes about 6.2±0.2°, 10.1±0.2°, 12.0±0.2°, 12.5±0.2°, 14.8±0.2°, 15.5±0.2°, 16.0±0.2°, 17.4±0.2°, 17.6±0.2°, 18.8±0.2°, 20.3±0.2°, 21.4±0.2°, 23.9±0.2°, 24.8±0.2°, 25.6±0.2°, 26.9±0.2°, 27.8±0.2°, 28.9±0.2°, 29.0±0.2°, 30.1±0.2°, 31.3±0.2°, 32. The diffraction angles (2θ) of FIG1 are as follows: peaks at diffraction angles (2θ) of 2θ and 3θ at 15.6±0.2°, 21.3±0.2°, 24.1±0.2°, 24.8±0.2°, 25.0±0.2°, 25.8±0.2°, 26.5±0.2°, 28.2±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.7±0.2°, 30.6±0.2° and 32.7±0.2°.

In a more preferred embodiment, the XRPD pattern of Form B of the compound of formula (I) comprises characteristic peaks at diffraction angles (2θ) substantially the same as those shown in Figure 3a. In a most preferred embodiment, the XRPD pattern of Form B of the compound of formula (I) is substantially the same as that shown in Figure 3a.

In a preferred embodiment, the DSC spectrum of the crystalline form B of the compound of formula (I) of the present invention includes a characteristic peak at about 153.7±0.2°C. In a more preferred embodiment, the DSC spectrum of the crystalline form B of the compound of formula (I) of the present invention includes a characteristic peak at substantially the same temperature as shown in Figure 3c. In a most preferred embodiment, the DSC spectrum of the crystalline form B of the compound of formula (I) is substantially the same as shown in Figure 3c.

In a preferred embodiment, in thermogravimetric analysis, Form B of the compound of formula (I) of the present invention has a weight loss of about 1.52% when heated to about 71±2° C., and a weight loss of 3.35% between 71±2° C. and 135±2° C. In a more preferred embodiment, the TGA spectrum of Form B of the compound of formula (I) of the present invention is substantially the same as shown in FIG. 3 b.

In a preferred embodiment, the crystalline form B of the compound of formula (I) of the present invention is a hydrate.

In some embodiments, the present invention also provides a method for preparing Form B, which includes but is not limited to: a suspension stirring method, a volatilization method, a cooling method, and a gas-liquid permeation method.

In some embodiments, the method is a suspension stirring method, which comprises adding the compound of formula (I) to a solvent, stirring at 20-80° C., and then filtering it to obtain Form B.

In some embodiments, the solvent is selected from water, alcohol solvents having 1-10 carbon atoms (e.g., methanol, ethanol, isopropanol, isoamyl alcohol, etc.), ether solvents (e.g., ethyl ether, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents (e.g., toluene, etc.), halogenated hydrocarbon solvents (e.g., chloroform, etc.), or mixed solvents thereof.

Preferably, the solvent is one or more of water, isopropanol, ethanol, acetone and ether.

Optionally, the solvent is a mixed solvent of ethanol and diethyl ether, wherein the volume ratio of ethanol to diethyl ether is preferably 1:1.

Optionally, the solvent is a mixed solvent of ethanol and acetone, wherein the volume ratio of ethanol to acetone is preferably 1:1.

Optionally, the solvent is water.

Preferably, the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.

Preferably, the stirring is continued for about 24 hours.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.

In some embodiments, the volatilization method comprises adding the compound of formula (I) to a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solid precipitates, and filtering to collect the solid.

In a preferred embodiment, the solvent in the volatilization method is selected from water and an alcohol solvent having 1 to 10 carbon atoms (such as methanol, ethanol, isoamyl alcohol, etc.), or a mixed solvent thereof; preferably, the solvent is water or a mixed solvent of methanol and water (the volume ratio of methanol to water is preferably about 1:1).

In preferred embodiments, the volatilization is carried out at about 25°C or about 50°C.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.

In some embodiments, the cooling method comprises adding the compound of formula (I) to a solvent (preferably water), heating (preferably heating to 50-80°C, most preferably to about 70°C) to completely dissolve the compound, cooling to crystallize, and filtering to collect the solid.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 8:1.

In some embodiments, the gas-liquid permeation method comprises dissolving the compound of formula (I) in a good solvent in a first container, charging an anti-solvent into a second container, placing the first container open in the second container, sealing the second container and allowing it to stand, and filtering the precipitated solid to obtain crystals.

In a preferred embodiment, the good solvent in the gas-liquid permeation method is a halogenated hydrocarbon solvent having 1-10 carbon atoms, such as chloroform; the anti-solvent is a hydrocarbon solvent having 5-10 carbon atoms, such as n-hexane, n-heptane, petroleum ether, etc.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the good solvent is about (1-10): 1. In a preferred embodiment, the volume ratio of the good solvent to the anti-solvent is 1: (1-10). In a preferred embodiment, the sealing of the second container and the standing may be performed at room temperature.

Crystalline Form C

In another embodiment, the present invention provides Form C of the compound of Formula (I), the XRPD pattern of Form C comprising characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 14.3±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 24.8±0.2° and 25.3±0.2°.

In another embodiment, the present invention provides Form C of the compound of Formula (I), the XRPD pattern of Form C comprising characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 12.7±0.2°, 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 20.0±0.2°, 24.0±0.2°, 24.8±0.2°, 25.3±0.2° and 26.5±0.2°.

In a preferred embodiment, the XRPD pattern of Form C of the compound of Formula (I) includes characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 12.7±0.2°, 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 16.5±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 20.0±0.2°, 21.9±0.2°, 22.4±0.2°, 23.2±0.2°, 24.0±0.2°, 24.8±0.2°, 25.3±0.2°, 25.9±0.2°, 26.5±0.2°, 28.4±0.2°, 29.5±0.2° and 35.2±0.2°.

In a more preferred embodiment, the XRPD pattern of Form C of the compound of formula (I) comprises characteristic peaks at diffraction angles (2θ) substantially the same as those shown in Figure 4a. In a most preferred embodiment, the XRPD pattern of Form C of the compound of formula (I) is substantially the same as that shown in Figure 4a.

In a preferred embodiment, the DSC spectrum of the crystalline form C of the compound of formula (I) of the present invention includes a characteristic peak at about 197.6±0.2°C. In a more preferred embodiment, the DSC spectrum of the crystalline form C of the compound of formula (I) of the present invention includes a characteristic peak at substantially the same temperature as shown in Figure 4c. In a most preferred embodiment, the DSC spectrum of the crystalline form C of the compound of formula (I) is substantially the same as shown in Figure 4c.

In a preferred embodiment, the TGA spectrum of the crystalline form C of the compound of formula (I) of the present invention is substantially the same as that shown in FIG. 4b .

In a preferred embodiment, the crystalline form C of the compound of formula (I) of the present invention is a non-hydrate and a non-solvate.

In some embodiments, the present invention also provides a method for preparing Form C, which is a suspension stirring method, comprising adding a compound of formula (I) to a solvent, stirring at 20-60° C., and then filtering it to obtain crystals.

In a preferred embodiment, the solvent is a ketone solvent having 1 to 10 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), a nitrile solvent (e.g., acetonitrile, etc.), an ester solvent (e.g., ethyl acetate, isopropyl acetate, etc.), an ether solvent (e.g., methyl tert-butyl ether, ethyl ether, tetrahydrofuran, etc.), an alcohol solvent (e.g., methanol, ethanol, isoamyl alcohol, etc.), a halogenated hydrocarbon solvent (e.g., dichloromethane or chloroform), or a mixed solvent thereof.

In a preferred embodiment, the solvent is acetone, or a mixed solvent of chloroform and isoamyl alcohol (preferably in a volume ratio of 1:1).

Preferably, the stirring is performed at 20-50°C. More preferably, the stirring is performed at about 25°C or about 50°C.

Preferably, the stirring is continued for about 24 hours.

In some embodiments, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.

Crystal form D

In another embodiment, the present invention provides Form D of the compound of Formula (I), the XRPD pattern of Form D comprising characteristic peaks at diffraction angles (2θ) of about 9.0±0.2°, 11.4±0.2°, 16.7±0.2°, 18.6±0.2°, 24.6±0.2°, 25.7±0.2° and 27.2±0.2°.

In a preferred embodiment, the present invention provides Form D of a compound of formula (I), the XRPD pattern of Form D comprising characteristic peaks at diffraction angles (2θ) of about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2°, 18.6±0.2°, 19.6±0.2°, 24.6±0.2°, 25.7±0.2° and 27.2±0.2°.

In a preferred embodiment, the present invention provides Form D of a compound of formula (I), the XRPD pattern of Form D comprising characteristic peaks at diffraction angles (2θ) of about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2°, 18.6±0.2°, 19.6±0.2°, 21.2±0.2°, 22.6±0.2°, 24.6±0.2°, 25.7±0.2°, 27.2±0.2° and 28.9±0.2°.

In a preferred embodiment, the XRPD pattern of Form D of the compound of Formula (I) includes characteristic peaks at diffraction angles (2θ) of about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2°, 17.6±0.2°, 18.6±0.2°, 19.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.8±0.2°, 22.6±0.2°, 24.6±0.2°, 25.7±0.2°, 26.7±0.2°, 27.2±0.2°, 28.9±0.2° and 31.5±0.2°.

In a more preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) comprises characteristic peaks at diffraction angles (2θ) substantially the same as those shown in Figure 5a. In a most preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) is substantially the same as that shown in Figure 5a.

In a more preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) comprises characteristic peaks at diffraction angles (2θ) substantially the same as those shown in Figure 5a-1. In a most preferred embodiment, the XRPD pattern of the crystalline form D of the compound of formula (I) is substantially the same as that shown in Figure 5a-1.

In a preferred embodiment, the DSC spectrum of the crystalline form D of the compound of formula (I) of the present invention includes a characteristic peak at about 163.6±0.2°C. In a more preferred embodiment, the DSC spectrum of the crystalline form D of the compound of formula (I) of the present invention includes a characteristic peak at substantially the same temperature as shown in Figure 5c. In a most preferred embodiment, the DSC spectrum of the crystalline form D of the compound of formula (I) is substantially the same as shown in Figure 5c.

Preferably, the crystalline form D of the compound of formula (I) of the present invention is a hydrate with a water content of 4.8%-5.7%.

More preferably, the crystalline form D of the compound of formula (I) of the present invention is a sesquihydrate.

In some embodiments, the present invention also provides a method for preparing Form D, which includes but is not limited to: a suspension stirring method and a volatilization method.

In some embodiments, the method is a suspension stirring method, which comprises adding the compound of formula (I) to a solvent, stirring at 20-80° C., and then filtering it to obtain Form D.

In some embodiments, the solvent is selected from water, alcohol solvents having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isopentanol, etc.), halogenated hydrocarbon solvents (such as chloroform, etc.), or mixed solvents thereof.

Preferably, the solvent is ethanol; isoamyl alcohol; a mixed solvent of ethanol and water; or a mixed solvent of isoamyl alcohol and water.

More preferably, the volume ratio of ethanol to water in the mixed solvent is 7: 1. More preferably, the volume ratio of isoamyl alcohol to water in the mixed solvent is 7: 1.

Preferably, the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.

Preferably, the stirring is continued for about 24 hours.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-60):1, preferably about 20:1 or about 50:1.

In some embodiments, the volatilization method comprises adding the compound of formula (I) to a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solid precipitates, and filtering to collect the solid.

In a preferred embodiment, the solvent in the volatilization method is selected from water and a ketone solvent having 1 to 10 carbon atoms (such as acetone or methyl ethyl ketone, etc.), or a mixed solvent thereof; preferably, the solvent is a mixed solvent of methyl ethyl ketone and water (the volume ratio of methyl ethyl ketone to water is preferably about 1:1).

In a preferred embodiment, the volatilization is carried out at 25°C.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.

Crystalline Form E

In another embodiment, the present invention provides Form E of a compound of formula (I), the XRPD pattern of Form E comprising characteristic peaks at diffraction angles (2θ) of about 9.3±0.2°, 11.9±0.2°, 12.6±0.2°, 14.4±0.2°, 17.2±0.2°, 18.9±0.2° and 24.9±0.2°.

In a preferred embodiment, the present invention provides Form E of a compound of formula (I), the XRPD pattern of Form E comprising characteristic peaks at diffraction angles (2θ) of about 9.3±0.2°, 11.9±0.2°, 12.6±0.2°, 13.2±0.2°, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.5±0.2°, 21.2±0.2°, 23.7±0.2°, 24.3±0.2°, 24.9±0.2°, 26.3±0.2° and 27.0±0.2°.

In a preferred embodiment, the XRPD pattern of Form E of the compound of Formula (I) includes about 9.3±0.2°, 10.4±0.2°, 11.9±0.2°, 12.6±0.2°, 13.2±0.2°, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 16.9±0.2°, 17.2±0.2°, 18.1±0.2°, 18.6±0.2°, 18.9±0.2°, 19. Characteristic peaks at diffraction angles (2θ) of 0.2°, 19.5±0.2°, 21.2±0.2°, 21.6±0.2°, 22.0±0.2°, 23.7±0.2°, 24.3±0.2°, 24.9±0.2°, 25.2±0.2°, 26.0±0.2°, 26.3±0.2°, 27.0±0.2°, 28.1±0.2°, 31.5±0.2° and 34.2±0.2°.

In a more preferred embodiment, the XRPD pattern of the crystalline form E of the compound of formula (I) comprises a characteristic peak at a diffraction angle (2θ) substantially the same as that shown in Figure 6a. In a most preferred embodiment, the XRPD pattern of the crystalline form E of the compound of formula (I) is substantially the same as that shown in Figure 6a.

In a preferred embodiment, the DSC spectrum of the crystalline form E of the compound of formula (I) of the present invention includes a characteristic peak at about 201.8±0.2°C. In a more preferred embodiment, the DSC spectrum of the crystalline form E of the compound of formula (I) of the present invention includes a characteristic peak at substantially the same temperature as shown in Figure 6c. In a most preferred embodiment, the DSC spectrum of the crystalline form E of the compound of formula (I) is substantially the same as shown in Figure 6c.

In a preferred embodiment, the crystalline form E of the compound of formula (I) of the present invention is a non-hydrate and a non-solvate.

In some embodiments, the present invention also provides a method for preparing Form E, which is a suspension stirring method, comprising adding a compound of formula (I) to an organic solvent, stirring at 40-60° C., and then filtering it to obtain Form E.

In a preferred embodiment, the organic solvent is selected from nitromethane, or a mixed solvent of nitromethane and other organic solvents.

The other organic solvents are, for example, alcohols, ethers, esters, ketones or halogenated hydrocarbon solvents having 1 to 10 carbon atoms. The alcohol solvents are, for example, isoamyl alcohol or methanol, the ether solvents are, for example, tetrahydrofuran or diethyl ether, the ester solvents are, for example, ethyl acetate, the ketone solvents are, for example, acetone, methyl ethyl ketone or methyl isobutyl ketone, and the halogenated hydrocarbon solvents are, for example, dichloromethane.

Preferably, the stirring is performed at about 50°C.

Preferably, the stirring is continued for about 24 hours.

In some embodiments, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the organic solvent is (10-30):1, preferably about 20:1.

Form F

In another embodiment, the present invention provides Form F of the compound of Formula (I), the XRPD pattern of Form F comprising characteristic peaks at diffraction angles (2θ) of about 8.9±0.2°, 11.3±0.2°, 14.8±0.2°, 15.2±0.2°, 16.1±0.2°, 16.4±0.2°, 17.8±0.2°, 18.6±0.2°, 19.4±0.2°, 20.8±0.2°, 21.3±0.2°, 24.8±0.2° and 27.4±0.2°.

In a preferred embodiment, the XRPD pattern of Form F of the compound of formula (I) comprises about 6.4±0.2°, 8.9±0.2°, 10.8±0.2°, 11.3±0.2°, 13.6±0.2°, 14.8±0.2°, 15.2±0.2°, 15.7±0.2°, 16.1±0.2°, 16.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6±0.2°, 19. Peaks at diffraction angles (2θ) of 0.2°, 19.4±0.2°, 19.9±0.2°, 20.8±0.2°, 21.3±0.2°, 21.8±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.8±0.2°, 27.4±0.2°, 28.1±0.2°, 28.7±0.2°, 30.1±0.2° and 32.6±0.2°.

In a more preferred embodiment, the XRPD pattern of the crystalline form F of the compound of formula (I) comprises a characteristic peak at a diffraction angle (2θ) substantially the same as that shown in Figure 7a. In a most preferred embodiment, the XRPD pattern of the crystalline form F of the compound of formula (I) is substantially the same as that shown in Figure 7a.

In a preferred embodiment, the DSC spectrum of Form F of the compound of formula (I) of the present invention includes a characteristic peak at about 153.9±0.2°C.

In a more preferred embodiment, the DSC spectrum of the crystalline form F of the compound of formula (I) of the present invention includes characteristic peaks at substantially the same temperature as shown in Figure 7c. In a most preferred embodiment, the DSC spectrum of the crystalline form F of the compound of formula (I) is substantially the same as shown in Figure 7c.

In a preferred embodiment, the crystalline form F of the compound of formula (I) of the present invention is a hydrate.

In some embodiments, the present invention also provides a method for preparing Form F, which includes but is not limited to: a suspension stirring method and a volatilization method.

In some embodiments, the method is a suspension stirring method, which comprises adding the compound of formula (I) to a solvent, stirring at 20-80° C., and then filtering it to obtain Form F.

In some embodiments, the solvent is selected from water, alcohol solvents having 1-10 carbon atoms (e.g., methanol, ethanol, isopropanol, isoamyl alcohol, etc.), ether solvents (e.g., diethyl ether, etc.), ketone solvents (e.g., methyl ethyl ketone, methyl isobutyl ketone, etc.), aromatic hydrocarbon solvents (e.g., toluene, etc.), halogenated hydrocarbon solvents (e.g., chloroform, etc.), or mixed solvents thereof.

Preferably, the solvent is chloroform or a mixed solvent of methanol and ethanol.

More preferably, the volume ratio of methanol to ethanol in the mixed solvent is 1:1.

Preferably, the stirring is performed at 20-60°C. More preferably, the stirring is performed at about 25°C or about 50°C.

Preferably, the stirring is continued for about 24 hours.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (10-30):1, preferably about 20:1.

In some embodiments, the volatilization method comprises adding the compound of formula (I) to a solvent, mixing, and dissolving; volatilizing at 20° C. to 60° C. until solid precipitates, and filtering to collect the solid.

In a preferred embodiment, the solvent in the volatilization method is selected from water and an alcohol solvent having 1-10 carbon atoms (such as methanol, ethanol, isoamyl alcohol, etc.), or a mixed solvent thereof; preferably, the solvent is a mixed solvent of isoamyl alcohol and water (the volume ratio of isoamyl alcohol to water is preferably about 1:7).

In a preferred embodiment, the volatilization is carried out at 25°C or 50°C, more preferably at 50°C.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the solvent is (5-30):1, preferably about 10:1.

Form G

In another embodiment, the present invention provides Form G of the compound of formula (I), the XRPD pattern of Form G comprising characteristic peaks at diffraction angles (2θ) of about 7.0±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2°, 20.7±0.2°, 21.3±0.2° and 27.8±0.2°.

In a preferred embodiment, the XRPD pattern of Form G of the compound of Formula (I) includes peaks at diffraction angles (2θ) of about 7.0±0.2°, 10.3±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2°, 16.1±0.2°, 19.1±0.2°, 19.6±0.2°, 20.7±0.2°, 21.3±0.2°, 26.7±0.2°, 27.8±0.2° and 28.6±0.2°.

In a more preferred embodiment, the XRPD pattern of the crystalline form G of the compound of formula (I) comprises a characteristic peak at a diffraction angle (2θ) substantially the same as that shown in Figure 8a. In a most preferred embodiment, the XRPD pattern of the crystalline form G of the compound of formula (I) is substantially the same as that shown in Figure 8a.

In a preferred embodiment, the DSC spectrum of the crystalline form G of the compound of formula (I) of the present invention includes a characteristic peak at about 182.5±0.2°C.

In a more preferred embodiment, the DSC spectrum of the crystalline form G of the compound of formula (I) of the present invention includes a characteristic peak at substantially the same temperature as shown in Figure 8c. In a most preferred embodiment, the DSC spectrum of the crystalline form G of the compound of formula (I) is substantially the same as shown in Figure 8c.

In a preferred embodiment, the crystalline form G of the compound of formula (I) of the present invention is a methanol solvate.

In some embodiments, the present invention also provides a method for preparing form G, which is a gas-liquid permeation method, which comprises dissolving a compound of formula (I) in a good solvent in a first container, charging an anti-solvent into a second container, placing the first container open in the second container, sealing the second container and allowing it to stand, and filtering the precipitated solid to obtain crystals.

In a preferred embodiment, the good solvent in the gas-liquid permeation method is methanol; and the anti-solvent is ethanol.

In a preferred embodiment, the weight-to-volume ratio (mg/mL) of the compound of formula (I) to the good solvent is about (1-10): 1. In a preferred embodiment, the volume ratio of the good solvent to the anti-solvent is 1: (1-10). In a preferred embodiment, the sealing of the second container and the standing may be performed at room temperature.

Pharmaceutical compositions and uses

In another embodiment, the present invention provides a pharmaceutical composition comprising any one or more of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G of the compound of formula (I) of the present invention, and one or more pharmaceutically acceptable carriers.

In another embodiment, the present invention provides the use of Form A, Form B, Form C, Form D, Form E, Form F and Form G of the compound of formula (I) of the present invention in the preparation of drugs for preventing or treating vitamin B1 deficiency and metabolic-related disorders, mental diseases and disorders, diabetes-related complications and/or neurodegenerative diseases.

In another embodiment, the present invention provides crystalline form A, form B, form C, form D, form E, form F and form G of the compound of formula (I) of the present invention, which are used to prevent or treat vitamin B1 deficiency and metabolic-related disorders, mental diseases and disorders, diabetes-related complications and/or neurodegenerative diseases.

In another embodiment, the present invention provides a method for preventing or treating vitamin B1 deficiency and metabolic-related disorders, psychiatric diseases and disorders, diabetes-related complications and/or neurodegenerative diseases, which comprises administering to an individual (preferably a mammal) in need thereof a preventive or therapeutically effective amount of any one or more of the crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, crystalline form F and crystalline form G of the compound of formula (I) of the present invention.

In a preferred embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, vascular dementia and psychiatric disorders.

As used herein, the term "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle with which a therapeutic agent is administered and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The composition may also contain a small amount of a wetting agent, emulsifier or pH buffer as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The compositions of the present invention can act systemically and/or locally. For this purpose, they can be administered by suitable routes, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these administration routes, the compositions of the present invention can be administered in suitable dosage forms.

The dosage form may be a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation, specifically including but not limited to tablets, capsules, powders, granules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, suspensions, elixirs, and syrups.

The pharmaceutical composition of the present invention can be prepared by any method well known in the art, for example, by mixing, dissolving, granulating, sugar coating, grinding, emulsifying, freeze-drying and the like.

As used herein, the term "therapeutically effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

The dosage regimen may be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

The amount of the compound of the present invention administered will depend on the severity of the individual, disease or condition treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg/kg/day (single or divided administration). For a 70kg person, this will add up to about 0.007mg/day to about 3500mg/day, for example, about 0.7mg/day to about 700mg/day. In some cases, the dosage level not higher than the lower limit of the aforementioned range may be sufficient, and in other cases, a larger dose may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

The content or dosage of the compound of the present invention in the pharmaceutical composition can be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, for example 1.5 mg, 2 mg, 4 mg, 10 mg and 25 mg, etc.

As used herein, unless otherwise indicated, the terms "treating" and "treating" mean reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

Example

The present invention will be explained in more detail below in conjunction with embodiments. The embodiments of the present invention are only used to illustrate the technical solution of the present invention and are not used to limit the scope of the present invention. Those skilled in the art may make some non-essential improvements and adjustments, which still fall within the scope of protection of the present invention.

The instruments and test conditions used in the examples are as follows:

X-ray powder diffraction (XRPD): instrument model: Bruker D8advance, target: Cu Kα (40 kV, 40 mA), distance from sample to detector: 30 cm, scanning range: 3°-40° (2θ value), scanning step: 0.1 s.

Instrument model: Smart Lab 9KW from Rigaku Corporation, Japan; target: Cu Kα (40 kV, 100 mA); distance from sample to detector: 30 cm; scanning range: 3°-50° (2θ value); scanning step: 0.02°.

Thermogravimetric analysis (TGA): instrument model: TA Discovery TGA55, temperature range: 25-400°C, scanning rate: 10°C/min, purge gas: 60 ml/min, protective gas: 40 mL/min.

Differential scanning calorimetry (DSC): instrument model: TA DSC Q2000, temperature range: 20-210°C, scanning rate: 10°C/min, nitrogen flow rate: 20 mL/min.

DVS analysis: Instrument model: SMS DVS Advantage, humidity range: 0-95% RH, temperature: 25°C.

Infrared analysis, instrument model: Thermo Scientific Nicolet 6700, scanning range: 4000 to 400 cm-1, resolution: 4 cm-1.

Example 1

Preparation of the compound of formula (I) ((Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamide)-5-(phosphonooxy)pent-2-en-3-yl)2-fluorobenzenethiol ester)

The compound of formula (I) was prepared according to the preparation method disclosed in Example 9 of CN109111478A.

Dissolve thiamine phosphate 1a (38 g, 0.09 mol) in water (103 g, 5.7 mol), cool to 0-5°C, add 30% sodium hydroxide solution (87.3 g, 0.65 mol), adjust the pH value between 11 and 12, and stir for 1.5 hours. Add 2-fluorobenzoyl chloride (19 g, 0.12 mol) dropwise at 0-5°C, and control the pH value between 11 and 12 during the addition. After the addition is complete, react at 5-10°C for 2 hours. Add concentrated hydrochloric acid (34 g, 0.33 mol) dropwise, adjust the pH value between 3 and 4, add 50 mL of ethyl acetate and stir for 16 hours. Filter, dry the filter cake, dissolve it in methanol, and evaporate it quickly to obtain an amorphous compound of formula (I), whose XRPD spectrum is shown in Figure 1a, TGA spectrum is shown in Figure 1b, and DSC spectrum is shown in Figure 1c.

Example 2: Preparation of Form A by single solvent suspension stirring method at room temperature

Weigh 20 mg of the compound of formula (I) prepared in Example 1 and add it to a 3 mL glass vial. Add 1 mL of nitromethane and stir the resulting suspension magnetically (500 rpm) at 25 °C for about 24 h. Filter the suspension and dry the solid portion in a vacuum drying oven for 10 min. This crystalline form is referred to as Form A (off-white powder).

The obtained crystal form A was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in FIG2a , and the positions of its characteristic peaks are shown in the following table:

2θ(°) strength% 11.7 twenty three 11.9 49 12.3 58 12.7 100 13.3 twenty one 13.9 7 14.8 31 15.1 8 16.0 26 17.0 40 17.3 18 17.5 twenty two 18.1 7 18.5 74 18.8 48 19.6 12 20.3 7 20.9 7 21.9 33 22.2 8 22.6 32 23.0 11 24.0 7 24.2 10 24.9 12 25.5 63 26.2 43 26.4 18 27.0 39 28.8 12 29.3 6 30.3 18 30.5 10 31.8 7 32.4 20 34.0 7 34.3 9 34.8 12 36.8 12 39.0 5

The obtained crystal form A was subjected to TGA analysis, and the obtained spectrum is shown in Figure 2b. From the analysis, it can be seen that the crystal form slowly desolvates at about 30°C and decomposes at about 170°C.

The obtained crystal form A was subjected to DSC analysis, and the obtained spectrum is shown in Figure 2c. From the analysis, it can be seen that the crystal form has endothermic peaks at about 92.6°C and about 144.0°C.

Example 3: Preparation of Form A by Suspension Stirring of Mixed Solvents at Room Temperature

20 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 3 mL glass vial, 1 mL of a mixed solvent of nitromethane and isoamyl alcohol (volume ratio 1:1) was added, and the resulting suspension was magnetically stirred (500 rpm) at 25° C. for about 24 h, the suspension was filtered, and the solid portion was dried in a vacuum drying oven for 10 min. The XRPD pattern of the obtained crystal form was substantially the same as that in Example 2, indicating that crystal form A was obtained.

Example 4: Preparation of Form B by single solvent suspension stirring method at room temperature

20 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 3 mL glass vial, 1 mL of isopropanol was added, and the resulting suspension was magnetically stirred (500 rpm) at 25 ° C. for about 24 h, the suspension was filtered, and the solid portion was dried in a vacuum drying oven for 10 min. This crystalline form was called Form B (off-white powder, flaky crystals).

The obtained crystal form B was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in FIG3a , and the positions of its characteristic peaks are shown in the following table:

2θ(°) strength% 6.2 100 10.1 5 10.5 4 12.0 5 12.5 69 14.8 5 15.5 5 16.0 20 17.4 5 17.6 5 18.3 4 18.8 98 19.7 4 20.0 4 20.3 7 21.3 6 22.3 4 22.7 4 22.9 4 24.1 13 24.8 twenty two 25.0 6 25.5 5 25.8 6 26.5 16 26.9 4 28.2 6 28.3 7 28.6 7 29.1 7 29.7 7 30.6 8 30.9 4 31.5 3 32.0 3 32.7 8 37.3 3

38.2 4 38.3 4 39.2 4

The obtained crystal form B was subjected to TGA analysis, and the obtained spectrum is shown in Figure 3b. From the analysis, it can be seen that the crystal form B slowly desolvates at about 30°C and decomposes at about 170°C.

The obtained crystal form B was subjected to DSC analysis, and the obtained spectrum is shown in Figure 3c. From the analysis, it can be seen that the crystal form has an endothermic peak at about 153.7°C.

Example 5: Preparation of Form B by mixed solvent suspension stirring at room temperature

20 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 3 mL glass vial, 1 mL of a mixture of ethanol and acetone (volume ratio 1:1) was added, and the resulting suspension was magnetically stirred (500 rpm) at 25° C. for about 24 h, the suspension was filtered, and the solid portion was dried in a vacuum drying oven for 10 min. The XRPD pattern of the obtained crystal form was substantially the same as that in Example 4, indicating that crystal form B was obtained.

Example 6: Preparation of Form B by high temperature single solvent suspension stirring method

20 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 3 mL glass vial, 1 mL of water was added, and the resulting suspension was magnetically stirred (500 rpm) at 50° C. for about 24 h, the suspension was filtered, and the solid portion was dried in a vacuum drying oven for 10 min. The XRPD pattern of the obtained crystalline form was substantially the same as that in Example 4, indicating that crystalline form B was obtained.

Example 7: Preparation of Form B by high temperature mixed solvent suspension stirring method

20 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 3 mL glass vial, 1 mL of a mixture of ethanol and ether (volume ratio 1:1) was added, the resulting suspension was magnetically stirred (500 rpm) at 50° C. for about 24 h, the suspension was filtered, and the solid portion was dried in a vacuum drying oven for 10 min. The XRPD pattern of the obtained crystal form was substantially the same as that in Example 4, indicating that crystal form B was obtained.

Example 8: Preparation of Form B by Room Temperature Volatilization Method

Weigh 10 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of a mixture of methanol and water (volume ratio 1:1), mix well, and dissolve. Slowly evaporate at 25° C. until solid precipitates, and collect the solid. The XRPD pattern of the obtained crystal form is substantially the same as the XRPD pattern in Example 4, indicating that crystal form B is obtained.

Example 9: Preparation of Form B by high temperature volatilization method

Weigh 10 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of water, mix well, and dissolve. Slowly evaporate at 50° C. until solid precipitates, and collect the solid. The XRPD pattern of the obtained crystal form is substantially the same as the XRPD pattern in Example 4, indicating that crystal form B is obtained.

Example 10: Preparation of Form B by Cooling Method

25 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 10 mL glass vial, 3 mL of water was added, and the mixture was heated to 70° C. under stirring until it was completely dissolved, and then cooled to 4° C. until a solid precipitated, and the solid was collected by filtration and dried. The XRPD pattern of the obtained crystalline form was substantially the same as that in Example 4, indicating that crystalline form B was obtained.

Example 11: Preparation of Form B by gas-liquid permeation method

5 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a small glass bottle containing 2 mL of chloroform (good solvent). Subsequently, the small glass bottle was placed in a large glass bottle containing 4 mL of n-hexane (anti-solvent), and the large glass bottle was sealed. The precipitated solid was filtered, collected and dried to obtain a solid. The XRPD pattern of the obtained solid was substantially the same as that of Example 4, indicating that Form B was obtained.

Example 12: Preparation of Form C by single solvent suspension stirring method at room temperature

Weigh 20 mg of the compound of formula (I) prepared in Example 1 and add it to a 3 mL glass vial. Add 1 mL of acetone and stir the resulting suspension magnetically (500 rpm) at 25 °C for about 24 h. Filter the suspension and dry the solid portion in a vacuum drying oven for 10 min. This crystalline form is referred to as crystalline form C.

The obtained crystal form C was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in FIG4a , and the positions of its characteristic peaks are shown in the following table:

2θ(°) strength% 10.8 48 12.7 32 13.6 10 14.0 32 14.3 75 15.6 25 16.5 18

16.9 80 18.0 83 18.5 100 20.0 28 21.9 11 22.4 11 23.2 17 24.0 25 24.8 41 25.0 10 25.3 37 25.6 8 25.9 13 26.5 twenty four 27.0 9 27.4 7 28.4 17 29.3 10 29.5 12 33.2 11 34.6 7 35.2 13 35.5 11 36.2 6 36.5 6 37.4 11 37.9 7 39.2 7 39.6 6

The obtained crystal form C was subjected to TGA analysis, and the obtained spectrum is shown in Figure 4b. From the analysis, it can be seen that the crystal form does not contain a crystallization solvent, decomposes at about 200°C, and has no crystal transformation before melting.

The obtained crystal form C was subjected to DSC analysis, and the obtained spectrum is shown in Figure 4c. From this analysis, it can be seen that the melting point of the crystal form C is about 197°C.

Example 13: Preparation of Form C by high temperature single solvent suspension stirring method

20 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 3 mL glass vial, 1 mL of acetone was added, and the resulting suspension was magnetically stirred (500 rpm) at 50° C. for about 24 h, the suspension was filtered, and the solid portion was dried in a vacuum drying oven for 10 min. The XRPD pattern of the obtained crystalline form was substantially the same as that in Example 12, indicating that crystalline form C was obtained.

Example 14: Preparation of Form C by high temperature mixed solvent suspension stirring method

20 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 3 mL glass vial, 1 mL of a mixture of chloroform and isoamyl alcohol (volume ratio 1:1) was added, the resulting suspension was magnetically stirred (500 rpm) at 50° C. for about 24 h, the suspension was filtered, and the solid portion was dried in a vacuum drying oven for 10 min. The XRPD pattern of the obtained crystal form was substantially the same as that in Example 12, indicating that crystal form C was obtained.

Example 15: Preparation of Form D by single solvent suspension stirring method at room temperature

Weigh 20 mg of the compound of formula (I) prepared in Example 1 and add it to a 3 mL glass vial. Add 1 mL of isoamyl alcohol and stir the resulting suspension magnetically (500 rpm) at 25 °C for about 24 h. Filter the suspension and dry the solid portion in a vacuum drying oven for 10 min. This crystalline form is referred to as Form D.

The obtained crystal form D was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in FIG5a , and the positions of its characteristic peaks are shown in the following table:

2θ(°) strength% 8.9 42 11.4 32 15.0 11 16.6 13

16.8 3 17.2 6 17.6 4 18.0 4 18.6 100 19.2 3 19.5 10 19.9 7 20.5 3 21.2 7 22.5 7 22.7 2 24.5 17 24.6 12 25.1 4 25.7 11 25.9 3 26.4 6 27.1 14 27.8 6 28.6 7 31.0 2 32.8 2 33.1 6 34.1 2 35.6 3 35.9 2 36.5 3 37.5 3

The obtained crystal form D was subjected to TGA analysis, and the obtained spectrum is shown in Figure 5b. From the analysis, it can be seen that the weight loss at 135°C is 4.84%.

The obtained crystal form D was subjected to DSC analysis, and the obtained spectrum is shown in Figure 5c. From the analysis, it can be seen that the crystal form begins to slowly dehydrate at about 60°C and decomposes at about 170°C.

Example 16: Preparation of Form D by mixed solvent suspension stirring at room temperature

20 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a 3 mL glass vial, 1 mL of a mixture of ethanol and water (volume ratio 7:1) was added, and the resulting suspension was magnetically stirred (500 rpm) at 25° C. for about 24 h, the suspension was filtered, and the solid portion was dried in a vacuum drying oven for 10 min. The XRPD pattern of the obtained crystal form was substantially the same as that in Example 15, indicating that crystal form D was obtained.

Example 17: Preparation of Form D by volatilization and crystallization at room temperature

Weigh 10 mg of the compound of formula (I) prepared in Example 1, add it to a 3 mL glass vial, add 1 mL of a mixture of methyl ethyl ketone and water (volume ratio 1:1), mix well, and dissolve. Slowly evaporate at 25° C. until solid precipitates, and collect the solid. The XRPD pattern of the obtained crystal form is substantially the same as the XRPD pattern in Example 15, indicating that crystal form D is obtained.

Example 18: Preparation of Form D by mixed solvent suspension stirring at room temperature

2.5 kg of the compound of formula (I) was weighed and added to a reactor, 50 L of a mixture of ethanol and water (volume ratio 7:1) was added, and the resulting suspension was mechanically stirred (500 rpm) at 25° C. for about 24 h, the suspension was filtered, and the solid part was dried in a vacuum drying oven for 10 h. The resulting crystalline form (batch number RXXX-238-012-LB4) was measured for moisture content using a moisture meter, and the moisture content was 5.5%.

The obtained crystal form was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in Figure 5a-1, indicating that crystal form D was obtained.

2θ(°) strength% 9.0 43 11.4 100

15.0 twenty two 16.2 12 16.7 twenty four 17.6 20 18.6 81 19.6 25 20.0 16 20.6 14 21.2 40 21.8 17 22.6 31 24.6 38 25.7 twenty two 26.7 20 27.2 31 27.8 13 28.9 28 31.5 17 32.2 10 34.2 8 34.9 10 37.7 9

Example 19: Preparation of Form D by mixed solvent suspension stirring at room temperature

4.5 kg of the compound of formula (I) was weighed and added to a reactor, 90 L of a mixture of ethanol and water (volume ratio 7:1) was added, and the resulting suspension was mechanically stirred (500 rpm) at 25° C. for about 24 h, the suspension was filtered, and the solid part was dried in a vacuum drying oven for 10 h. The resulting crystalline form (batch number RXXX-238-010-LB3) was measured for moisture content using a moisture meter, and the moisture content was 4.9%.

The obtained crystal form was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in Figure 5a-2, indicating that crystal form D was obtained.

Example 20: Preparation of Form D by mixed solvent suspension stirring at room temperature

5.0 kg of the compound of formula (I) was weighed and added to a reactor, 100 L of a mixture of ethanol and water (volume ratio 7:1) was added, and the resulting suspension was mechanically stirred (500 rpm) at 25° C. for about 24 h, the suspension was filtered, and the solid part was dried in a vacuum drying oven for 10 h. The resulting crystalline form (batch number RXXX-238-012-LB3) was measured for moisture content using a moisture meter, and the moisture content was 5.1%.

The obtained crystal form was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in Figure 5a-2, indicating that crystal form D was obtained.

Example 21: Preparation of Form D by mixed solvent suspension stirring at room temperature

2.5 kg of the compound of formula (I) was weighed and added to a reactor, 50 L of a mixture of ethanol and water (volume ratio 7:1) was added, and the resulting suspension was mechanically stirred (500 rpm) at 25° C. for about 24 h, the suspension was filtered, and the solid part was dried in a vacuum drying oven for 10 h. The resulting crystalline form (batch number RXXX-238-010-LB4) was measured for moisture content using a moisture meter, and the moisture content was 5.2%.

The obtained crystal form was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in Figure 5a-2, indicating that crystal form D was obtained.

Example 22: Preparation of Form E by high temperature single solvent suspension stirring method

Weigh 20 mg of the compound of formula (I) prepared in Example 1 and add it to a 3 mL glass vial. Add 1 mL of nitromethane and stir the resulting suspension magnetically (500 rpm) at 50 °C for about 24 h. Filter the suspension and dry the solid portion in a vacuum drying oven for 10 min. This crystalline form is referred to as Form E.

The obtained crystal form E was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in FIG6a , and the positions of its characteristic peaks are shown in the following table:

2θ(°) strength% 9.3 41.2 10.4 12 11.5 8.8 11.9 100 12.6 61

13.2 26.1 13.4 20.7 14.0 8.2 14.4 39.4 15.1 26.5 15.6 29.7 15.9 18.3 16.9 10.6 17.2 56.2 18.1 21.9 18.4 9.2 18.6 10.6 18.9 54.6 19.5 35.1 21.2 25.5 21.6 12.2 22.0 12.4 23.7 16.5 24.3 29.9 24.7 13.7 24.9 42.6 25.2 14.7 26.0 11.2 26.3 27.9 27.0 28.5 27.2 20.5 27.9 10.6 28.1 13.7 28.8 9.2 30.2 9.2 30.6 8.2 31.5 10.6 34.2 10.6 34.5 7.8 35.2 8 35.7 7.2 35.9 6.8 37.6 8.6

The obtained crystal form E was subjected to TGA analysis, and the obtained spectrum is shown in Figure 6b. From this analysis, it can be seen that the crystal form E does not contain a crystallization solvent.

The obtained crystal form E was subjected to DSC analysis, and the obtained spectrum is shown in Figure 6c.

Example 23: Preparation of Form F by high temperature single solvent suspension stirring method

Weigh 20 mg of the compound of formula (I) prepared in Example 1 and add it to a 3 mL glass vial. Add 1 mL of chloroform and stir the resulting suspension magnetically (500 rpm) at 50° C. for about 24 h. Filter the suspension and dry the solid portion in a vacuum drying oven for 10 min. This crystalline form is referred to as Form F.

The obtained crystal form F was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in FIG7a , and the positions of its characteristic peaks are shown in the following table:

2θ(°) strength% 6.4 16 8.6 15 8.9 51

9.2 11 10.8 11 11.3 100 13.6 16 14.8 32 15.2 twenty four 15.7 11 16.1 19 16.4 32 16.9 6 17.0 11 17.8 30 18.4 19 18.6 52 19.1 12 19.4 27 19.9 18 20.6 17 20.8 twenty one 21.1 25 21.3 34 21.8 8 22.5 11 22.7 7 23.4 10 23.9 12 24.6 19 24.8 29 27.4 19 28.1 11 28.7 11 29.3 7 30.1 11 30.6 10 30.9 8 32.6 7 34.1 6 38.2 5 38.6 6

The obtained crystal form F was subjected to TGA analysis, and the obtained spectrum is shown in Figure 7b.

The obtained crystal form F was subjected to DSC analysis, and the obtained spectrum is shown in Figure 7c.

Example 24: Preparation of Form F by mixed solvent suspension stirring at room temperature

20 mg of the compound of formula (I) prepared in Example 1 was stirred with 1 mL of a mixture of methanol and ethanol (volume ratio 1:1) at 25° C. for at least 24 h, and then the suspension was filtered and the solid portion was dried in a vacuum drying oven for 10 min. The XRPD pattern of the obtained crystalline form was substantially the same as that in Example 23, indicating that crystalline form F was obtained.

Example 25: Preparation of Form F by high temperature slow volatilization method

Take 10 mg of the compound of formula (I) prepared in Example 1, add 1 mL of a mixture of isoamyl alcohol and water (volume ratio 1:7), mix and dissolve. Slowly evaporate at 50° C. until solid precipitates, collect the solid, and detect by XRPD. The XRPD spectrum of the obtained crystal form is substantially the same as the XRPD spectrum in Example 23, indicating that crystal form F is obtained.

Example 26: Preparation of Form G

5 mg of the compound of formula (I) prepared in Example 1 was weighed and added to a small glass bottle containing 2 mL of methanol (good solvent). Subsequently, the small glass bottle was placed in a large glass bottle containing 4 mL of ethanol (anti-solvent), and the large glass bottle was sealed. The precipitated solid was filtered, collected and dried to obtain a solid. The solid was called Form G.

The obtained crystal form G was subjected to XRPD analysis, and the obtained XRPD spectrum is shown in FIG8a , and the positions of its characteristic peaks are shown in the following table:

2θ(°) strength% 7.0 18 10.3 9 11.1 3 12.2 100 12.6 25 15.4 14 16.1 13 18.6 3 19.1 6 19.6 7 19.8 8 20.1 3 20.7 48 21.3 twenty two 21.6 4 22.0 4 23.3 3 24.1 3 25.2 4 26.7 11 27.0 4 27.5 4 27.8 14 28.2 5 28.6 8 31.0 3 33.2 3 33.6 3 33.9 4 36.0 4 37.1 2 37.8 3 38.2 2 38.5 4

The obtained crystal form G was subjected to TGA analysis, and the obtained spectrum is shown in Figure 8b.

The obtained crystal form G was subjected to DSC analysis, and the obtained spectrum is shown in Figure 8c.

Example 27: Preparation and Single Crystal Structure of Form H

Take 5 mg of the compound of formula (I) prepared in Example 1 and add it to a small glass bottle containing 2 mL of methanol solvent (good solvent). Subsequently, the small glass bottle is placed in a large glass bottle containing 4 mL of methyl ethyl ketone solution (anti-solvent), and the large glass bottle is sealed. The precipitated solid is filtered and collected, and the crystal form is called crystal form H, and the XRPD spectrum is shown in Figure 9a. Crystal form H is a single crystal structure, the single crystal parameters are shown in the following table, and the stereoscopic structure is shown in Figure 9b.

Example 28: Preparation and Single Crystal Structure of Form I

Take 10 mg of the compound of formula (I) prepared in Example 1, add it to 3 mL of water, and heat it to 70° C. while stirring. Filter the solution while hot, and then cool it to 4° C. until solid precipitates. After the solid precipitates, filter and collect it, dry the solid, and the crystal form is called crystal form I. The XRPD spectrum is shown in Figure 10a. Crystal form I is a single crystal structure, the single crystal parameters are shown in the following table, and the stereoscopic structure is shown in Figure 10b.

Basic information of single crystal H and I

Test Case

Test Example 1: Stability Test

Equal weights of amorphous form, crystalline forms A, B, C, D and E of the compound of formula (I) were weighed and placed into a double-layer medicinal low-density polyethylene bag, and then placed in a constant temperature and humidity chamber at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. After 15 days, the bags were taken out for X-ray powder diffraction (XRPD) analysis. The results are shown in Figures 11a-11f.

The experimental results show that the XRPD peaks of Form B, Form D and Form E of the compound of formula (I) remain essentially unchanged when placed at 40°C ± 2°C and 75% ± 5% RH for 15 days, indicating that the crystal forms are stable.

Test Example 2: Moisture absorption test

A dynamic water sorption instrument (DVS) was used to examine the adsorption and desorption of water by the crystal form in the present application at a temperature of 25°C and a relative humidity of 0 to 95%. The evaluation was conducted according to the hygroscopic characteristics description and hygroscopic weight gain evaluation criteria in the "9103 Drug Hygroscopicity Guidelines" in the fourth volume of the 2015 edition of the Chinese Pharmacopoeia. After the hygroscopicity test, the crystal form was analyzed by XRPD again to determine whether the crystal form has changed.

deliquescence Absorb enough water to form a liquid Highly hygroscopic The weight gain due to moisture absorption is not less than 15% Hygroscopic The weight gain due to moisture absorption is less than 15% but not less than 2% Slightly hygroscopic The weight gain due to moisture absorption is less than 2% but not less than 0.2% No or almost no hygroscopicity The weight gain due to moisture absorption is less than 0.2%

Table 1 Summary of water adsorption and desorption experimental results

Test Example 3: High Temperature Experiment

An appropriate amount of the crystal form D of the compound of formula (I) was weighed as a sample to be tested, and a high temperature experiment was performed under the following high temperature conditions. The results showed that the crystal form D of the compound of formula (I) had good high temperature resistance (thermal stability) under high temperature conditions.

(1) Place the mixture under high temperature conditions (60° C., open) for 30 days, take samples at 5 days, 10 days, and 30 days, observe changes in sample properties, and detect impurities, moisture, crystal form, and the content of the compound of formula (I).

Experimental results: The appearance, XRPD and infrared detection results at each time point were consistent with the results on day 0; neither known impurities nor unknown impurities were detected in the related substances; the content detection results fluctuated within the range of 99.0% to 100.6%; the moisture detection results fluctuated within the range of 5.5% to 5.6%.

(2) Place the mixture under high temperature conditions (60°C, with packaging materials, inner packaging is a medicinal low-density polyethylene bag heat-sealed, and outer packaging is a polyester/aluminum/polyethylene medicinal composite film heat-sealed) for 30 days, and take samples at 5 days, 10 days, and 30 days, respectively, to observe changes in sample properties and detect impurities, moisture, crystal form, and the content of the compound of formula (I).

Experimental results: The appearance, XRPD and infrared detection results at each time point were consistent with the results on day 0; neither known impurities nor unknown impurities were detected in the related substances; the content detection results fluctuated within the range of 100.2% to 101.7%; the moisture detection results fluctuated within the range of 5.4% to 5.6%.

Test Example 4: High Humidity Test

An appropriate amount of the crystal form D of the compound of formula (I) was weighed as a sample to be tested, and a high humidity test was performed under the following high humidity conditions. The results showed that the crystal form D of the compound of formula (I) had good high humidity resistance under high temperature conditions.

(1) Place under high humidity conditions (92.5% RH, open) for 30 days, take samples at 5 days, 10 days and 30 days, observe changes in sample properties, and detect impurities, moisture, crystal form and the content of the compound of formula (I).

Experimental results: The appearance, XRPD and infrared test results at each time point were consistent with the results on day 0. No known impurities or unknown impurities were detected in the relevant substances. The content test results fluctuated between 100.6% and 101.9%. The moisture test results fluctuated between 5.5% and 5.7%.

(2) Place the mixture under high humidity conditions (92.5% RH, with packaging materials, inner packaging is a medicinal low-density polyethylene bag heat-sealed, and outer packaging is a polyester/aluminum/polyethylene medicinal composite film heat-sealed) for 30 days, and take samples at 5 days, 10 days, and 30 days, respectively, to observe changes in sample properties and detect impurities, moisture, crystal form, and the content of the compound of formula (I).

Experimental results: The appearance, XRPD and infrared test results at each time point were consistent with the results on day 0. No known impurities or unknown impurities were detected in the relevant substances. The content test results fluctuated within the range of 100.6% to 101.6%. The moisture test results fluctuated within the range of 5.6%.

Test Example 5: Lighting Experiment

An appropriate amount of the crystal form D of the compound of formula (I) is weighed as a sample to be tested, and an illumination experiment is carried out under the following illumination conditions, wherein the total illumination is not less than 2×10 6 Lux·hr, and the near-ultraviolet energy is not less than 200 w·hr/m 2 .

(1) Place under illumination conditions (strong white light + ultraviolet light, open) for 30 days, take samples at 5 days, 10 days, and 30 days, observe changes in sample properties, and detect impurities, moisture, crystal form, and the content of the compound of formula (I).

Experimental results: The appearance, XRPD and infrared test results at each time point were consistent with the results on day 0. No known impurities or unknown impurities were detected in the relevant substances. The content test results fluctuated within the range of 100.1% to 101.6%. The moisture test results fluctuated within the range of 5.5% to 5.6%.

(2) Place the mixture under illumination conditions (strong white light + ultraviolet light, inner packaging material: the inner packaging is a medicinal low-density polyethylene bag sealed with heat plastic) for 30 days, take samples at 5 days, 10 days, and 30 days, observe changes in sample properties, and detect impurities, moisture, crystal form, and the content of the compound of formula (I).

Experimental results: The appearance, XRPD and infrared test results at each time point were consistent with the results on day 0. No known impurities or unknown impurities were detected in the relevant substances. The content test results fluctuated between 100.3% and 101.6%. The moisture test results fluctuated between 5.4% and 5.6%.

(3) Place the mixture under illumination conditions (strong white light + ultraviolet light, inner and outer packaging materials: inner packaging is a medicinal low-density polyethylene bag sealed by heat plastic, and outer packaging is a polyester/aluminum/polyethylene medicinal composite film sealed by heat plastic) for 30 days, and take samples at 5 days, 10 days, and 30 days, respectively, to observe changes in sample properties, and to detect impurities, moisture, crystal form, and the content of the compound of formula (I).

Experimental results: The appearance, XRPD and infrared test results at each time point were consistent with the results on day 0. No known impurities or unknown impurities were detected in the relevant substances. The content test results fluctuated between 100.5% and 101.4%. The moisture test results fluctuated between 5.4% and 5.6%.

The results show that the crystal form D of the compound of formula (I) has good photostability under illumination conditions, which can ensure that the crystal form D will not produce photosensitivity reactions due to exposure to sunlight during storage, transportation and administration, and does not require special packaging treatment to prevent the influence of light, thereby ensuring the safety of the drug and the effectiveness of long-term storage, while reducing costs.

In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims (19)

Crystalline Form A of the compound of formula (I): The XRPD pattern of the crystalline form A includes characteristic peaks at diffraction angles (2θ) of about 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 18.5±0.2°, 18.8±0.2°, 25.5±0.2° and 26.2±0.2°, preferably includes characteristic peaks at diffraction angles (2θ) of about 11.9±0.2°, 12.3±0.2°, 12.7±0.2°, 17.0±0.2°, 18.5±0.2°, 18.8±0.2°, 21.9±0.2°, 22.6±0.2°, 25.5±0.2°, 26.2±0.2° and 27.0±0.2°, and most preferably includes characteristic peaks at diffraction angles (2θ) of about 11.7±0.2°, 11.9±0.2°, 12.7±0.2°, 17.0±0.2°, 18.5±0.2°, 18.8±0.2°, 21.9±0.2°, 22.6±0.2°, 25.5±0.2°, 26.2±0.2° and 27.0±0.2°. , 12.3±0.2°, 12.7±0.2°, 13.3±0.2°, 14.8±0.2°, 16.0±0.2°, 17.0±0.2°, 17.3±0.2°, 17.5±0.2°, 18.5±0.2°, 18.8±0.2°, 19.6±0.2°, 21.9±0.2°, 22.6±0.2° Characteristic peaks at diffraction angles (2θ) of 2θ: 2.0±0.2°, 23.0±0.2°, 24.9±0.2°, 25.5±0.2°, 26.2±0.2°, 26.4±0.2°, 27.0±0.2°, 28.8±0.2°, 30.3±0.2°, 32.4±0.2°, 34.8±0.2° and 36.8±0.2°. A method for preparing the crystalline form A of the compound of formula (I) according to claim 1, the method being a suspension stirring method, which comprises adding the compound of formula (I) to an organic solvent, stirring at 20-35° C., and then filtering it to obtain the crystalline form A; The organic solvent is nitromethane, or a mixed solvent of nitromethane and other organic solvents; The other organic solvents are alcohols, hydrocarbons, ethers, esters, ketones or halogenated hydrocarbon solvents having 1 to 10 carbon atoms. Crystalline Form B of the compound of formula (I): The XRPD pattern of the crystalline form B includes characteristic peaks at diffraction angles (2θ) of about 6.2±0.2°, 12.5±0.2°, 16.0±0.2°, 18.8±0.2°, 24.1±0.2°, 24.8±0.2° and 26.5±0.2°, preferably includes characteristic peaks at diffraction angles (2θ) of about 6.2±0.2°, 10.1±0.2°, 12.0±0.2°, 12.5±0.2°, 14.8±0.2°, 15.5±0.2°, 16.0±0.2°, 17. The diffraction angles (2θ) of Figure 2 are as follows: peaks at 4±0.2°, 17.6±0.2°, 18.8±0.2°, 20.3±0.2°, 21.3±0.2°, 24.1±0.2°, 24.8±0.2°, 25.0±0.2°, 25.8±0.2°, 26.5±0.2°, 28.2±0.2°, 28.3±0.2°, 28.6±0.2°, 29.1±0.2°, 29.7±0.2°, 30.6±0.2° and 32.7±0.2° diffraction angles (2θ). A method for preparing the crystalline form B of the compound of formula (I) according to claim 3, wherein the method is selected from: a suspension stirring method, a volatilization method, a cooling method and a gas-liquid permeation method; wherein: The suspension stirring method comprises adding the compound of formula (I) to a solvent, stirring at 20-80° C., and then filtering it to obtain Form B; wherein the solvent is selected from water, an alcohol solvent having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), an ether solvent (such as ether, etc.), a ketone solvent (such as acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), an aromatic hydrocarbon solvent (such as toluene, etc.), a halogenated hydrocarbon solvent (such as chloroform, etc.), or a mixed solvent thereof; The volatilization method comprises adding the compound of formula (I) to a solvent, mixing and dissolving; volatilizing at 20°C to 60°C until solid precipitates, and filtering to collect the solid; wherein the solvent is water or a mixed solvent of methanol and water; The cooling method comprises adding the compound of formula (I) to a solvent (preferably water), heating to completely dissolve the compound, cooling to crystallize, and filtering to collect the solid; The gas-liquid permeation method comprises dissolving the compound of formula (I) in a good solvent in a first container, charging an anti-solvent into a second container, placing the first container open in the second container, sealing the second container and allowing it to stand, filtering the precipitated solid to obtain crystals; wherein the good solvent is a halogenated hydrocarbon solvent having 1 to 10 carbon atoms, such as chloroform; and the anti-solvent is a hydrocarbon solvent having 5 to 10 carbon atoms, such as n-hexane, n-heptane, and petroleum ether. Crystalline Form C of the compound of formula (I): The XRPD pattern of the crystalline form C includes characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 14.3±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 24.8±0.2° and 25.3±0.2°, preferably includes characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 12.7±0.2°, 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 20.0±0.2°, 24.0±0.2°, 24.8±0.2°, 25.3±0.2° and 26.5±0.2°. The invention relates to a diffraction angle (2θ) of at least one embodiment of the present invention, and most preferably includes characteristic peaks at diffraction angles (2θ) of about 10.8±0.2°, 12.7±0.2°, 14.0±0.2°, 14.3±0.2°, 15.6±0.2°, 16.5±0.2°, 16.9±0.2°, 18.0±0.2°, 18.5±0.2°, 20.0±0.2°, 21.9±0.2°, 22.4±0.2°, 23.2±0.2°, 24.0±0.2°, 24.8±0.2°, 25.3±0.2°, 25.9±0.2°, 26.5±0.2°, 28.4±0.2°, 29.5±0.2° and 35.2±0.2°. A method for preparing Form C of the compound of formula (I) of claim 5, the method being a suspension stirring method, which comprises adding the compound of formula (I) to a solvent, stirring at 20-60° C., and then filtering it to obtain crystals; wherein the solvent is a ketone solvent having 1-10 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), a nitrile solvent (e.g., acetonitrile, etc.), an ester solvent (e.g., ethyl acetate, isopropyl acetate, etc.), an ether solvent (e.g., methyl tert-butyl ether, ethyl ether, tetrahydrofuran, etc.), an alcohol solvent (e.g., methanol, ethanol, isoamyl alcohol, etc.), a halogenated hydrocarbon solvent (e.g., dichloromethane or chloroform), or a mixed solvent thereof. Crystalline form D of the compound of formula (I): The XRPD spectrum of the crystalline form D includes characteristic peaks at diffraction angles (2θ) of about 9.0±0.2°, 11.4±0.2°, 16.7±0.2°, 18.6±0.2°, 24.6±0.2°, 25.7±0.2° and 27.2±0.2°, preferably includes characteristic peaks at diffraction angles (2θ) of about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, The characteristic peaks at diffraction angles (2θ) of about 16.7±0.2°, 18.6±0.2°, 19.6±0.2°, 24.6±0.2°, 25.7±0.2° and 27.2±0.2°, more preferably including characteristic peaks at diffraction angles (2θ) of about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, ... The characteristic peaks at diffraction angles (2θ) of about 0.2°, 21.2±0.2°, 22.6±0.2°, 24.6±0.2°, 25.7±0.2°, 27.2±0.2° and 28.9±0.2° are most preferably included at about 9.0±0.2°, 11.4±0.2°, 15.0±0.2°, 16.7±0.2°, 17.6±0.2° , characteristic peaks at diffraction angles (2θ) of 18.6±0.2°, 19.6±0.2°, 20.0±0.2°, 21.2±0.2°, 21.8±0.2°, 22.6±0.2°, 24.6±0.2°, 25.7±0.2°, 26.7±0.2°, 27.2±0.2°, 28.9±0.2° and 31.5±0.2°. The crystalline form D of the compound of formula (I) according to claim 7, wherein the crystalline form D of the compound of formula (I) is a hydrate with a water content of 4.8%-5.7%. The crystalline form D of the compound of formula (I) according to claim 7 or 8, wherein the crystalline form D of the compound of formula (I) is a sesquihydrate. A method for preparing the crystalline form D of the compound of formula (I) according to any one of claims 7 to 9, the method being selected from: a suspension stirring method and a volatilization method; wherein The suspension stirring method comprises adding the compound of formula (I) to a solvent, stirring at 20-80° C., and then filtering it to obtain Form D; wherein the solvent is selected from water, an alcohol solvent having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isopentanol, etc.), a halogenated hydrocarbon solvent (such as chloroform, etc.), or a mixed solvent thereof; The volatilization method comprises adding the compound of formula (I) to a solvent, mixing and dissolving; volatilizing at 20° C. to 60° C. until solid precipitates, and filtering to collect the solid; wherein the solvent is selected from water and a ketone solvent having 1 to 10 carbon atoms (such as acetone or methyl ethyl ketone, etc.), or a mixed solvent thereof. Crystalline Form E of the compound of formula (I): The XRPD spectrum of the crystalline form E includes characteristic peaks at diffraction angles (2θ) of about 9.3±0.2°, 11.9±0.2°, 12.6±0.2°, 14.4±0.2°, 17.2±0.2°, 18.9±0.2° and 24.9±0.2°, preferably includes characteristic peaks at diffraction angles (2θ) of about 9.3±0.2°, 11.9±0.2°, 12.6±0.2°, 13.2±0.2°, The characteristic peaks at diffraction angles (2θ) of 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 17.2±0.2°, 18.1±0.2°, 18.9±0.2°, 19.5±0.2°, 21.2±0.2°, 23.7±0.2°, 24.3±0.2°, 24.9±0.2°, 26.3±0.2° and 27.0±0.2° are the most Preferably, the above range includes about 9.3±0.2°, 10.4±0.2°, 11.9±0.2°, 12.6±0.2°, 13.2±0.2°, 14.4±0.2°, 15.1±0.2°, 15.6±0.2°, 16.9±0.2°, 17.2±0.2°, 18.1±0.2°, 18.6±0.2°, 18.9±0.2°, 19.5±0.2°. , characteristic peaks at diffraction angles (2θ) of 21.2±0.2°, 21.6±0.2°, 22.0±0.2°, 23.7±0.2°, 24.3±0.2°, 24.9±0.2°, 25.2±0.2°, 26.0±0.2°, 26.3±0.2°, 27.0±0.2°, 28.1±0.2°, 31.5±0.2° and 34.2±0.2°. A method for preparing the crystalline form E of the compound of formula (I) according to claim 11, the method being a suspension stirring method, which comprises adding the compound of formula (I) to an organic solvent, stirring at 40-60° C., and then filtering it to obtain the crystalline form E; wherein the organic solvent is selected from nitromethane, or a mixed solvent of nitromethane and other organic solvents; The other organic solvents are alcohols, ethers, esters, ketones or halogenated hydrocarbon solvents having 1 to 10 carbon atoms. Crystalline Form F of the compound of formula (I): The XRPD pattern of the crystalline form F includes characteristic peaks at diffraction angles (2θ) of about 8.9±0.2°, 11.3±0.2°, 14.8±0.2°, 15.2±0.2°, 16.1±0.2°, 16.4±0.2°, 17.8±0.2°, 18.6±0.2°, 19.4±0.2°, 20.8±0.2°, 21.3±0.2°, 24.8±0.2° and 27.4±0.2°, preferably includes characteristic peaks at diffraction angles (2θ) of about 6.4±0.2°, 8.9±0.2°, 10.8±0.2°, 11.3±0.2°, 13.6±0.2°, 14.8±0.2°, Peaks at diffraction angles (2θ) of 15.2±0.2°, 15.7±0.2°, 16.1±0.2°, 16.4±0.2°, 17.0±0.2°, 17.8±0.2°, 18.6±0.2°, 19.4±0.2°, 19.9±0.2°, 20.8±0.2°, 21.3±0.2°, 21.8±0.2°, 22.5±0.2°, 23.4±0.2°, 23.9±0.2°, 24.8±0.2°, 27.4±0.2°, 28.1±0.2°, 28.7±0.2°, 30.1±0.2° and 32.6±0.2°. A method for preparing the crystalline form F of the compound of formula (I) according to claim 13, wherein the method is selected from: a suspension stirring method and a volatilization method; wherein: The suspension stirring method comprises adding the compound of formula (I) to a solvent, stirring at 20-80° C., and then filtering it to obtain Form F; wherein the solvent is selected from water, an alcohol solvent having 1-10 carbon atoms (such as methanol, ethanol, isopropanol, isoamyl alcohol, etc.), an ether solvent (such as ether, etc.), a ketone solvent (such as methyl ethyl ketone, methyl isobutyl ketone, etc.), an aromatic hydrocarbon solvent (such as toluene, etc.), a halogenated hydrocarbon solvent (such as chloroform, etc.), or a mixed solvent thereof; The volatilization method comprises adding the compound of formula (I) into a solvent, mixing and dissolving; volatilizing at 20° C. to 60° C. until solid precipitates, and filtering to collect the solid; wherein the solvent is a mixed solvent of isoamyl alcohol and water. Crystalline Form G of the compound of formula (I): The XRPD pattern of the crystalline form G includes characteristic peaks at diffraction angles (2θ) of about 7.0±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2°, 20.7±0.2°, 21.3±0.2° and 27.8±0.2°, preferably includes peaks at diffraction angles (2θ) of about 7.0±0.2°, 10.3±0.2°, 12.2±0.2°, 12.6±0.2°, 15.4±0.2°, 16.1±0.2°, 19.1±0.2°, 19.6±0.2°, 20.7±0.2°, 21.3±0.2°, 26.7±0.2°, 27.8±0.2° and 28.6±0.2°. A method for preparing the crystalline form G of the compound of formula (I) of claim 15, the method being a gas-liquid permeation method, which comprises dissolving the compound of formula (I) in a good solvent in a first container, charging an anti-solvent into a second container, placing the first container open in the second container, sealing the second container and allowing it to stand, and filtering the precipitated solid to obtain crystals; wherein the good solvent is methanol; and the anti-solvent is ethanol. A pharmaceutical composition comprising Form A, Form B, Form C, Form D, Form E, Form F or Form G of a compound of formula (I) according to any one of claims 1, 3, 5, 7-9, 11, 13 and 15, and one or more pharmaceutically acceptable carriers. Use of crystalline form A, form B, form C, form D, form E, form F or form G of a compound of formula (I) according to any one of claims 1, 3, 5, 7-9, 11, 13 and 15 in the preparation of a medicament for preventing or treating vitamin B1 deficiency and metabolic-related disorders, mental illnesses and disorders, diabetes-related complications and/or neurodegenerative diseases. The use of claim 18, wherein the neurodegenerative disease is selected from Alzheimer's disease, vascular dementia and mental disorders, preferably Alzheimer's disease.