Polymorph of a vortioxetine prodrug, preparation method thereof and application thereof

Abstract

The present invention relates to polymorph I of a compound (1) as shown below, its preparation method and application. The polymorph I of the compound (1) obtained in the present invention has good crystal form stability and chemical stability, and can be better used for clinical treatment, #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a crystal form of a vortioxetine prodrug, a preparation method thereof, and an application thereof in the pharmaceutical industry. Background Art

[0002] Major depressive disorder (MDD) is an emotional dysfunction disorder, with a series of depressive symptoms mainly characterized by persistent spontaneous low mood, which causes troubles to the patient's working ability, sleep, study, diet and enjoyment of current happiness. Patients with major depressive disorder will show pessimism, despair, hallucinations and delusions, functional decline, and are accompanied by serious suicidal attempts and even suicidal behaviors. It poses a serious threat to human health and therefore must be highly regarded.

[0003] Vortioxetine is a new drug for the treatment of depression, jointly developed by Lundbeck of Denmark and Takeda of Japan, and was approved by the FDA for marketing on September 30, 2013, with the trade name Brintellix, for the treatment of MDD. The common adverse reactions of vortioxetine are gastrointestinal side effects, such as nausea, constipation and vomiting, which are the main side effects of SSRIs antidepressants. Compared with the placebo group, the incidence of adverse reactions in the 5 mg vortioxetine group was higher for nausea (19.4 vs 9.4%) and diarrhea (11.4 vs 7.0%). With the further increase of the administered dose, the incidence of gastrointestinal side effects also increased ([J]. Pharmacology & therapeutics, 2015, 145: 43-57).

[0004] PCT / CN2020 / 135200 describes a vortioxetine prodrug and its application. Pharmacodynamic experiments showed that the vortioxetine prodrug has good pharmacokinetic properties, including a more gentle release curve of the drug in vivo compared with vortioxetine, a higher exposure in the brain (AUC0-last), a reduction in the exposure of vortioxetine in plasma, an increase in relative bioavailability, and advantages such as improved uptake of vortioxetine, and has the potential to improve the drug efficacy.

[0005] In view of the fact that such vortioxetine prodrugs are modified by long lipophilic side chains and exist in the form of oily liquids, making these compounds unsuitable as drugs. Generally, drugs exist in different physical forms (for example, liquid or different crystalline solids, amorphous, polymorphic, hydrate or solvated forms), which may change the stability, solubility, bioavailability, pharmacokinetics (absorption, distribution, metabolism, excretion, etc.) or bioequivalence of the drug. Therefore, in drug research and development, in-depth study of the crystal form of drug compounds is of great significance for developing drugs suitable for industrial production and having good biological activity. SUMMARY OF THE INVENTION

[0006] Unless otherwise specified, implied from the context, or in accordance with the convention of the prior art, all parts and percentages in this application are based on weight, and the test and characterization methods used are synchronized with the filing date of this application. If the definition of a specific term disclosed in the prior art is inconsistent with any definition provided in this application, the definition of the term provided in this application shall prevail.

[0007] The terms "preferred", "preferably", "more preferably", "even more preferred", etc. in the present invention refer to embodiments of the present invention that can provide certain beneficial effects in certain cases. However, in the same or other cases, other embodiments may also be preferred. In addition, the description of one or more preferred embodiments does not imply that other embodiments are not available, nor is it intended to exclude other embodiments from the scope of the present invention. "Optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and this description includes the cases where the event or circumstance occurs or does not occur. The sources of components not mentioned in the present invention are all commercially available.

[0008] Drug active ingredients exhibit different physical properties according to their respective solid forms. These differences in physical properties can affect, for example, the manufacturing method or administration method of the drug active ingredient, as well as the formulation, etc. Generally, the physical properties can be changed by using salts or crystalline solids.

[0009] Patent PCT / CN2020 / 135200 discloses that the compound (1), also known as 1-(dodecanoyloxy)ethyl 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carboxylate, is an amorphous substance. When used as a drug active ingredient or its raw material, its own purity, stability, etc. do not meet the requirements. Therefore, it is desired to develop a crystalline solid of compound (1) with good crystal form stability and chemical stability, which can be better applied clinically.

[0010]

[0011] The so-called "crystalline solid" adopted in this specification means a crystal having a certain crystal form and formed by the regular arrangement of atoms, ions, molecules, etc. that make up the solid. Unless otherwise specified, "crystallization", "crystalline solid" or "crystal form" in this specification are synonymous. The crystallinity of the crystal form can be measured by various techniques such as X-ray powder diffraction measurement, moisture adsorption and desorption measurement, differential scanning calorimetry, solution colorimetry, solubility characteristics, etc.

[0012] The crystalline solid of the present invention can be a single crystal, twin crystal, polycrystal, etc., and is usually mostly a single crystal or a mixed crystal thereof. There is no particular limitation on the crystal form (outer shape), for example, it can be triclinic, monoclinic, orthorhombic (rectangular crystal), tetragonal, cubic, trigonal (rhombohedral crystal), hexagonal, etc., or it can be spherulite, skeletal crystal, bark-like crystal, needle crystal (such as whisker crystal), etc. There is no particular limitation on the crystal size. For example, based on the laser diffraction method, the average particle size of the crystal can be 0.5 μm to 1 mm, preferably about 1 to 500 μm.

[0013] In addition, the crystalline solid of compound (1) can also adsorb moisture due to the change in relative humidity, that is, the water molecules in the air can easily enter and exit the crystalline solid in the lattice in the form of crystal water due to the change in external humidity; for such a crystalline solid, when the X-ray powder diffraction pattern shows several changes with the change in moisture content, as long as it has the characteristic peaks described in this specification, it can be interpreted as substantially the same crystalline solid. This moisture can be any one of crystal water, adsorbed water, and other residual solvents.

[0014] <Polymorph I of compound (1)>

[0015] Through the screening of the crystalline solid of compound (1) by the present inventors, polymorph I of compound (1) is preferably selected; more preferably, it is characterized by the characteristic peaks in the powder X-ray powder diffraction spectrum.

[0016] It should be understood here that these characteristic peaks can be one gentle peak (broad peak shape), can be about 2 to 5 multiple peaks (multiple peak shapes such as double peak shape, triple peak shape, quadruple peak shape, quintuple peak shape, etc.), and usually mostly one steep peak.

[0017] As the preferred polymorph I of compound (1) of the present invention, an X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is obtained using Cu-Kα radiation.

[0018] The "2θ or 2θ angle" mentioned refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of 2θ of each characteristic peak in the X-ray powder diffraction pattern can be ±0.3, ±0.2, ±0.1, preferably ±0.2.

[0019] In a preferred embodiment, the X-ray powder diffraction pattern of polymorph I of compound (1) shows characteristic peaks at 4.58° ± 0.2°, 6.48° ± 0.2°, 9.10° ± 0.2°, 12.31° ± 0.2°, 13.89° ± 0.2°, 14.97° ± 0.2°.

[0020] In a preferred embodiment, the X-ray powder diffraction pattern of Form I of the compound (1) shows characteristic peaks at angles selected from 4.58° ± 0.2°, 6.48° ± 0.2°, 9.10° ± 0.2°, 12.31° ± 0.2°, 13.89° ± 0.2°, 14.97° ± 0.2°, 16.17° ± 0.2°, 18.29° ± 0.2°, 19.04° ± 0.2°, 20.14° ± 0.2°, 21.72° ± 0.2°.

[0021] In a preferred embodiment, the X-ray powder diffraction pattern of Form I of the compound (1) shows characteristic peaks at 4.58° ± 0.2°, 6.48° ± 0.2°, 9.10° ± 0.2°, 11.0° ± 0.2°, 12.31° ± 0.2°, 13.89° ± 0.2°, 14.97° ± 0.2°, 16.17° ± 0.2°, 17.74° ± 0.2°, 18.29° ± 0.2°, 19.04° ± 0.2°, 20.14° ± 0.2°, 21.72° ± 0.2°, 22.98° ± 0.2°, 24.29° ± 0.2°.

[0022] In a preferred embodiment, the X-ray powder diffraction pattern of Form I of the compound (1) shows characteristic peaks at 4.58° ± 0.2°, 6.48° ± 0.2°, 9.10° ± 0.2°, 11.0° ± 0.2°, 12.31° ± 0.2°, 13.89° ± 0.2°, 14.97° ± 0.2°, 16.17° ± 0.2°, 17.74° ± 0.2°, 18.29° ± 0.2°, 19.04° ± 0.2°, 20.14° ± 0.2°, 21.72° ± 0.2°, 22.98° ± 0.2°, 24.29° ± 0.2°, 27.51° ± 0.2°.

[0023] In a preferred embodiment, the X-ray powder diffraction pattern of Form I of the compound (1) expressed in terms of diffraction angle 2θ is substantially as Figure 1 shown.

[0024] In a preferred embodiment, the diffraction angle 2θ ± 0.2° of the X-ray powder diffraction of Form I of the compound (1), its corresponding d value, and relative peak intensity are shown in Table 1:

[0025] Table 1

[0026]

[0027] The absolute and relative intensities of the peaks shown in the foregoing tables and figures may vary due to various factors, such as the effect of the preferred orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed, or the crystallinity of the sample. Additionally, the peak positions may also shift according to changes in the sample height. Furthermore, if measurements are made using different wavelengths, different displacement values are obtained according to Bragg's law (nλ = 2dsinθ), and such different XRPD patterns obtained by using different wavelengths are also included within the scope of the present invention.

[0028] In addition to the determination of crystalline form I of compound (1) by X-ray powder diffraction spectroscopy as described above, it can also be determined by thermal analysis methods, such as including but not limited to DSC, TG / DTA, Raman.

[0029] DSC (Differential Scanning Calorimetry) is one of the main measurement methods in thermal analysis, which measures the thermal properties of substances as aggregates of atoms and molecules. By DSC, the heat change of the drug active ingredient with temperature or time is measured, and a differential scanning heat curve is obtained, from which information related to the onset temperature of melting of the drug active ingredient, the maximum value of the endothermic peak curve accompanying melting, and the enthalpy can be obtained.

[0030] TG / DTA (Thermogravimetry-Differential Thermal Analysis) is one of the main measurement methods in thermal analysis, which measures the weight and thermal properties of substances as aggregates of atoms and molecules. TG / DTA is a method for measuring the weight and heat changes of the drug active ingredient with temperature or time, and through this method, information on the weight and heat changes related to the decomposition, dehydration, oxidation, reduction, sublimation, and evaporation of the drug active ingredient can be obtained.

[0031] Raman spectroscopy shows the vibrational characteristics of molecules or composite systems. Generally, the absorption bands (cm -1 ) in Raman spectroscopy may have an error within the range of ±2 cm -1 . Therefore, the values of the above absorption peaks should be understood to also include values within the range of about ±2 cm -1 . Thus, not only crystals with exactly the same absorption band peaks in Raman spectroscopy, but also crystals with absorption band peaks that are consistent within an error range of about ±2 cm -1 are included within the scope of the present invention.

[0032] In a preferred embodiment, the melting endothermic peak value of DSC of crystalline form I of the compound (1) is between 40 and 60 °C, more preferably between 43.5 and 57.1 °C, and most preferably 49.6 °C. Further preferably, the DSC spectrum thereof is substantially as Figure 2 shown.

[0033] In a preferred embodiment, there is no obvious weight loss for the crystalline form I of the compound (1) at 25 to 200 °C, and more preferably no obvious weight loss at 30 to 200 °C. Further preferably, its TGA spectrum is substantially as Figure 3 shown.

[0034] In a preferred embodiment, the Raman spectrum of the crystalline form I of the compound (1) shows characteristic peaks at 553 ± 2 cm -1 , 724 ± 2 cm -1 , 1037 ± 2 cm -1 , 1063 ± 2 cm -1 , 1129 ± 2 cm -1 , 1158 ± 2 cm -1 , 1235 ± 2 cm -1 , 1442 ± 2 cm -1 , 1581 ± 2 cm -1 .

[0035] In a preferred embodiment, the crystalline form I of the compound (1) optionally conforms to one or more of the following characteristics:

[0036] (1) Substantially conforms to the Figure 1 shown powder X-ray diffraction pattern;

[0037] (2) Substantially conforms to the Figure 2 shown DSC spectrum;

[0038] (3) Substantially conforms to the Figure 3 shown TGA spectrum;

[0039] (4) Substantially conforms to the Figure 4 shown Raman spectrum.

[0040] <Preparation Method>

[0041] The crystalline solid of the compound (1) of the present invention is mostly obtained by dissolving the compound (1) in a crystallization solvent to make it supersaturated and then crystallizing (or precipitating) the compound (1).

[0042] The present invention has no particular limitation on the crystallization method. For example, it can include: solvent evaporation method (a method of evaporating the crystallization solvent from the crystallization system), gas diffusion method (a method of volatilizing the crystallization solvent into the compound (1)), cooling method (a method of cooling the crystallization system (or the solution of the compound (1))), solvent volatilization method (a method of volatilizing the crystallization solvent from the crystallization system); poor solvent addition method (a method of adding a poor solvent of the compound (1) to the crystallization system), seed addition method (a method of adding seeds containing the compound (1) to the crystallization system), etc.

[0043] Specifically, the evaporation method: a method of forming a supersaturated state by evaporating the crystallization solvent from a crystallization system (or solution) containing compound (1) and the crystallization solvent, and performing crystallization from this supersaturated state; the gas-phase diffusion method: a method of forming a supersaturated state by volatilizing a poor solvent into a crystallization system containing compound (1) and the crystallization solvent, and performing crystallization from this supersaturated state; the solvent evaporation method: a method of forming a supersaturated state by volatilizing the crystallization solvent from a crystallization system (or solution) containing compound (1) and the crystallization solvent, and performing crystallization from this supersaturated state; the cooling method: a method of forming a supersaturated state by cooling a crystallization system (or solution) containing compound (1) and the crystallization solvent, and performing crystallization from this supersaturated state; the poor solvent addition method: a method of adding a poor solvent to a system containing compound (1) and a good solvent to obtain a crystallization system containing compound (1) and the crystallization solvent, thereby forming a supersaturated state, and performing crystallization from this supersaturated state; the seed addition method: a method of performing crystallization by adding seeds after obtaining the seeds and dissolving compound (1) in the crystallization solvent; by these methods, a crystalline solid of compound (1) can be efficiently prepared.

[0044] As the crystallization solvent, for example, it includes but is not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.; C5-6 alkanes such as pentane, hexane, etc.; di-C1-4 linear or branched ethers such as diisopropyl ether; cyclic ethers such as 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.; esters such as ethyl acetate, ethyl formate, methyl acetate, or isopropyl acetate; C2-4 ketones such as acetone, methyl ethyl ketone; amides such as dimethylacetamide, N-methylpyrrolidone; acetonitrile, water, etc. These can be used alone or in combination of multiple kinds. Methanol, ethanol, n-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, water are preferred.

[0045] In the aforementioned crystallization methods, usually the usage amount of the crystallization solvent is quantified based on the sample usage amount. Specifically, with respect to the amount of 1 ml of the crystallization solvent of the present invention, the amount of compound (1) is 1 to 1000 mg, preferably 1 to 400 mg, more preferably 1 to 200 mg.

[0046] The crystallization operation is usually performed once, but in order to improve the purity of the crystalline solid, it can also be repeated multiple times. It can be that the crystallization operation of one crystallization method is repeated multiple times for crystallization, or it can be that different crystallization operations of different crystallization methods are repeated multiple times or performed once for crystallization. The drug crystal form obtained after crystallization is usually refined (separated from the amorphous component) by separation methods such as filtration, centrifugation, etc. In addition, the separated drug component can be further dried.

[0047] For the drying method, the present invention does not impose any restrictions thereon. For example, it can be any one or more of natural drying, ventilation drying, and reduced-pressure drying. When performing reduced-pressure drying, for example, it can be dried under a pressure of about 1 to 100 hPa, preferably about 1 to 40 hPa, such as about 1.5 to 10 hPa or 10 to 35 hPa. The drying temperature can be, for example, room temperature or a higher temperature, preferably about 20 to 80 °C. The drying time can be, for example, 0.5 to 48 h, preferably 0.5 to 24 h.

[0048] In a preferred embodiment, the preparation method of crystalline form I of the compound (1) is selected from:

[0049] Method 1: Dissolve the compound (1) in solvent A, stir and precipitate it under the condition of not higher than 10 °C, and separate and dry the solid; wherein the solvent A is selected from at least one of water, alcohols, nitriles, esters, and cyclic ethers;

[0050] Or Method 2: Dissolve the compound (1) in solvent B, let it stand and volatilize at room temperature, and separate and dry the obtained solid; wherein the solvent B is selected from at least one of water, alcohols, nitriles, esters, and cyclic ethers;

[0051] Or Method 3: Dissolve the compound (1) in a good solvent, then add a poor solvent, cool and precipitate it under the condition of not higher than 10 °C, and then separate and dry the solid; wherein the good solvent is selected from at least one of alcohols and cyclic ethers; the poor solvent is water;

[0052] Or Method 4: Dissolve the compound (1) in solvent C, heat it to form a saturated or nearly saturated solution, then cool the obtained solution to below 10 °C and let it stand, and separate and dry the solid; wherein the solvent C is selected from at least one of alcohols, nitriles, esters, and cyclic ethers;

[0053] Or Method 5: At room temperature, place the container containing the compound (1) in another container containing solvent D, seal it, and take it out after placing it for 0.5 to 48 h; wherein the solvent D is selected from at least one of alcohols, nitriles, esters, and cyclic ethers.

[0054] Method 1

[0055] For Method 1, which is a kind of cooling method, the specific steps include: dissolving compound (1) in solvent A, stirring and precipitating it below 10 °C, separating and drying the solid; wherein the solvent A is selected from at least one of water, alcohols, nitriles, esters, and cyclic ethers; preferably, the solvent A is selected from at least one of water, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; more preferably, the solvent A is selected from at least one of water, methanol, ethanol, n-propanol, isopropanol, acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran; most preferably, the solvent A is selected from at least one of water, methanol, ethanol, isopropanol, and acetonitrile.

[0056] The solvent A can be a single solvent selected from any of the above, or a mixed solvent selected from any 2 or more of the above; when it is a single solvent, preferably, relative to 1 ml of the solvent A, the amount of compound (1) is 1 - 400 mg, preferably 20 - 300 mg; when it is a mixed solvent, preferably, relative to 1 ml of the solvent A, the amount of compound (1) is 1 - 200 mg, preferably 30 - 100 mg.

[0057] As a mixed solvent, it is preferred to mix water and the above-preferred non-aqueous solvents such as methanol, ethanol, n-propanol, isopropanol, acetonitrile, tetrahydrofuran, and 2-methyltetrahydrofuran. The non-aqueous solvent can include any one of these or any 2 or more. If it includes 2 or more non-aqueous solvents, the ratio between various arbitrary solvents in the non-aqueous solvent can be arbitrary. Preferably, the volume ratio of water to the non-aqueous solvent is 50:1 - 1:10, more preferably 20:1 - 1:5.

[0058] In Method 1 of the present invention, the temperature for stirring and precipitating is usually not higher than 10 °C, preferably between 0 and 10 °C.

[0059] Method 2

[0060] For Method 2, which is a solvent evaporation method, the specific steps include: dissolving compound (1) in solvent B, standing at room temperature to evaporate, separating and drying the obtained solid; wherein the solvent B is selected from at least one of water, alcohols, nitriles, esters, and cyclic ethers; preferably, the solvent B is selected from at least one of water, methanol, ethanol, n-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; more preferably, the solvent B is selected from at least one of methanol, ethanol, n-propanol, isopropanol, acetonitrile, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran; most preferably, the solvent B is selected from at least one of methanol, ethanol, n-propanol, acetonitrile, ethyl acetate, and tetrahydrofuran.

[0061] The solvent B can be a single solvent selected from any of the above, or a mixed solvent selected from any 2 or more of the above; when it is a single solvent, preferably, relative to the amount of 1 ml of the solvent B, the amount of the compound (1) is 1 to 100 mg, preferably 1 to 60 mg, more preferably 10 to 40 mg; when it is a mixed solvent, preferably, relative to the amount of 1 ml of the solvent B, the amount of the compound (1) is 1 to 100 mg, preferably 5 to 20 mg.

[0062] As the mixed solvent, preferably C 1-3 of alcohols and the above-preferred non-alcohol solvents such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane are mixed; the non-alcohol solvents can include any one of these or any 2 or more, and if there are 2 or more non-alcohol solvents, the ratio between various arbitrary solvents in the non-alcohol solvents can be arbitrary, preferably C 1-3 the volume ratio of the alcohol and the non-alcohol solvent is 50:1 to 1:20, more preferably 20:1 to 1:10. Among them, C 1-3 of alcohols can include one or more alcohol solvents, and the ratio between the various alcohol solvents can be arbitrary. The C 1-3 of alcohols includes methanol, ethanol, and n-propanol.

[0063] In the second method of the present invention, the room temperature is 20 ± 5 °C.

[0064] Method 3

[0065] For the third method, it is the poor solvent addition method. The specific steps include: dissolving the compound (1) in a good solvent, then adding a poor solvent, cooling and precipitating at a temperature below 10 °C, and then separating and drying the solid; wherein the good solvent is selected from at least one of alcohols and cyclic ethers; the poor solvent is water; preferably, the good solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane; more preferably, the good solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran; most preferably, the good solvent is selected from at least one of methanol, ethanol, n-propanol.

[0066] Preferably, the volume ratio of the good solvent to the poor solvent is 5:1 to 1:5, more preferably 2:1 to 1:2. The good solvent can be a single solvent selected from any of the above, or a mixed solvent selected from any 2 or more of the above; when it is a mixed solvent, the ratio between the mixed solvents can be arbitrary, and its total amount remains the same as that in the case of a single solvent. Preferably, relative to the amount of 1 ml of the good solvent, the amount of the compound (1) is 1 to 100 mg, preferably 10 to 50 mg.

[0067] In the third method of the present invention, the cooling temperature is generally not higher than 10°C, preferably between 0 and 10°C.

[0068] Method 4

[0069] For the fourth method, which is a kind of cooling method, the specific steps include: dissolving compound (1) in solvent C, heating to form a saturated or nearly saturated solution, then cooling the obtained solution to below 10°C and standing, separating and drying the solid; wherein the solvent C is selected from at least one of alcohols, nitriles, esters, and cyclic ethers; preferably the solvent C is selected from at least one of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; more preferably the solvent C is selected from at least one of methanol, ethanol, n-propanol, acetonitrile, ethyl acetate, isopropyl acetate, tetrahydrofuran, and 2-methyltetrahydrofuran; most preferably the solvent C is selected from at least one of methanol, ethanol, and tetrahydrofuran.

[0070] The solvent C can be a single solvent selected from any of the above, or a mixed solvent selected from any 2 or more of the above; when it is a single solvent, preferably relative to 1 ml of the solvent C, the amount of compound (1) is 1 - 400 mg, preferably 50 - 400 mg, more preferably 50 - 300 mg; when it is a mixed solvent, preferably relative to 1 ml of the solvent C, the amount of compound (1) is 1 - 200 mg, preferably 20 - 100 mg.

[0071] As the mixed solvent, preferably mix the alcohol of C 1-3 with the non-alcohol solvents preferably selected above, such as ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; the non-alcohol solvents can include any one of the above or any 2 or more; if it includes 2 or more non-alcohol solvents, the ratio between various solvents in the non-alcohol solvents can be arbitrary, preferably the volume ratio of the alcohol of C 1-3 to the non-alcohol solvent is 50:1 - 1:20, more preferably 20:1 - 5:1. Among them, the alcohol of C 1-3 can include one or more alcohol solvents, and the ratio between the multiple alcohol solvents can be arbitrary, and the alcohol of C 1-3 includes methanol, ethanol, and n-propanol.

[0072] In the fourth method of the present invention, the heating temperature is 30 - 50°C, preferably 35 - 45°C.

[0073] Method 5

[0074] For Method 5, which is the gas diffusion method, the specific steps include: at room temperature, placing a container containing Compound (1) in another container containing Solvent D, sealing it, and taking it out after placing for 0.5 - 48 h; wherein Solvent D is selected from at least one of alcohols, nitriles, esters, and cyclic ethers; preferably, Solvent D is selected from at least one of methanol, ethanol, n-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and water; more preferably, Solvent D is selected from at least one of methanol, ethanol, n-propanol, acetonitrile, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane; most preferably, Solvent D is selected from at least one of methanol, ethanol, n-propanol, ethyl acetate, and acetonitrile.

[0075] Solvent D can be a single solvent selected from any of the above, or a mixed solvent selected from any 2 or more of the above; when it is a mixed solvent, the ratio between the mixed solvents can be arbitrary, and its total amount remains the same as that of the single solvent. Preferably, relative to 1 ml of Solvent D, the amount of Compound (1) is 1 - 100 mg, preferably 5 - 50 mg.

[0076] In Method 5 of the present invention, the placing temperature is room temperature, usually 20 ± 5°C; the placing time is 0.5 - 48 h, preferably 1 - 24 h.

[0077] The crystalline form I of Compound (1) of the present invention can be administered to mammals in its own form, or can be administered in the form of a pharmaceutical composition by mixing the crystalline form with at least one selected from pharmaceutically acceptable carriers, diluents, or excipients.

[0078] When it is used in a pharmaceutical composition, the appropriate formulation depends on the selected administration route. For example, oral preparations may contain carriers, diluents, or excipients such as inorganic salts, organic salts, sugars or sugar alcohols, acids or polymers, etc.; common examples include lactose, stearic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, tartaric acid, citric acid, fumaric acid, etc. Parenteral preparations may contain buffers, dispersants, solubilizing aids, stabilizers, absorption promoters, antioxidants, fragrances, analgesics, suspending agents, side effect inhibitors, activity enhancers, etc.

[0079] The pharmaceutical composition of the present invention can be administered by any oral or parenteral route, and the parenteral routes that can be enumerated include transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, etc.

[0080] For oral administration, any internal solid preparation can be prepared according to conventional methods, such as tablets, powders, granules, capsules, pills, films, etc.; internal liquid preparations such as suspensions, emulsions, elixirs, syrups, lemonade, spirits, aromatic waters, extracts, decoctions, tinctures, etc. Among them, tablets can be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, buccal tablets, sublingual tablets, oral tablets, chewable tablets or orally disintegrating tablets. Powders and granules can be dry syrups, and capsules can be soft capsules, microcapsules or sustained-release capsules.

[0081] For parenteral administration, any injection can be prepared according to conventional methods, such as intravenous injection, intramuscular injection, drip, ampoules for subcutaneous injection, vials, liquids, suspensions, etc.; topical medicaments such as ear drops, nose drops, eye drops, ointments, emulsions, sprays, aerosols, inhalants, suppositories, etc.; external medicaments such as lotions, injections, coatings, gargles, enemas, ointments, plasters, gels, creams, patches, pastes, external powders, suppositories, etc. Among them, the injection can also be an emulsion of the O / W, W / O, O / W / O, W / O / W type, etc.

[0082] The present invention also provides the use of polymorph I of the aforementioned compound (1), or a pharmaceutical composition containing polymorph I of compound (1) in the preparation of a drug for neuropsychiatric diseases, wherein the neuropsychiatric diseases are selected from any one or more of schizophrenia, depression, anxiety, sleep disorders, cognitive disorders, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, addictive diseases, withdrawal syndromes or attention deficits, preferably any one or more of depression, cognitive disorders, anxiety, schizophrenia, sleep disorders, neurodegenerative diseases or bipolar disorder; further preferably, the use of polymorph I of the aforementioned compound (1), or a pharmaceutical composition containing polymorph I of compound (1) in the preparation of a drug for treating depression. The depression described herein includes, but is not limited to, mild to severe depression, preferably moderate to severe depression. When used as a pharmaceutical composition, the pharmaceutical composition may further optionally contain one or more other active agents that regulate the mammalian nervous system or relieve depressive symptoms.

[0083] All details of compound (1) of the present invention can be found in PCT / CN2020 / 135200, the entire content of which is incorporated herein by reference.

[0084] The following describes the method or terms for determining polymorph I of compound (1) of the present invention.

[0085] The "X-ray powder diffraction pattern or XRPD" as described in the present invention refers to according to Bragg's formula 2d sinθ = nλ (where λ is the wavelength of the X-ray, The diffraction order n is any positive integer. Generally, the first-order diffraction peak is taken (n = 1). When X-rays are incident on an atomic plane with a d lattice plane spacing in a crystal or a partial crystal sample at a glancing angle θ (the complementary angle of the incident angle, also known as the Bragg angle), the Bragg equation can be satisfied, and thus this set of X-ray powder diffraction patterns can be measured.

[0086] The "interplanar spacing or interplanar spacing (d value)" described in the present invention refers to three non-parallel unit vectors a, b, c that connect adjacent two lattice points in the space lattice. They divide the lattice into juxtaposed parallelepiped units, which are called interplanar spacings. The space lattice is divided by connecting the determined parallelepiped units to obtain a set of straight grids, which are called space lattices or crystal lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure with geometric points and lines. For different crystal planes, their interplanar spacings (i.e., the distance between two adjacent parallel crystal planes) are different; the unit is or angstrom.

[0087] The "differential scanning calorimetry or DSC" described in the present invention measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting. For the same crystal form of the same compound, in continuous analysis, the thermal transition temperature and the melting point error can be within about 5 °C, usually within about 3 °C. When describing that a certain compound has a given DSC peak or melting point, it refers to the DSC peak or melting point ±5 °C. "Basically" also takes into account such temperature changes. DSC provides an auxiliary method for distinguishing different crystal forms. Different crystal forms can be identified according to their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary within a larger range. In addition, since there is decomposition during the melting process of the substance, the melting temperature is related to the heating rate.

[0088] The "thermogravimetric analysis (TGA)" used in the present invention is a common method for measuring the thermal stability of compounds. In the present invention, TGA can also be used to measure the hydration state of compounds, and the heating rate during the test will have a certain impact on the spectrum. The error of TGA can be within about ±0.5 mass%. Exemplary test conditions are a temperature range of 25 - 200 °C, a heating rate of 5 K / min, and the purge gas is nitrogen.

[0089] The "Fourier transform Raman spectroscopy (FT-Raman)" used in the present invention is generally used to study the structure and chemical bonds of molecules, and can also be used as a method for characterizing and identifying chemical species. In the present invention, Fourier transform Raman spectroscopy is used to characterize the molecular structure and crystal form. The peak position error range of FT-Raman can be ±2 cm -1 .

[0090] Beneficial effects: Compared with the prior art, the compound (1) of the present invention does not undergo obvious degradation, has weak hygroscopicity, has good crystal form stability, and also has good crystal form stability in a high-humidity environment. Therefore, the properties of the bulk drug can be maintained stable under conventional humidity storage conditions, and it can be better used in clinical treatment. Description of the Drawings

[0091] Figure 1 It is the X-ray powder diffraction pattern of Form I of compound (1).

[0092] Figure 2 It is the DSC pattern of Form I of compound (1).

[0093] Figure 3 It is the TGA pattern of Form I of compound (1).

[0094] Figure 4 It is the Raman pattern of Form I of compound (1).

[0095] Figure 5 It is the comparative X-ray powder diffraction pattern of Form I of compound (1) before and after the accelerated test.

[0096] Figure 6 It is the comparative X-ray powder diffraction pattern of Form I of compound (1) before and after the hygroscopicity test.

[0097] Figure 7 It is the TGA graph of Form I of compound (1) after the hygroscopicity test. Detailed Description of the Invention

[0098] The present invention will be explained in more detail below in conjunction with the embodiments. The embodiments of the present invention are only used to illustrate the technical solutions of the present invention and do not limit the essence and scope of the present invention.

[0099] Test conditions of the instruments used in the experiment:

[0100] (1) X-ray powder diffraction detection (XRPD)

[0101] The X-ray powder diffractometer (Aeris DY883 of PANalytical B.V., Netherlands) was used to collect data of the samples. The specific test parameters are as follows: Cu / Kα was used as the X-ray source, the working voltage and current were 40 Kv and 20 mA respectively, and the 2θ scanning range was 3-40°.

[0102] (2) Differential scanning calorimetry detection (DSC)

[0103] The differential scanning calorimeter (Discovery DSC25 of TA Instruments, USA) was used to perform differential scanning calorimetry tests on the samples. The scanning range was 0-250 °C, and the heating rate was 10 °C / min.

[0104] (3) Thermogravimetric analysis (TGA)

[0105] The sample was subjected to thermogravimetric test using a thermogravimetric analyzer (TGA / DSC 3+ synchronous analyzer from Mettler Toledo, Switzerland). The scanning range was 25 °C to 200 °C, and the heating rate was 10 °C / min.

[0106] (4) Raman spectroscopy detection (FT-Raman)

[0107] The sample was subjected to Raman spectroscopy test using a micro-Raman spectrometer (Renishaw inVia from Renishaw, UK). The detection conditions were as follows: detection wavelength 785 nm, detection range 200 - 2000 cm -1 , and the exposure time was 10 s.

[0108] Example 1. Preparation method of compound (1)

[0109] The preparation scheme of compound (1) refers to EP-0015-010 described in PCT / CN2020 / 135200. The reaction equation is as follows:

[0110]

[0111] (1) In a 50 mL single-necked flask, 0.5 g of vortioxetine (1.68 mmol) and 5 mL of dichloromethane were added. Then, 510 mg of triethylamine (5.04 mmol) and 360 mg of 1-chloroethyl chloroformate (2.52 mmol) were added successively. The mixture was stirred at room temperature for 2 hours. After the reaction, 10 mL of water and 15 mL of dichloromethane were added for extraction to obtain the organic phase. The organic phase was concentrated under reduced pressure to obtain the crude product, which was separated by column chromatography (petroleum ether: ethyl acetate = 10:1, v / v) to obtain 550 mg of yellow oil EP0015-003-A, with a yield of 81.1%,

[0112] 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.10–7.00 (m, 3H), 6.91 - 6.87 (m, 1H), 6.65–6.60 (m, 1H), 6.53 (d, J = 8.0 Hz, 1H), 3.75–3.66 (m, 4H), 3.08–3.03 (m, 4H), 2.36 (s, 3H), 2.31 (s, 3H), 1.84 (d, J = 8.0 Hz, 3H); LCMS: [M+H]+ 405.0.

[0113] (2) 150 mg (0.371 mmol) of intermediate EP0015-003-A, 600 mg (1.85 mmol) of cesium carbonate, and 111 mg (0.557 mmol) of lauric acid were dissolved in DMF (5 ml), and the reaction was stirred at room temperature for 3 h. The reaction was monitored by TLC, and the raw materials were basically reacted. After adding 30 mL of water to the reaction solution, it was extracted twice with 25 mL of ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to obtain a crude product. Column chromatography separation with an eluent (petroleum ether:ethyl acetate = 2:1, v / v) gave 45 mg of a white solid, which was compound (1) with a yield of 22% and an HPLC purity of 97%.

[0114] 1 HNMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 7.10 - 7.00 (m, 3H), 6.90 - 6.86 (m, 1H), 6.53 - 6.51 (m, 1H), 3.67 (s, 4H), 3.03 (s, 4H), 2.62 - 2.55 (m, 1H), 2.36 (s, 3H), 2.31 (s, 3H), 2.36 - 2.28 (m, 8H), 1.67 - 1.61 (m, 2H), 1.51 (d, J = 8.0 Hz, 3H), 1.34 - 1.20 (m, 16H), 0.09 - 0.85 (m, 3H), [M + H]+ 569.2.

[0115] Example 2. Preparation method I of polymorph I of compound (1)

[0116] Weigh 20 mg of compound (1) sample and place it in a 3 mL glass bottle. Then add 0.1 mL of acetonitrile and stir at 5 °C until a large amount of solid precipitates. Filter the precipitate and dry it under vacuum at 30 °C. The XRPD pattern is shown in Figure 1 , and the characteristic peak positions in the figure are shown in Table 2 below. The DSC pattern is shown in Figure 2 , and its TGA pattern is shown in Figure 3 . During the DSC heating process, the starting point of the endothermic peak is 43.5 °C, the ending point is 57.1 °C, and the peak value is 49.6 °C; the TGA pattern shows no obvious weight loss from 30 to 200 °C. This polymorph is defined as polymorph I, and the characteristic peak positions are shown in Table 2 below:

[0117] Table 2

[0118]

[0119] Example 3. Preparation method II of polymorph I of compound (1)

[0120] Weigh 19.5 mg of the compound (1) sample and place it in a 3 mL glass bottle. Add 1.2 mL of ethanol solvent, and use ultrasonic assistance to dissolve until the solution is clear and transparent. Then, place the sample at room temperature and let it stand and volatilize to obtain a solid sample. After testing, the obtained sample is consistent with the crystal form I obtained in Example 2.

[0121] Example 4, Preparation Method III of Crystal Form I of Compound (1)

[0122] Weigh 19.5 mg of the compound (1) sample and place it in a 3 mL glass bottle. Add 2 mL of a mixed solvent of methanol and ethyl acetate (9:1), and use ultrasonic assistance to dissolve until the solution is clear and transparent. Then, place the sample at room temperature and let it stand and volatilize to obtain a solid sample. After testing, the obtained sample is consistent with the crystal form I obtained in Example 2.

[0123] Example 5, Preparation Method IV of Crystal Form I of Compound (1)

[0124] Weigh 20.5 mg of the compound (1) sample and place it in a 3 mL glass bottle. Add 0.5 mL of a mixed solvent of methanol and water (1:9), then place the sample under low temperature conditions and stir for a period of time. Separate and dry the residual solid sample. After testing, the obtained sample is consistent with the crystal form I obtained in Example 2.

[0125] Example 6, Preparation Method V of Crystal Form I of Compound (1)

[0126] Weigh 20.5 mg of the compound (1) sample and place it in a 3 mL glass bottle. Add 0.6 mL of ethanol solvent, and use ultrasonic assistance to dissolve until the solution is clear and transparent. Then, slowly add 0.2 mL of water, and a solid precipitate will form. Then, place the sample under low temperature conditions and let it stand. Finally, separate and dry the solid precipitate. After testing, the obtained sample is consistent with the crystal form I obtained in Example 2.

[0127] Example 7, Preparation Method VI of Crystal Form I of Compound (1)

[0128] Weigh 53.9 mg of the compound (1) sample and place it in a 3 mL glass bottle. Add 0.6 mL of acetonitrile solvent, heat and use ultrasonic assistance to dissolve until the solution is clear and transparent. Then, place the sample under low temperature conditions and let it stand for a period of time, and a solid will precipitate. Finally, separate and dry the solid precipitate. After testing, the obtained sample is consistent with the crystal form I obtained in Example 2.

[0129] Example 8, Preparation Method VII of Crystal Form I of Compound (1)

[0130] Weigh 82.7 mg of the compound (1) sample and place it in a 3-mL glass bottle. Add 1 mL of a mixed solvent of methanol and tetrahydrofuran (9:1), heat and sonicate to dissolve until the solution is clear and transparent. Then let the sample stand at low temperature for a period of time, and solids will precipitate. Finally, separate and dry the solid precipitate. The obtained sample is detected to be consistent with the crystal form I obtained in Example 2.

[0131] Example 9. Preparation method VIII of crystal form I of compound (1)

[0132] Weigh 29.6 mg of the compound (1) sample and place it in a 3-mL glass bottle. Then put it into a large glass bottle containing 2 mL of methanol solvent, seal it, and let it stand at room temperature for a period of time. The obtained sample is detected to be consistent with the crystal form I obtained in Example 2.

[0133] Example 10. Investigation of crystal form stability

[0134] Experimental method: Place the crystal form I of compound (1) prepared in Example 2 under accelerated conditions of 25 °C and relative humidity of 60%. Take samples for XRPD detection on the 7th and 14th days respectively, and simultaneously determine the HPLC content (w / w, %). Compare with the results on the 0th day. The test results are shown in Table 3 below.

[0135] Table 3 Results of accelerated test of crystal form I of compound (1)

[0136]

[0137] Experimental results:

[0138] The test results show that before and after the 14-day accelerated test of crystal form I of compound (1), the XRPD spectra Figure 1 are consistent, no crystal transformation occurs, the content of compound (1) is stable, and no obvious degradation occurs, indicating that crystal form I of compound (1) has good stability.

[0139] Example 11. Investigation of crystal form hygroscopicity

[0140] Experimental method:

[0141] Place the crystal form I of compound (1) prepared in Example 2 at room temperature and relative humidity of 80% for 7 days. After the test, detect the sample. The test results are shown in Table 4 below.

[0142] Table 4 Results of hygroscopicity test of compound (1)

[0143]

[0144] Experimental results:

[0145] The test results show that for polymorph I of compound (1), before and after the 7-day hygroscopicity test, the XRPD patterns Figure 1 are consistent and there is no crystal transformation. TGA (see Figure 7 ) shows that the mass change of polymorph I before and after the test is 0.6528%, with weak hygroscopicity, good crystal stability in a high-humidity environment, not easily deliquescent, and the content of compound (1) is stable, and the properties of the bulk drug can be maintained stable under conventional humidity storage conditions.

Claims

1. Crystal Form I of the following compound (1), characterized in that, Using Cu-Kα radiation, an X-ray powder diffraction pattern is obtained, expressed in terms of the diffraction angle 2θ, which shows characteristic peaks at 4.58° ± 0.2°, 6.48° ± 0.2°, 9.10° ± 0.2°, 12.31° ± 0.2°, 13.89° ± 0.2°, 14.97° ± 0.2°, 16.17° ± 0.2°, 18.29° ± 0.2°, 19.04° ± 0.2°, 20.14° ± 0.2°, 21.72° ± 0.2°.

2. The crystalline form I according to claim 1, wherein The X-ray powder diffraction pattern of the crystalline form I shows characteristic peaks at 4.58° ± 0.2°, 6.48° ± 0.2°, 9.10° ± 0.2°, 11.0° ± 0.2°, 12.31° ± 0.2°, 13.89° ± 0.2°, 14.97° ± 0.2°, 16.17° ± 0.2°, 17.74° ± 0.2°, 18.29° ± 0.2°, 19.04° ± 0.2°, 20.14° ± 0.2°, 21.72° ± 0.2°, 22.98° ± 0.2°.

3. The crystalline form I according to claim 1, wherein The X-ray powder diffraction pattern of the crystalline form I shows characteristic peaks at 4.58° ± 0.2°, 6.48° ± 0.2°, 9.10° ± 0.2°, 11.0° ± 0.2°, 12.31° ± 0.2°, 13.89° ± 0.2°, 14.97° ± 0.2°, 16.17° ± 0.2°, 17.74° ± 0.2°, 18.29° ± 0.2°, 19.04° ± 0.2°, 20.14° ± 0.2°, 21.72° ± 0.2°, 22.98° ± 0.2°, 27.51° ± 0.2°.

4. The crystalline form I according to any one of claims 1 to 3, characterized in that, The crystalline form I of the compound (1) optionally has one or more of the following characteristics: (1) Substantially conforms to the powder X-ray diffraction pattern shown in Figure 1; (2) Substantially conforms to the DSC pattern shown in Figure 2; (3) Substantially conforms to the TGA pattern shown in Figure 3; (4) Substantially conforms to the Raman spectrum shown in Figure 4.

5. The crystalline form I according to any one of claims 1 to 3, characterized in that, The X-ray powder diffraction pattern expressed in terms of the diffraction angle 2θ is substantially as shown in Figure 1.

6. A method for preparing polymorph I as described in any one of claims 1 to 5, characterized in that, Selected from: Method 1: Dissolve the compound (1) in solvent A, stir and precipitate at a temperature not higher than 10°C, separate and dry the solid; wherein the solvent A is selected from at least one of water, methanol, ethanol, n-propanol, isopropanol, acetonitrile, and tetrahydrofuran; Or Method 2: Dissolve the compound (1) in solvent B, leave it to evaporate at room temperature, separate and dry the resulting solid; wherein the solvent B is selected from at least one of water, methanol, ethanol, acetonitrile, ethyl acetate, and tetrahydrofuran; Or Method 3: Dissolve the compound (1) in a good solvent, then add a poor solvent, cool and precipitate at a temperature not higher than 10°C, and then separate and dry the solid; wherein the good solvent is selected from at least one of methanol, ethanol, n-propanol, isopropanol, and tetrahydrofuran; the poor solvent is water. Or Method 4: Dissolve compound (1) in solvent C, heat to form a saturated or nearly saturated solution, then cool the resulting solution to below 10 °C and let it stand, and separate and dry the solid; wherein the solvent C is selected from at least one of methanol, ethanol, n-propanol, acetonitrile, ethyl acetate, and tetrahydrofuran; Or Method 5: Under room temperature conditions, place the container containing compound (1) in another container containing solvent D, seal it, and take it out after placing it for 0.5 - 48 h; wherein the solvent D is selected from at least one of methanol, ethanol, n-propanol, acetonitrile, ethyl acetate, and tetrahydrofuran.

7. A method according to claim 6, wherein In Method 1, the solvent A is selected from at least one of water, methanol, ethanol, isopropanol, and acetonitrile; In Method 2, the solvent B is selected from at least one of methanol, ethanol, n-propanol, acetonitrile, ethyl acetate, and tetrahydrofuran; In Method 3, the good solvent is selected from at least one of methanol, ethanol, and n-propanol; In Method 4, the solvent C is selected from at least one of methanol, ethanol, and tetrahydrofuran; In Method 5, the solvent D is selected from at least one of methanol, ethanol, n-propanol, ethyl acetate, and acetonitrile.

8. The method according to claim 7, wherein In Method 4, the heating temperature is 30 - 50 °C.

9. A pharmaceutical composition comprising crystalline form I of compound (1) as described in any one of claims 1 - 5, and at least one pharmaceutical excipient selected from pharmaceutically acceptable carriers, diluents, or excipients.

10. Use of crystalline form I of compound (1) as described in any one of claims 1 - 5, or the pharmaceutical composition as described in claim 9, in the preparation of a drug for treating neuropsychiatric diseases.

11. The use according to claim 10, characterized in that, The neuropsychiatric diseases are selected from any one or more of schizophrenia, depression, anxiety disorder, sleep disorder, cognitive disorder, neurodegenerative disease, bipolar disorder, post-traumatic stress syndrome, addictive disease, withdrawal syndrome, or attention deficit.

12. The use according to claim 10, wherein The neuropsychiatric diseases are selected from any one or more of depression, cognitive disorder, anxiety disorder, schizophrenia, sleep disorder, neurodegenerative disease, or bipolar disorder.

13. The use according to claim 11, characterized in that, The depression is selected from mild depression, moderate depression, or severe depression.

14. The use according to claim 11, wherein The depression is selected from depression accompanied by other mental disorders.

15. The use according to claim 11, wherein The depression is selected from recurrent depression.

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