CN116041323A - Acid salt of sigma-1 receptor agonist, its crystal form and its preparation method and application - Google Patents

Abstract

The invention provides an acid salt of a Sigma‑1 receptor agonist or a crystal form thereof, a preparation method and application thereof. It specifically relates to a 5‑((2‑(cyclopropylmethyl)‑1,2,3,4‑tetrahydroisoquinolin‑7‑yl) (isopropylmethyl) with high affinity for sigma‑1 receptors )amino)-1-picoline-2(1H)-keto acid salt and its crystal form, the present invention relates to the preparation method of the acid salt and its crystal form and its application in the field of medicine. Compound 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl) (isopropyl)amino)-1-picoline provided by the invention The acid salt of ‑2(1H)‑ketone and its crystal form have improved physical and chemical properties, such as appearance, hygroscopicity and chemical stability.

Description

Acid salt of Sigma-1 receptor agonist, its crystal form and its preparation method and application

technical field

The invention belongs to the medical field, and relates to an acid salt of a Sigma-1 receptor agonist, its crystal form, its preparation method and application. Specifically relate to a kind of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropylmethyl) with high affinity for sigma-1 receptor )amino)-1-picoline-2(1H)-one acid salt and its crystal form, the present invention also relates to the preparation method of the acid salt and the crystal form and its application in the field of medicine.

Background technique

Sigma receptors (σ receptors) are cell surface receptors of the central nervous system (CNS) that may be associated with the dysphoric, hallucinogenic and cardiostimulatory effects of opioids. Through studies of the biology and function of the sigma receptor, sigma receptor ligands have been shown to be useful in the treatment of psychiatric and movement disorders, such as dystonia and tardive dyskinesia, and those associated with Huntington's disease or tic disorders movement disorders and Parkinson's disease (Walker, J.M. et al., Pharmacological Reviews, 1990, 42, 355). It has been reported that the known sigma-receptor ligand rincazole clinically shows therapeutic effects on psychosis (Snyder, S.H., Largent, B.L.J. Neuropsychiatry 1989, 1, 7).

Sigma receptor has at least two subtypes, among which Sigma-1 receptor (σ1 receptor) is an emerging drug target in recent years, and it is a binding protein of various specific psychotropic drugs. Sigma-1 receptor is a ligand-regulated protein chaperone, which plays the role of its molecular chaperone by interacting with NMDA and other receptors: regulating NMDA, APMA plasma channels and downstream receptors, thereby regulating mitochondrial function and 5- Release of neurotransmitters such as serotonin, dopamine, etc.

Known sigma-1 receptor agonists such as opipramol, igmetacin, SA-4503, ANAVEX2-73, etc. have clinically shown antidepressant and anti-anxiety effects. Compounds such as benzomorphinanes (SKF10047, dextromethorphan), SSRI antidepressants (fluvoxamine, sertraline, fluoxetine, etc.) all have high affinity to the Sigma-1 binding site.

Currently, the prior art discloses different Sigma-1 receptor agonists, such as: Igmesine, Cutamesine, OPC-14523, Opipramol, PRE-084, SA-4503, ANAVEX2-73, ANAVEX1-41, ANAVEX3-71d, etc. have Obvious antidepressant effect; Patent WO2017190109 discloses the structure of some sigma receptor agonists and its use in CNS-related diseases.

However, Igmesine, which has the fastest clinical progress, has failed in the third phase of clinical trials. In addition to targeting sigma-1, the marketed Opipramol is also a dopamine D2 receptor antagonist and histamine H1 receptor antagonist. Point effect brought certain side effects at the same time.

Contents of the invention

The inventors first studied and found that 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl Pyridin-2(1H)-one has good affinity and selectivity to sigma-1 receptors, and has good safety and metabolic stability. It is used in the treatment and prevention of central nervous diseases, especially antidepressant and anti-anxiety It has very good application prospects. Relevant content is described in PCT/CN2021/103543, and the entire content described in this patent is incorporated into the present invention by reference.

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H) -The ketone structural formula is shown in the following formula I:

There is no literature report about the compound 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methanol Research on the acid salt and crystal form of pyridin-2(1H)-one.

Active pharmaceutical ingredients exhibit different physical properties depending on their solid form. The difference in these physical properties may affect, for example, the manufacturing method or administration method and preparation of the pharmaceutical active ingredient. Generally speaking, the physical properties can be changed by using salts or crystalline solids. Another important solid-state property of a pharmaceutical compound is its rate of dissolution in aqueous fluids. The solid state form of an active ingredient, especially for oral administration, may also affect its solubility, bioavailability, stability, and the like. The solid-state physical properties of polymorphic compounds also include, for example, the fluidity of pulverized solids. Fluidity will affect the ease of handling during processing into pharmaceuticals. The solid-state form of the compound also affects its compression properties and storage stability.

During the research process, the inventors found that the compound represented by formula I is usually in the form of viscous jelly, which is not convenient for storage and weighing, and is not conducive to the subsequent development of formulations. The purpose of the present invention is to further research and develop different salts and/or crystalline solids of the compound, so as to make the active pharmaceutical compound more favorable for drug-making.

In order to improve compound 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The physicochemical properties of (1H)-ketones, such as traits, hygroscopicity and chemical stability, the inventors have thoroughly studied 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroiso Different solid forms of quinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one. Provided 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2( Acid salts of 1H)-ketones, their crystal forms and preparation methods.

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H) - Ketone, defined as compound I, its structure is shown in the following formula:

其制备方法在PCT/CN2021/103543中进行了记载。

Its preparation method is described in PCT/CN2021/103543.

The first aspect of the present invention provides 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The acid salt of base pyridin-2 (1H)-one, described acid salt comprises inorganic acid salt or organic acid salt; Said inorganic acid salt is selected from hydrochloride, sulfate, hydrobromide, hydrofluoric acid salt, hydroiodide or phosphate, more preferably hydrochloride; the organic acid salt is selected from p-toluenesulfonate, fumarate, tartrate, maleate, acetate, adipate , Benzenesulfonate, 4-Chlorobenzenesulfonate, Benzoate, Caprate, Caproate, Caprylate, Cinnamate, Citrate, Cyclosulfamate, Gluconate , glucuronate, glutamate, erythorbate, lactate, aspartate, malate, mandelate, methanesulfonate, ethanesulfonate, galactose, pentanoate Dialate, hippurate, lactobionate, ascorbate, aspartate, laurate, malonate, 1,5-naphthalene disulfonate, naphthalene-2-sulfonate, tobacco salt, oleate, oxalate, palmitate, sebacate, stearate, succinate, trifluoroacetate, succinate, more preferably p-toluenesulfonate, fumarate salt, or maleate.

In a specific embodiment of the present invention, the 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino )-1-methylpyridin-2(1H)-one acid salt, wherein, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline-7 -yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one (compound I) to acid molar ratio is 1:1~2, preferably 1:1 or 1:2.

Another aspect of the present invention provides crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)- The acid salt of 1-picoline-2(1H)-one, the acid salt is hydrochloride, selected from hydrochloride crystal form I or hydrochloride crystal form II, wherein the hydrochloride Form I, whose X-ray powder diffraction pattern includes diffraction angles at 10.00°±0.2°, 11.99°±0.2°, 17.45°±0.2°, 23.15°±0.2°, 24.22°±0.2° and 26.58°±0.2° The peak at (2θ);

Preferably, including those located at 7.97°±0.2°, 9.19°±0.2°, 10.00°±0.2°, 11.99°±0.2°, 17.45°±0.2°, 20.92°±0.2°, 23.15°±0.2°, 24.22°±0.2 °, and the peak at the diffraction angle (2θ) of 26.58°±0.2°;

More preferably, including those located at 7.97°±0.2°, 9.19°±0.2°, 10.00°±0.2°, 11.11±0.2°, 11.99°±0.2°, 12.64±0.2°, 13.16±0.2°, 16.94±0.2°, 17.45 °±0.2°, 18.40±0.2°, 20.39±0.2°, 20.92°±0.2°, 21.71±0.2°, 23.15°±0.2°, 24.22°±0.2°, 26.58°±0.2°, 28.79±0.2° The peak at (2θ).

Most preferably, its X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 1, and its X-ray powder diffraction data are as shown in Table 1:

Table 1:

The present invention provides the hydrochloride salt crystal form II of compound I, and its X-ray powder diffraction pattern includes positions at 9.17°±0.2°, 15.33°±0.2°, 16.17°±0.2°, 18.24°±0.2°, 18.77°±0.2° , peaks at diffraction angles (2θ) of 22.58°±0.2° and 24.10°±0.2°.

Preferably, the X-ray powder diffraction pattern of the hydrochloride salt form II includes positions at 9.17°±0.2°, 11.18°±0.2°, 14.75°±0.2°, 15.33°±0.2°, 16.17°±0.2°, 18.24 Peaks at diffraction angles (2θ) of °±0.2°, 18.77°±0.2°, 22.58°±0.2°, 24.10°±0.2° and 29.52°±0.2°.

More preferably, the X-ray powder diffraction pattern of the hydrochloride salt form II includes positions at 9.17°±0.2°, 11.18°±0.2°, 14.75°±0.2°, 15.33°±0.2°, 16.17°±0.2°, 17.80±0.2°, 18.24°±0.2°, 18.77°±0.2°, 21.32±0.2°, 22.01±0.2°, 22.58°±0.2°, 23.48±0.2°, 24.10°±0.2°, 24.85±0.2°27.46± Peaks at diffraction angles (2Θ) of 0.2°, 28.67±0.2° and 29.52°±0.2°.

Most preferably, the X-ray powder diffraction pattern of the hydrochloride salt form II is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 2, and its X-ray powder diffraction data are shown in Table 2:

Table 2:

Crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The hydrochloride salt of ylpyridin-2(1H)-one, including hydrochloride crystal form I and hydrochloride salt form II, can also be characterized by DSC, analyzed and identified by differential scanning calorimetry, and the scanning speed is 10 °C/min, the hydrochloride salt form I contains an endothermic peak with a peak temperature of 238.8°C±3°C; the hydrochloride salt form II contains an endothermic peak with a peak temperature of 101.46°C±3°C and 219.39°C±3°C endothermic peak.

In one embodiment of the present invention, the 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino) - The molar ratio of 1-methylpyridin-2(1H)-one to hydrochloric acid is 1:1 or 1:2.

In one embodiment of the present invention, a crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(iso Acid salt of propyl)amino)-1-methylpyridin-2(1H)-one, said acid salt is p-toluenesulfonate, selected from p-toluenesulfonate crystal form I, its X-ray powder Diffraction patterns include those located at 7.78°±0.2°, 10.34°±0.2°, 11.50°±0.2°, 12.03°±0.2°, 14.00°±0.2°, 16.64°±0.2°, 17.66°±0.2°, 19.71°±0.2 °, peaks at diffraction angles (2θ) of 20.86°±0.2°, 22.26±0.2° and 23.08°±0.2°.

Preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt crystal form I includes positions at 7.78°±0.2°, 10.34°±0.2°, 11.50°±0.2°, 12.03°±0.2°, 14.00°±0.2° , 15.46±0.2°, 15.91±0.2°, 16.64°±0.2°, 17.66°±0.2°, 19.04±0.2°, 19.71°±0.2°, 20.86°±0.2°, 21.66±0.2°, 22.26±0.2°, Peaks at diffraction angles (2Θ) of 23.08°±0.2° and 24.58±0.2°.

Most preferably, the X-ray powder diffraction pattern of the p-toluenesulfonate salt form I is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 3, and its X-ray powder diffraction data are shown in Table 3:

table 3:

The p-toluenesulfonate salt crystal form I described in the present invention can also be characterized by DSC, analyzed and identified by differential scanning calorimetry, and the scanning speed is 10°C/min, and the p-toluenesulfonate salt crystal form I contains The peak temperature is an endothermic peak at 203.15°C±3°C.

Further preferably, the 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine The molar ratio of -2(1H)-ketone to p-toluenesulfonic acid is 1:1.

In one embodiment of the present invention, a crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(iso Propyl)amino)-1-methylpyridin-2(1H)-one acid salt, the acid salt is fumarate, including fumarate crystal form I or fumarate salt crystal form II ,in,

The fumarate crystal form I is described, and its X-ray powder diffraction pattern includes 7.90°±0.2°, 10.36°±0.2°, 11.89°±0.2°, 12.44°±0.2°, 15.89°±0.2°, 17.73 Peaks at diffraction angles (2θ) of °±0.2°, 19.91°±0.2°, 22.15°±0.2°, 23.98°±0.2° and 28.04°±0.2°.

Preferably, the fumarate salt crystal form I has an X-ray powder diffraction pattern at 7.90°±0.2°, 10.36°±0.2°, 11.89°±0.2°, 12.44°±0.2°, 14.53±0.2°, 15.89° °±0.2°, 17.08±0.2°, 17.73°±0.2°, 19.91°±0.2°, 20.38±0.2°, 22.15°±0.2°, 23.98°±0.2°, 24.54±0.2° and 28.04°±0.2° Peaks at diffraction angles (2θ).

Most preferably, the fumarate crystal form I, its X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 4, and its X-ray powder diffraction data are shown in Table 4:

Table 4:

The fumarate crystal form II, its X-ray powder diffraction pattern includes 9.56°±0.2°, 12.50°±0.2°, 16.79°±0.2°, 21.60°±0.2°, 23.06°±0.2° and 25.79° Peaks at diffraction angles (2Θ) of ±0.2°.

Preferably, the fumarate salt crystal form II has an X-ray powder diffraction pattern at 8.35°±0.2°, 9.56°±0.2°, 12.50°±0.2°, 16.79°±0.2°, 18.66°±0.2°, Peaks at diffraction angles (2θ) of 20.40°±0.2°, 21.60°±0.2°, 23.06°±0.2° and 25.79°±0.2°.

More preferably, the fumarate salt crystal form II has an X-ray powder diffraction pattern at 8.35°±0.2°, 9.56°±0.2°, 12.50°±0.2°, 13.40±0.2°, 15.52±0.2°, 16.79 Peaks at diffraction angles (2θ) of °±0.2°, 18.66°±0.2°, 20.40°±0.2°, 21.60°±0.2°, 23.06°±0.2° and 25.79°±0.2°.

Most preferably, the fumarate crystalline form II, its X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 5, and its X-ray powder diffraction data are shown in Table 5:

table 5:

The fumarate salt crystal form I or fumarate salt crystal form II described in the present invention can also be characterized by DSC, analyzed and identified by differential scanning calorimetry, and the scanning speed is 10°C/min.

The fumarate salt form I contains endothermic peaks with peak temperatures of 115.47±3°C and 157.84°C±3°C,

The fumarate salt form II contains an endothermic peak with a peak temperature of 180.03°C±3°C.

Further preferably, the crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1- The acid salt of picoline-2(1H)-one is fumarate, including fumarate crystal form I or fumarate salt form II, wherein 5-((2-(cyclopropylmethyl )-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one and the molar ratio of fumaric acid salt formation is 1:1.

In one embodiment of the present invention, a crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(iso Propyl)amino)-1-methylpyridin-2(1H)-one acid salt, the acid salt is maleate, selected from maleate crystal form I,

The maleate salt crystal form I has an X-ray powder diffraction pattern at 4.06°±0.2°, 8.11°±0.2°, 10.82°±0.2°, 12.18°±0.2°, 13.58°±0.2°, 16.27° Peaks at diffraction angles (2θ) of ±0.2°, 18.23°±0.2°, 20.38°±0.2°, 24.28°±0.2° and 28.68°±0.2°.

Preferably, the maleate salt crystal form I, its X-ray powder diffraction pattern includes positions at 4.06°±0.2°, 8.11°±0.2°, 9.08±0.2°, 10.82°±0.2°, 12.18°±0.2°, Diffraction angles (2θ ) at the peak.

Most preferably, the maleate salt crystal form I, its X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 6, and its X-ray powder diffraction data are shown in Table 6:

Table 6:

Further preferably, the crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1- The acid salt of methylpyridin-2(1H)-one is maleate, selected from maleate crystal form I, wherein 5-((2-(cyclopropylmethyl)-1,2,3 , The molar ratio of 4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to maleic acid salt formation is 1:1.

The term "substantially the same" as used herein with respect to X-ray diffraction peak positions is meant to take into account typical peak position and intensity variability. For example, those skilled in the art will appreciate that the peak position (2Θ) will vary from measurement to XRPD instrument, sometimes by as much as 0.2°. In addition, those skilled in the art will understand that factors such as XRPD sample preparation method, XRPD instrument, sample crystallinity, sample amount and crystal preferred orientation will lead to changes in the relative peak intensity in the sample XRPD diffraction pattern.

Another aspect of the present invention also provides 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1- The preparation method of the acid salt of picoline-2 (1H)-one, comprising:

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone free base is dissolved or dispersed in organic solvent, then add the liquid of inorganic acid or organic acid, or add the solid of inorganic acid or organic acid, or the solution of acid, prepare 5-((2-(cyclopropyl methyl yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one acid salt; or,

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone is added to a solution of acid to prepare 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino) -Acid salt of 1-methylpyridin-2(1H)-one; where 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl )(isopropyl)amino)-1-methylpyridin-2(1H)-one and acid molar ratio is 1:1～2.5. The molar ratio of the acid feed is related to the acid content in the prepared acid salt, for example, when preparing an acid salt with a molar ratio of 1:1, 5-((2-(cyclopropylmethyl)-1,2 ,3,4-Tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one and acid molar feed ratio is 1:1～1.1;

When preparing an acid salt with a molar ratio of 1:2, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(iso The molar ratio of propyl)amino)-1-methylpyridin-2(1H)-one to acid is 1:2-2.5, preferably 1:2-2.1.

In another aspect, the present invention also provides crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino The preparation method of the acid salt of )-1-methylpyridin-2(1H)-one, comprising:

Prepare 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine- Acid salts of 2(1H)-ketones;

Collect the solid product precipitated during the above-mentioned salt-forming reaction, or obtain the solid product by creating a supersaturated solution in the salt-forming system. The method for creating a supersaturated solution includes: volatilizing the solvent, or adding an anti-solvent, or by cooling the method to obtain Crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2( 1H)-keto acid salt;

And/or, one crystal form of the acid salt is converted into another crystal form of the salt by means of crystal form conversion. The crystal transformation method includes: heating or suspending in a suitable solvent to transform the crystal.

In the above method, the suitable organic solvents used in the salt-forming process include alcohols (such as methyl alcohol, ethanol, isopropanol), chlorinated alkanes (such as dichloromethane), ketones (such as acetone), ethers ( Such as ether), esters (such as ethyl acetate), alkanes (such as n-hexane, n-heptane), acetonitrile, benzene, amides or mixtures thereof, preferably methanol, ethanol, ethyl acetate, acetonitrile or mixtures thereof; The solution of the acid is an acid ethyl acetate solution or an acid acetonitrile solution.

For example, the preparation method of hydrochloride crystal form I includes:

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone was added into dichloromethane and dissolved completely, then an ethyl acetate solution of hydrochloric acid was added to precipitate a solid, concentrated under reduced pressure, and dried to obtain a dark green solid;

Among them, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2( The molar feed ratio of 1H)-ketone to hydrochloric acid is 1:1-2.5, preferably 1:2-2.1.

For example, the preparation method of compound I hydrochloride crystal form II includes:

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone is dissolved in ethanol, preferably diluted with ethyl acetate dropwise, then added concentrated hydrochloric acid, stirred at room temperature, after the reaction is completed, centrifuged, and the solid is vacuum-dried; wherein, 5-((2-(cyclopropylmethyl)- The molar ratio of 1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to hydrochloric acid is 1:1～2.5 , preferably 1:1 to 1.1.

For example, the preparation method of compound I p-toluenesulfonate crystal form I includes:

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone was dissolved in ethanol, then added an acetonitrile solution of p-toluenesulfonic acid, stirred at room temperature, after the reaction was completed, centrifuged, and the solid was vacuum-dried;

Among them, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2( The molar ratio of 1H)-ketone to p-toluenesulfonic acid is 1:1-2.5, preferably 1:1-1.1.

For example, the preparation method of compound I fumarate crystal form I includes:

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone was dissolved in ethanol, then added to the acetonitrile solution of fumaric acid, stirred at room temperature, after the reaction was completed, centrifuged, and the solid was vacuum-dried; wherein, 5-((2-(cyclopropylmethyl)-1,2, The molar ratio of 3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to fumaric acid is 1:1～2.5, preferably 1:1～1.1.

For example, the preparation method of compound I fumarate salt crystal form II includes:

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone was dissolved in ethanol, then added fumaric acid ethyl acetate solution, stirred at room temperature, after the reaction was completed, centrifuged, and the solid was vacuum-dried;

Among them, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2( The molar ratio of 1H)-ketone to fumaric acid is 1:1-2.5, preferably 1:1-1.1.

For example, the preparation method of compound I maleate crystal form I includes:

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone was dissolved in ethanol, then added an acetonitrile solution of maleic acid, stirred at room temperature, after the reaction was finished, centrifuged, and the solid was vacuum-dried for 10 hours;

Among them, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2( The molar ratio of 1H)-ketone to maleic acid is 1:1-2.5, preferably 1:1-1.1.

Another aspect of the present invention provides a pharmaceutical composition, comprising 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline-7- base) (isopropyl) amino) -1-picoline-2 (1H)-one acid salt and pharmaceutically acceptable carrier or excipient, preferably the acid salt is the hydrochloric acid of compound I Salt, fumarate, maleate or p-toluenesulfonate, more preferably, the acid salt is the hydrochloride of compound I.

In another embodiment of the present invention, a pharmaceutical composition is provided, comprising the crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroiso Quinolin-7-yl) (isopropyl) amino)-1-picoline-2 (1H)-one acid salt and pharmaceutically acceptable carrier or excipient; Preferably, the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H) - The acid salt of the ketone is hydrochloride form I, hydrochloride form II, fumarate form I, fumarate form II, p-toluenesulfonate form I or maleate Form I.

Another aspect of the present invention provides the 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino) - the acid salt of 1-methylpyridin-2(1H)-one, or the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroiso Quinolin-7-yl) (isopropyl) amino)-1-methylpyridin-2 (1H)-one acid salt, or the application of the pharmaceutical composition in the preparation of drugs for the treatment of neuropsychiatric diseases ; Preferably, the neuropsychiatric diseases are selected from any one of depression and anxiety.

The present invention also provides a method for treating and/or preventing a sigma-1 receptor-related disease or disease state, which comprises administering the acid salt of Compound I or the crystalline compound I of the present invention to an individual in need thereof Acid salt of compound I, or a pharmaceutical composition comprising an acid salt of compound I or a crystal form thereof.

In another embodiment of the present invention, the acid salt of Compound I or the acid salt of Compound I in crystalline form according to the present invention, or the pharmaceutical composition comprising the acid salt of Compound I or its crystal form is used For the treatment and/or prevention of sigma-1 receptor related diseases or disease states. Further, the sigma-1 receptor-related diseases are depression, anxiety, Alzheimer's and other mental diseases, preferably depression.

Beneficial effect: Compared with the prior art, the acid salt of Compound I provided by the present invention, especially the hydrochloride, has significantly improved physicochemical properties, such as no obvious degradation, weak hygroscopicity, and good crystal Form stability, and the crystal form stability is also good in high humidity environment, so the raw material drug can be kept stable under conventional humidity storage conditions, and can be better used in clinical treatment. In addition, the acid salt of compound I provided by the present invention has better sigma-1 affinity, and shows good drug efficacy in mice. Compared with the free base of the compound, the acid salt of the compound I provided by the present invention is in the form of solid crystal or powder, which is convenient for storage, weighing and subsequent formulation development.

Description of drawings

The technical solution of the present application will be further described below in conjunction with the accompanying drawings and embodiments.

Figure 1 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The XRPD pattern of the hydrochloride salt form I of (1H)-ketone;

Figure 2 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The XRPD pattern of the hydrochloride salt form II of (1H)-ketone;

Figure 3 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The XRPD pattern of the p-toluenesulfonate salt crystal form I of (1H)-ketone;

Figure 4 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The XRPD pattern of the fumarate salt crystal form I of (1H)-ketone;

Figure 5 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The XRPD pattern of the fumarate salt crystal form II of (1H)-ketone;

Figure 6 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The XRPD pattern of the maleate salt crystal form I of (1H)-ketone;

Figure 7 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The XRPD comparison chart of the crystal form of (1H)-ketone hydrochloride placed under room temperature and room humidity conditions for 5 days and 10 days respectively;

Figure 8 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 (1H)-ketone hydrochloride is placed at 40°C and 75% RH for 5 days and 10 days respectively, and the XRPD comparison chart of the crystal form;

Figure 9 is 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 The XRPD comparison chart of the crystal form of (1H)-ketone hydrochloride before and after storage at 25°C±1°C, 80%±4%RH humidity for 5 days.

Detailed ways

Unless otherwise stated, implied from the context, or customary in the art, all parts and percentages in this application are by weight and the testing and characterization methods used are current as of 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 the present application, the definition of the term provided in the present application shall prevail.

The words "preferred", "preferably", "more preferred", "most preferred" and the like in the present invention refer to embodiments of the invention which may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention. "Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. The sources of components not mentioned in the present invention are all commercially available.

The term "crystal form" used in this specification refers to a crystal with a certain crystal form, which is formed by the regular arrangement of atoms, ions, molecules, etc. constituting a solid. Unless otherwise specified, "crystal" in the present specification is synonymous with "crystal form" and "crystal form". The degree of crystallinity of a crystalline form can be measured by various techniques including, for example, X-ray powder diffraction measurement, moisture adsorption-desorption measurement, differential scanning calorimetry, solution colorimetry, solubility characteristics, and the like.

The crystalline solid of the present invention may be single crystal, twin crystal, polycrystal, etc., usually single crystal or its mixed crystal. The form (shape) of the crystal is not particularly limited, for example, it may be triclinic crystal, monoclinic crystal, orthorhombic crystal (cubic crystal), tetragonal crystal, cubic crystal, trigonal crystal (rhombohedral crystal), hexagonal crystal, etc. It may be spherulites, skeletal crystals, bark crystals, needle crystals (such as whisker crystals) and the like. The size of the crystals is not particularly limited. For example, based on the laser diffraction method, the average particle size of the crystals may be 0.5 μm to 1 mm, preferably about 1 to 500 μm.

In addition, the crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine The acid salt of -2(1H)-ketone can also absorb moisture due to changes in relative humidity, that is, it can also cause water molecules in the air to easily enter and exit the crystal lattice in the form of crystal water due to changes in external humidity crystalline solids; for such crystalline solids, even when the X-ray powder diffraction pattern changes slightly with changes in water content, as long as it has the characteristic peaks described in this specification, it can be interpreted as substantially the same Crystalline solid. The moisture can be any one of residual solvents such as crystal water and attached water; in a preferred embodiment of the present invention, the crystalline 5-((2-(cyclopropylmethyl)-1,2, The acid salt of 3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one is free of crystal water.

"Compound I" described in the present invention and "5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino) -1-methylpyridin-2(1H)-one" means the same compound, which can be replaced with each other, and all refer to compounds with the following structure:

The crystal forms of the acid salts of Compound I described in the present invention are characterized by their X-ray powder diffraction patterns. That is, using Cu-Kα radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2θ angle is obtained. The "2θ or 2θ angle" refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2θ in the X-ray powder diffraction pattern can be ± 0.3, ± 0.2, ± 0.1, preferably ±0.2.

The absolute and relative intensities of the peaks shown in the aforementioned tables and figures may be due to various factors, such as the effect of the selected orientation of the crystalline solid on the X-ray beam, the effect of coarse particles, the purity of the substance being analyzed or the quality of the sample. Changes in crystallinity. In addition, the peak position can also shift according to the variation of the sample height. Furthermore, when different wavelengths are used for measurement, different shift values are obtained according to the Braggiant (nλ=2dsinθ), and such different XRPD patterns obtained by using different wavelengths are also included in the scope of the present invention.

In addition to the determination of the crystal form of the acid salt of Compound I by X-ray powder diffraction spectroscopy, it can also be determined by thermal analysis methods, such as but not limited to DSC, TG/DTA, and Raman.

"Differential Scanning Calorimetry" or "DSC," as described herein, measures the transition temperature at which a crystal absorbs or releases heat as a result of a change in its crystal structure or as the crystal melts. For the same crystal form of the same compound, the error of thermal transition temperature and melting point can be within about 5°C, usually within about 3°C, in successive analyses. When it is described that a compound has a given DSC peak or melting point, it is meant that the DSC peak or melting point ± 5°C. "Substantially" also takes this temperature change into account.

The X-ray powder diffraction patterns of the following examples were collected on a PANalytical Aeris X-ray powder diffractometer, and the test temperature was a conventional temperature, such as 25°C. The method parameter of described X-ray powder diffraction is as follows:

X-ray reflection parameters: Cu, Kα

wavelength:

Pipe pressure: 40KV

Pipe flow: 15mA

Step size: 0.0110°

Scanning time per step: 18.87s

Scanning range: from 3.0 to 40.0 degrees

Differential scanning calorimetry (DSC) images were collected on a TA DSC25 differential scanning calorimeter. The parameters of the method are as follows: heating rate: 10° C./min; protective gas: nitrogen.

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H) - Preparation of ketones:

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H) -The preparation scheme of ketone is with reference to the method described in PCT/CN2021/103543 embodiment 1 and embodiment 4, and reaction equation is as follows:

(1) Synthesis of 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline

Dissolve 7-bromo-1,2,3,4-tetrahydroisoquinoline (4.71g, 22.2mmol) and bromomethylcyclopropane (3.15g, 23.13mmol) in 150mL acetonitrile, stir the reaction overnight with magnetic force, and the reaction is complete , purified by silica gel column chromatography (PE/EA=15/1) to obtain 5.8 g of 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline (98.3% yield ).

(2) 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 Synthesis of (1H)-ketone

The reactant 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline (266mg, 1.0mmol), 5-(isopropylamino)-1-methylpyridine -2(1H)-one (182.8 mg, 1.1 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (48 mg, 0.10 mmol), Pd ₂ (dba) ₃ (92mg, 0.10mmol), Cs ₂ CO ₃ (630mg, 1.9mmol) and xylene (10ml) were sequentially added into the reaction flask, and reacted at 100°C for 16 hours under the protection of nitrogen. After the reaction, the solution was cooled to room temperature, filtered with diatomaceous earth, the filter cake was washed with EA (30ml x 2) and DCM (50ml x 2), the organic phases were combined, concentrated, and separated by column chromatography (DCM/MeOH=10 : 1) purification to obtain 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl) (isopropyl) amino)-1-methylpyridine -2(1H)-ketone is a dark green gelatinous and viscous substance.

¹ H NMR (400MHz, Methanol-d4) δ7.65(d, J=2.8Hz, 1H), 7.47(d, J=2.8Hz, 0.5H), 7.44(d, J=2.9Hz, 0.5H), 7.20(d, J=8.5Hz, 1H), 6.85(d, J=9.4Hz, 2H), 6.74(d, J=2.1Hz, 1H), 4.60(d, J=15.4Hz, 1H), 4.38– 4.25(m,2H),3.86(d,J=16.4Hz,1H),3.78(s,3H),3.42(d,J=6.2Hz,1H),3.27–3.05(m,4H),1.24(s ,1H),1.18(d,J=6.5Hz,6H),0.81(d,J=8.1Hz,2H),0.50(q,J=4.8Hz,2H).MS(ESI)m/z 352.3([ M+H] ⁺ ).

Example 1 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2 Preparation of (1H)-ketone hydrochloride crystal form I

In a 200ml one-necked flask, add 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl Pyridin-2(1H)-one (4.9g, 13.94mmol) and dichloromethane (50ml) were completely dissolved, then added hydrochloric acid in ethyl acetate solution (15ml, 2mol/L), there was obvious solid precipitation, sonicated for 10min and then decompressed Concentrate and dry to obtain a dark green solid, HPLC: 98.24%. Through Aeris X-ray powder diffraction (XRPD) analysis and identification, its XRPD data are shown in Table 1, and the XRPD figure is shown in Figure 1, which is 5-((2-(cyclopropylmethyl)-1,2,3, 4-Tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one hydrochloride crystal form I.

¹ H NMR (400MHz, Methanol-d4): δ7.64 (d, J = 2.7Hz, 1H), 7.45 (dd, J = 9.5, 2.9Hz, 1H), 7.19 (d, J = 8.4Hz, 1H) ,6.84(d,J=9.3Hz,2H),6.73(d,J=2.4Hz,1H),4.60(d,J=15.3Hz,1H),4.37–4.24(m,2H),3.86(d, J=11.7Hz, 1H), 3.76(s, 3H), 3.45-3.34(m, 5.2Hz, 1H), 3.29-3.14(m, 3H), 3.13-3.04(m, 1H), 1.30-1.22(m , 1H), 1.17(d, J=6.5Hz, 6H), 0.85–0.77(m, 2H), 0.50(t, J=5.0Hz, 2H).

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The chemical ratio of pyridin-2(1H)-one to hydrochloric acid is 1:2.

Analysis and identification by differential scanning calorimeter, the scanning speed is 10°C/min, including an endothermic peak of 238.8°C (peak temperature), and there is an error tolerance of ±3°C. The hydrochloride salt form I is an anhydrous crystal form.

Example 2: 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine- Preparation of Hydrochloride Form II of 2(1H)-Kone

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone (1.5g, 4.268mmol) was dissolved in ethanol (7mL), 100μL of the above solution was added dropwise with 0.5ml of ethyl acetate to dilute, then 37% hydrochloric acid (4.7μL) was added, and the reaction was stirred at room temperature for 72 hours, centrifuged, and the solid was vacuum dried for 4 hours. Through Aeris X-ray powder diffraction (XRPD) analysis and identification, its XRPD data are shown in Table 2, and the XRPD figure is shown in Figure 2, which is 5-((2-(cyclopropylmethyl)-1,2,3, 4-Tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one hydrochloride salt form II.

¹ H NMR (400MHz, Methanol-d 4): δ7.55 (d, J = 2.7Hz, 1H), 7.30 (dd, J = 9.5, 2.8Hz, 1H), 7.06 (d, J = 8.6Hz, 1H ),6.68(dd,J=8.6,2.6Hz,1H),6.61(d,J=9.5Hz,1H),6.50(d,J=2.6Hz,1H),4.33(s,2H),3.60(s ,3H),3.54–3.51(m,1H),3.16–2.99(m,4H),1.28–1.19(m,1H),1.17(s,3H),1.16(s,3H),0.85–0.73(m ,2H),0.51–0.42(m,2H).

It was analyzed and identified by differential scanning calorimetry with a scanning speed of 10°C/min, including endothermic peaks at 101.46°C and 219.39°C (peak temperature), with an error tolerance of ±3°C.

Example 3: 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine- Preparation of p-toluenesulfonate crystal form I of 2(1H)-ketone

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone (1.5g, 4.268mmol) was dissolved in ethanol (7mL), 10.3mg of p-toluenesulfonic acid was weighed and 0.5ml of acetonitrile was added, and 100 μL of the above solution was added dropwise, stirred and reacted at room temperature for 60 hours, centrifuged, and the solid was vacuum-dried for 10 Hour. Through Aeris X-ray powder diffraction (XRPD) analysis and identification, its XRPD data are shown in Table 3, and the XRPD figure is shown in Figure 3, which is 5-((2-(cyclopropylmethyl)-1,2,3, 4-Tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, p-toluenesulfonate salt form I.

¹ H NMR (400MHz, Methanol-d4): δ7.67 (d, J = 7.8Hz, 2H), 7.56 (d, J = 2.7Hz, 1H), 7.30 (dd, J = 9.5, 2.8Hz, 1H) ,7.22(d,J=7.9Hz,2H),7.06(d,J=8.6Hz,1H),6.69(dd,J=8.6,2.6Hz,1H),6.61(d,J=9.5Hz,1H) ,6.50(d,J＝2.5Hz,1H),4.62–4.44(m,1H),4.37–4.17(m,2H),3.90–3.74(m,1H),3.59(s,3H),3.42–3.32 (m,1H),3.23–3.07(m,3H),3.06–2.94(m,1H),2.37(s,3H),1.25–1.18(m,1H),1.16(d,J＝6.5Hz,6H ), 0.83–0.76 (m, 2H), 0.47 (d, J=4.9Hz, 2H). Through nuclear magnetic spectrum analysis, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The chemical ratio of pyridin-2(1H)-one to p-toluenesulfonic acid is 1:1.

Analysis and identification by differential scanning calorimeter, the scanning speed is 10°C/min, including an endothermic peak at 203.15°C (peak temperature), and there is an error tolerance of ±3°C. The p-toluenesulfonate is in the form of anhydrous crystals.

Example 4: 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine- Preparation of fumarate crystal form I of 2(1H)-ketone

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone (1.5g, 4.268mmol) was dissolved in ethanol (7mL), weighed 6.2mg of fumaric acid and added 0.5ml of acetonitrile, continued to drop 100μL of the above solution, stirred and reacted at room temperature for 60 hours, centrifuged, and dried the solid in vacuum for 10 Hour. Through Aeris X-ray powder diffraction (XRPD) analysis and identification, its XRPD data are as shown in Table 4, and the XRPD figure is as shown in Figure 4, which is 5-((2-(cyclopropylmethyl)-1,2,3, Form I of fumarate salt of 4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

¹ H NMR (400MHz, Methanol-d4): δ7.56 (d, J = 2.8Hz, 1H), 7.30 (dd, J = 9.5, 2.8Hz, 1H), 7.05 (d, J = 8.6Hz, 1H) ,6.70–6.65(m,1H),6.65(s,2H),6.61(d,J=9.5Hz,1H),6.49(d,J=2.6Hz,1H),4.36(s,2H),3.60( s, 3H), 3.57–3.53(m, 1H), 3.13(d, J=7.3Hz, 2H), 3.07(t, J=6.4Hz, 2H), 1.26–1.18(m, 1H), 1.17(s ,3H), 1.15(s,3H), 0.84–0.74(m,2H), 0.50-0.42(m,2H). Through nuclear magnetic spectrum analysis, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The chemical ratio of pyridin-2(1H)-one to fumaric acid is 1:1.

Analysis and identification by differential scanning calorimeter, the scanning speed is 10°C/min, including endothermic peaks at 115.47 and 157.84°C (peak temperature), and there is an error tolerance of ±3°C. The fumarate is in anhydrous crystal form.

Example 5: 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine- Preparation of fumarate salt form II of 2(1H)-keto

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone (1.5g, 4.268mmol) was dissolved in ethanol (7mL), weighed 6.3mg p-fumaric acid and added 0.5ml ethyl acetate, continued to add 100μL of the above solution, stirred and reacted at room temperature for 60 hours, centrifuged, solid vacuum Let dry for 10 hours. Through Aeris X-ray powder diffraction (XRPD) analysis identification, its XRPD data are as shown in table 5, and XRPD pattern is as shown in Figure 5, is 5-((2-(cyclopropylmethyl)-1,2,3,4 -Form II fumarate salt of tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

¹ H NMR (400MHz, Methanol-d4): δ7.56 (d, J = 2.8Hz, 1H), 7.30 (dd, J = 9.5, 2.8Hz, 1H), 7.05 (d, J = 8.6Hz, 1H) ,6.69–6.65(m,1H),6.64(s,2H),6.61(d,J=9.5Hz,1H),6.49(d,J=2.6Hz,1H),4.36(s,2H),3.59( s, 3H), 3.56–3.52(m, 1H), 3.12(d, J=7.3Hz, 2H), 3.07(t, J=6.4Hz, 2H), 1.26–1.18(m, 1H), 1.17(s ,3H), 1.15(s,3H), 0.83–0.72(m,2H), 0.46(q,J=5.2Hz,2H).

Through nuclear magnetic spectrum analysis, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The chemical ratio of pyridin-2(1H)-one to fumaric acid is 1:1.

Analysis and identification by differential scanning calorimeter, the scanning speed is 10°C/min, including an endothermic peak of 180.03°C (peak temperature), and there is an error tolerance of ±3°C. The fumarate is in anhydrous crystal form.

Example 6: 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine- Preparation of the maleate crystal form I of 2(1H)-ketone

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone (1.5g, 4.268mmol) was dissolved in ethanol (7mL), weighed 6.3mg p-maleic acid and added 0.5ml acetonitrile, continued to drop 100μL of the above solution, stirred and reacted at room temperature for 60 hours, centrifuged, and dried the solid in vacuum for 10 Hour. Through Aeris X-ray powder diffraction (XRPD) analysis and identification, its XRPD data are shown in Table 6, and the XRPD figure is shown in Figure 6, which is 5-((2-(cyclopropylmethyl)-1,2,3, Form I of the maleate salt of 4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

¹ H NMR (400MHz, Methanol-d4): δ7.28 (d, J = 2.7Hz, 1H), 7.02 (dd, J = 9.5, 2.8Hz, 1H), 6.77 (d, J = 8.6Hz, 1H) ,6.39(dd,J=8.6,2.6Hz,1H),6.32(d,J=9.5Hz,1H),6.21(d,J=2.6Hz,1H),5.93(s,2H),4.11(s, 2H), 3.31(s, 3H), 3.06-2.99(m, 1H), 2.88(d, J=7.3Hz, 2H), 2.80(t, J=6.5Hz, 2H), 1.06-0.92(m, 1H ), 0.88(s,3H), 0.87(s,3H), 0.60–0.44(m,2H), 0.22–0.16(m,2H).

Through nuclear magnetic spectrum analysis, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The chemical ratio of pyridin-2(1H)-one to maleic acid is 1:1.

test case

Test Example 1: Trait Study

5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H) - The appearance of the ketone raw material drug is dark green gelatinous and viscous, which is not conducive to the use in the subsequent development of preparations.

After being made into acid salt, the appearance is crystal or powdery solid, which is convenient for storage, weighing and subsequent preparation processing and use.

Test Example 2: 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine- Hygroscopicity test of 2(1H)-ketone salt type

Take an appropriate amount of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2( 1H)-Different salt forms of ketones are laid flat in glass bottles with a thickness of about 1mm. Place the open glass bottles in a closed environment at 25°C±1°C and relative humidity of 80%±4%. After 5 days of constant humidity Investigate the hygroscopicity of each salt type. Among them, the hygroscopicity results of hydrochloride are shown in Table 7 and Figure 9 below.

Table 7:

XRPD detection showed that, as shown in FIG. 9 , the crystal form I of the hydrochloride salt did not change after being placed at a humidity of 80%±4%RH for 5 days. The results show that the acid salt of Compound I provided by the present invention has little or no hygroscopicity.

Test Example 3: 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine- Stability test of 2(1H)-keto salt

Take an appropriate amount of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2( 1H)-Different salt forms of ketones are laid flat in glass bottles with a thickness of about 1.5mm, and the open glass bottles are placed at 25°C±3°C and relative humidity 60%±5% (i.e. room temperature, room humidity) And in the environment of 40 ℃, relative humidity 75%, take samples at 5 days and 10 days, carry out XRPD detection, carry out HPLC content (w/w, %) determination at the same time, and compare with the result of 0 days, evaluate the salt type stability.

Taking hydrochloride as an example, under the conditions of room temperature, room humidity and 40°C 75% RH, the physical and chemical stability of hydrochloride is good, and the test results are shown in Table 8.

Table 8:

As shown in Figures 7 and 8, the crystal form of the hydrochloride salt form I did not change for 10 days under the conditions of room temperature, room humidity and 40°C 75%RH.

Test example 4: sigma-1 agonist function test

According to literature reports ([J].Synapse,2005,55(3):192-195.), phenytoin can change the configuration of sigma-1 receptors, in the presence of phenytoin, the Ki value of the agonist and the normal Ki value Relatively smaller, the Ki value of the inhibitor is larger than the normal Ki value.

The specific operations in the references ([J].Synapse, 2005,55(3):192-195.), taking compound I hydrochloride as an example, detect the Ki value of the compound of the present invention, and the Ki value detection method of the phenytoin group is Add phenytoin additionally to the test substance tube, and check the Ki value after adding phenytoin. Normal Ki value/Ki value of phenytoin group>1, can be judged as agonist.

The experimental results in Table 9 indicate that compound I hydrochloride has a ratio (normal Ki/phenytoin group Ki)>1, which means it is an agonist.

Table 9. Ki value and ratio between normal group and phenytoin group

Ki value (nM) Sigma-1 (Normal Ki) 49.62 Sigma-1 (phenytoin group Ki) 47.88 ratio 1.04

Test Example 5: Drug efficacy test in mice

Mice forced swimming test (FST): adopt male ICR mice, body weight 18-22g, be divided into vehicle control group, positive control group (duloxetine, 15mg/kg), test group (acid salt of compound I , 30, 60, 90mg/kg). The test group, the vehicle group and the positive control group were intraperitoneally injected with the test substance or vehicle 30 minutes before formal swimming, and then the mice were subjected to the forced swimming test. Put the mouse into a transparent glass cylinder (water depth 15cm, water temperature 23-25°C) for 6 minutes, and video record the activity state of the mouse. After the experiment, use the Forced Swim ScanTM 2.0 software to analyze the mouse's forced swimming in 6 minutes. Cumulative immobility time results for 4 minutes after the period.

Taking compound I hydrochloride as an example, in the forced swimming model of mice, the duloxetine group (positive control) showed a very significant drug effect (p<0.0001), and compound I hydrochloride had no drug effect at 30 mg/kg , at 60mg/kg there is a significant effect (p<0.05), at 90mg/kg there is a very significant effect (p<0.0001).

Claims (15)

1. A 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl) (isopropyl) amino)-1-methylpyridine- The acid salt of 2 (1H)-ketone is characterized in that, described acid salt is selected from hydrochloride, tosylate, fumarate, or maleate, and preferably described acid salt is Hydrochloride or p-toluenesulfonate. 2. 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1 according to claim 1 -Acid salt of methylpyridin-2(1H)-one, characterized in that 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline-7- The molar ratio of (isopropyl)amino)-1-methylpyridin-2(1H)-one to acid is 1:1~2, preferably 1:1. 3. A crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The acid salt of pyridin-2 (1H)-one is characterized in that, the acid salt is selected from hydrochloride crystal form I or hydrochloride crystal form II, Said hydrochloride salt form I, its X-ray powder diffraction pattern includes positions at 10.00°±0.2°, 11.99°±0.2°, 17.45°±0.2°, 23.15°±0.2°, 24.22°±0.2° and 26.58°±0.2° The peak at the diffraction angle (2θ) of 0.2°; Said hydrochloride salt form II, its X-ray powder diffraction pattern includes positions at 9.17°±0.2°, 15.33°±0.2°, 16.17°±0.2°, 18.24°±0.2°, 18.77°±0.2°, 22.58°±0.2° Peaks at diffraction angles (2θ) of 0.2° and 24.10°±0.2°; Further preferably, the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1 - an acid salt of methylpyridin-2(1H)-one, characterized in that, The X-ray powder diffraction pattern of the hydrochloride salt form I includes 7.97°±0.2°, 9.19°±0.2°, 10.00°±0.2°, 11.99°±0.2°, 17.45°±0.2°, 20.92°±0.2°, 20.92°±0.2° Peaks at diffraction angles (2θ) of 0.2°, 23.15°±0.2°, 24.22°±0.2°, and 26.58°±0.2°; The X-ray powder diffraction pattern of the hydrochloride salt form II includes positions at 9.17°±0.2°, 11.18°±0.2°, 14.75°±0.2°, 15.33°±0.2°, 16.17°±0.2°, 18.24°±0.2°, Peaks at diffraction angles (2θ) of 0.2°, 18.77°±0.2°, 22.58°±0.2°, 24.10°±0.2° and 29.52°±0.2°. 4. crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl) (isopropyl) amino according to claim 3 )-1-methylpyridin-2(1H)-one acid salt, characterized in that, The hydrochloride salt form I, its X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 1; The X-ray powder diffraction pattern of the hydrochloride salt form II is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 2; and/or, The crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The acid salt of pyridin-2(1H)-one is characterized in that, when characterized by DSC, it is analyzed and identified by differential scanning calorimetry, and the scanning speed is 10°C/min. The hydrochloride salt form I contains an endothermic peak with a peak temperature of 238.8°C±3°C; The hydrochloride salt form II contains endothermic peaks with peak temperatures of 101.46±3°C and 219.39°C±3°C. 5. A crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The acid salt of ylpyridin-2(1H)-one is characterized in that, the acid salt is selected from p-toluenesulfonate crystal form I, and its X-ray powder diffraction pattern includes 7.78°±0.2°, 10.34° ±0.2°, 11.50°±0.2°, 12.03°±0.2°, 14.00°±0.2°, 16.64°±0.2°, 17.66°±0.2°, 19.71°±0.2°, 20.86°±0.2°, 22.26±0.2° and the peak at the diffraction angle (2θ) of 23.08° ± 0.2°; Further preferably, the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1 - the acid salt of methylpyridin-2(1H)-one, characterized in that the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I includes positions at 7.78°±0.2°, 10.34°±0.2°, 11.50°±0.2°, 12.03°±0.2°, 14.00°±0.2°, 15.46±0.2°, 15.91±0.2°, 16.64°±0.2°, 17.66°±0.2°, 19.04±0.2°, 19.71°±0.2° , peaks at diffraction angles (2θ) of 20.86°±0.2°, 21.66±0.2°, 22.26±0.2°, 23.08°±0.2° and 24.58±0.2°. 6. crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl) (isopropyl) amino according to claim 5 )-1-methylpyridin-2(1H)-one acid salt, characterized in that, the X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I and the diffraction angle (2θ) shown in Figure 3 The peaks at are substantially identical; and/or, The crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The acid salt of pyridin-2(1H)-one is characterized in that, when characterized by DSC, it is analyzed and identified by differential scanning calorimetry, and the scanning speed is 10°C/min. The p-toluenesulfonate crystal form I contains an endothermic peak with a peak temperature of 203.15°C ± 3°C. 7. A crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The acid salt of ylpyridin-2(1H)-one is characterized in that, the acid salt is selected from fumarate crystal form I or fumarate crystal form II, The fumarate crystal form I, its X-ray powder diffraction pattern includes 7.90°±0.2°, 10.36°±0.2°, 11.89°±0.2°, 12.44°±0.2°, 15.89°±0.2°, 17.73° Peaks at diffraction angles (2θ) of ±0.2°, 19.91°±0.2°, 22.15°±0.2°, 23.98°±0.2° and 28.04°±0.2°; The fumarate salt crystal form II has an X-ray powder diffraction pattern at 9.56°±0.2°, 12.50°±0.2°, 16.79°±0.2°, 21.60°±0.2°, 23.06°±0.2° and 25.79° Peaks at diffraction angles (2θ) of ±0.2°; Preferably, the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1- An acid salt of picoline-2(1H)-one, characterized in that, The fumarate salt crystal form I, its X-ray powder diffraction pattern includes: Diffraction angles of 0.2°, 17.08±0.2°, 17.73°±0.2°, 19.91°±0.2°, 20.38±0.2°, 22.15°±0.2°, 23.98°±0.2°, 24.54±0.2° and 28.04°±0.2° The peak at (2θ); The fumarate salt form II, its X-ray powder diffraction pattern includes 8.35°±0.2°, 9.56°±0.2°, 12.50°±0.2°, 16.79°±0.2°, 18.66°±0.2°, 20.40° Peaks at diffraction angles (2θ) of ±0.2°, 21.60°±0.2°, 23.06°±0.2° and 25.79°±0.2°. 8. crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl) (isopropyl)amino according to claim 7 )-1-methylpyridin-2(1H)-one acid salt, characterized in that, The fumarate crystal form I, its X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 4; The fumarate salt crystal form II, its X-ray powder diffraction pattern is substantially the same as the peak at the diffraction angle (2θ) shown in Figure 5; and/or, The crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The acid salt of pyridin-2(1H)-one is characterized in that, when characterized by DSC, it is analyzed and identified by differential scanning calorimetry, and the scanning speed is 10°C/min. The fumarate salt form I contains endothermic peaks with peak temperatures of 115.47±3°C and 157.84°C±3°C; The fumarate salt form II contains an endothermic peak with a peak temperature of 180.03°C±3°C. 9. A crystalline form of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methyl The acid salt of base pyridin-2 (1H)-one is characterized in that, the acid salt is selected from the maleate crystal form I, the maleate salt crystal form I, and its X-ray powder diffraction pattern includes Located at 4.06°±0.2°, 8.11°±0.2°, 10.82°±0.2°, 12.18°±0.2°, 13.58°±0.2°, 16.27°±0.2°, 18.23°±0.2°, 20.38°±0.2°, 24.28 Peaks at diffraction angles (2θ) of °±0.2° and 28.68°±0.2°; Further preferably, the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1 - the acid salt of methylpyridin-2(1H)-one, characterized in that, the maleate salt crystal form I, its X-ray powder diffraction pattern includes positions at 4.06°±0.2°, 8.11°±0.2°, 9.08±0.2°, 10.82°±0.2°, 12.18°±0.2°, 13.58°±0.2°, 16.27°±0.2°, 16.82±0.2°, 18.23°±0.2°, 20.38°±0.2°, 24.28°±0.2 °, peaks at diffraction angles (2θ) of 28.21±0.2° and 28.68°±0.2°; More preferably, the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)- The acid salt of 1-methylpyridin-2(1H)-one is characterized in that, the maleate salt crystal form I, its X-ray powder diffraction pattern is the same as that at the diffraction angle (2θ) shown in Figure 6 The peaks are essentially the same. 10. 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl) as described in any one of claims 1 to 2 The preparation method of the acid salt of amino)-1-methylpyridin-2(1H)-one, comprising: 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone free base is dissolved or dispersed in organic solvent, then add the liquid of inorganic acid or organic acid, or add the solid of inorganic acid or organic acid, or the solution of acid, prepare 5-((2-(cyclopropyl methyl base)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one acid salt; or 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H )-ketone is added to a solution of acid to prepare 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino) - Acid salt of 1-methylpyridin-2(1H)-one; Wherein 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridine-2(1H The molar ratio of )-ketone to acid is 1:1~2.5. 11. 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl) (iso The preparation method of the acid salt of propyl) amino)-1-methylpyridin-2 (1H)-one comprises: (1) Prepare 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino) by the method described in claim 10 - Acid salt of 1-methylpyridin-2(1H)-one; (2) Collect the solid product precipitated during the salt-forming reaction in step (1), or obtain the solid product by creating a supersaturated solution in the salt-forming system. The method for creating a supersaturated solution includes: volatilizing the solvent, or adding an anti-solvent , or by cooling down to obtain crystallized 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)- Acid salt of 1-methylpyridin-2(1H)-one; And/or, one crystal form of the acid salt is converted into another crystal form of the salt by means of crystal form conversion. 12. according to the described preparation method of any one of claim 10～11, wherein used organic solvent in the salt-forming process is methyl alcohol, ethanol, Virahol, methylene chloride, acetone, ether, ethyl acetate, such as normal hexane, n-heptane, acetonitrile or mixtures thereof, preferably ethanol, ethyl acetate, acetonitrile or mixtures thereof. 13. The preparation method according to any one of claims 10-12, characterized in that the acid solution is an acid ethyl acetate solution or an acid acetonitrile solution. 14. A pharmaceutical composition, characterized in that it comprises the 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquine described in any one of claims 1 to 2 Lin-7-yl) (isopropyl) amino)-1-methylpyridin-2 (1H)-one acid salt, or the 5-((( Acid of 2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one Formula salt and pharmaceutically acceptable carrier or excipient. 15. 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl) as described in any one of claims 1 to 2 Acid salt of amino)-1-methylpyridin-2(1H)-one, or 5-((2-(cyclopropylmethyl)-1 , the acid salt of 2,3,4-tetrahydroisoquinolin-7-yl) (isopropyl) amino)-1-methylpyridin-2 (1H)-one, or the medicine described in claim 14 The application of the composition in the preparation of drugs for treating neuropsychiatric diseases; preferably, the neuropsychiatric diseases are selected from any one of depression and anxiety.

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