Acid salts of Sigma-1 receptor agonists, their crystal forms, and methods for their preparation and uses

Abstract

The present invention provides an acid salt of a Sigma-1 receptor agonist or a crystal form thereof, and a preparation method and application thereof. Specifically, it relates to an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one having high affinity for the sigma-1 receptor and a crystal form thereof. The present invention relates to a preparation method of the acid salt and the crystal form and its application in the pharmaceutical field. The acid salt of the compound 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one and the crystal form thereof provided by the present invention have improved physical and chemical properties, such as appearance, hygroscopicity and chemical stability.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to an acid salt of a Sigma-1 receptor agonist, its crystal form, and its preparation method and application. Specifically, it relates to an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one which has a high affinity for the sigma-1 receptor and its crystal form. The present invention also relates to the preparation method of the acid salt and crystal form and their application in the medical field. Background Art

[0002] Sigma receptors (σ receptors) are cell surface receptors in the central nervous system (CNS), which may be related to the restlessness, hallucination and cardiac stimulation effects of opioid drugs. Through the research on the biology and function of σ receptors, it has been confirmed that σ receptor ligands can be used to treat mental diseases and movement disorders, such as dystonia and tardive dyskinesia, as well as movement disorders related to Huntington's chorea or Tourette's syndrome and Parkinson's disease (Walker, J.M. et al., Pharmacological Reviews, 1990, 42, 355). It has been reported that the known σ receptor ligand, lincosamide, has shown clinical therapeutic effects on mental diseases (Snyder, S.H., Largent, B.L. J. Neuropsychiatry 1989, 1, 7).

[0003] Sigma receptors have at least two subtypes, among which Sigma-1 receptor (σ1 receptor) is a newly emerging drug target in recent years and is the binding protein of a variety of specific psychotropic drugs. Sigma-1 receptor is a ligand-regulated protein molecular chaperone, which plays its molecular chaperone role by interacting with receptors such as NMDA: regulating NMDA, APMA and other ion channels and downstream receptors, thereby regulating mitochondrial function and the release of neurotransmitters such as serotonin and dopamine.

[0004] Known sigma-1 receptor agonists such as opipramol, igmesine, SA-4503, ANAVEX2-73, etc. have shown antidepressant and anxiolytic effects clinically. Compounds such as benzomorphans (SKF10047, dextromethorphan), SSRI antidepressants (fluvoxamine, sertraline, fluoxetine, etc.) all have a high affinity for the Sigma-1 binding site.

[0005] Currently, the prior art has disclosed different Sigma-1 receptor agonists, such as: Igmesine, Cutamesine, OPC-14523, Opipramol, PRE-084, SA-4503, ANAVEX2-73, ANAVEX1-41, ANAVEX3-71d, etc., which have obvious antidepressant effects; Patent WO2017190109 has disclosed the structures of some sigma receptor agonists and their uses for CNS-related diseases.

[0006] However, Igmesine, which has made the fastest clinical progress, has failed in the clinical phase 3 experiment. In addition to targeting the sigma-1 target, the marketed Opipramol is also a dopamine D2 receptor antagonist and a histamine H1 receptor antagonist. This multi-target effect has brought certain side effects at the same time. Summary of the Invention

[0007] The inventors of the present invention have for the first time studied and found that 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one has good affinity and selectivity for the sigma-1 receptor, has good safety and metabolic stability, and has very good application prospects in the treatment and prevention of central nervous system diseases, especially in anti-depression and anti-anxiety. The relevant content is recorded in PCT / CN2021 / 103543, and all the content recorded in this patent is incorporated into the present invention by reference.

[0008] The structural formula of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one is shown as Formula I below:

[0009]

[0010] There is currently no literature reporting on the study of the acid salts and crystal forms of the compound 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

[0011] The physical properties of a pharmaceutically active ingredient vary depending on its solid form. These differences in physical properties can affect, for example, the manufacturing method, the mode of administration, and the formulation of the pharmaceutically active ingredient. Generally, the physical properties can be modified by using salts or crystalline solids. Another important solid-state property of a pharmaceutical compound is its dissolution rate in aqueous fluids. In particular, the solid form of an active ingredient for oral administration may also affect its solubility, bioavailability, stability, etc. The solid-state physical properties of polymorphic compounds also include, for example, the flowability of the comminuted solid, which affects the ease of operation during the processing of the drug product, and the solid form of the compound also affects its compressibility and storage stability.

[0012] During the research process, the inventors found that the compound represented by Formula I is usually a viscous gel, which is inconvenient for storage and weighing and is not conducive to subsequent formulation development. The object of the present invention is to further study and develop different salts and / or crystalline solids of this compound to make the active pharmaceutical compound more suitable for drug development.

[0013] To improve the physicochemical properties of the compound 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, such as appearance, hygroscopicity, and chemical stability, the inventors have conducted in-depth research on the different solid forms of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one. Acid salts of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, their crystal forms, and preparation methods are provided.

[0014] 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, defined as Compound I, has the following structure:

[0015] Its preparation method is described in PCT / CN2021 / 103543.

[0016] The first aspect of the present invention provides acid salts of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, and the acid salts include inorganic acid salts or organic acid salts; the inorganic acid salts are selected from hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide or phosphate, more preferably hydrochloride; the organic acid salts are selected from p-toluenesulfonate, fumarate, tartrate, maleate, acetate, adipate, benzenesulfonate, 4-chlorobenzenesulfonate, benzoate, caprate, caproate, caprylate, cinnamate, citrate, cyclohexanesulfamate, gluconate, glucuronate, glutamate, isoascorbate, lactate, aspartate, malate, mandelate, mesylate, esylate, galactonate, glutarate, hippurate, lactobionate, ascorbate, aspartate, laurate, malonate, 1,5-naphthalenedisulfonate, naphthalene-2-sulfonate, nicotinate, oleate, oxalate, palmitate, sebacate, stearate, succinate, trifluoroacetate, succinate, more preferably p-toluenesulfonate, fumarate, or maleate.

[0017] In a specific embodiment of the present invention, for the acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, the molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one (Compound I) to the acid is 1:1 to 2, preferably 1:1 or 1:2.

[0018] Another aspect of the present invention provides a crystalline acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, and the acid salt is hydrochloride, selected from hydrochloride crystal form I or hydrochloride crystal form II, wherein, for the hydrochloride crystal form I, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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°.

[0019] Preferably, it includes peaks at diffraction angles (2θ) of 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 26.58° ± 0.2°.

[0020] More preferably, it includes peaks at diffraction angles (2θ) of 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°.

[0021] Most preferably, its X-ray powder diffraction pattern is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 1 and its X-ray powder diffraction data are shown in Table 1 as follows:

[0022] Table 1:

[0023]

[0024]

[0025] The present invention provides crystalline form II of the hydrochloride salt of compound I, and its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.17° ± 0.2°, 15.33° ± 0.2°, 16.17° ± 0.2°, 18.24° ± 0.2°, 18.77° ± 0.2°, 22.58° ± 0.2°, and 24.10° ± 0.2°.

[0026] Preferably, the crystalline form II of the hydrochloride salt, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.17° ± 0.2°, 11.18° ± 0.2°, 14.75° ± 0.2°, 15.33° ± 0.2°, 16.17° ± 0.2°, 18.24° ± 0.2°, 18.77° ± 0.2°, 22.58° ± 0.2°, 24.10° ± 0.2°, and 29.52° ± 0.2°.

[0027] More preferably, the crystalline form II of the hydrochloride salt, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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 ± 0.2°, 28.67 ± 0.2°, and 29.52° ± 0.2°.

[0028] Most preferably, for the hydrochloride crystal form II, its X-ray powder diffraction pattern is substantially the same as the peaks at the diffraction angles (2θ) shown in Figure 2 and its X-ray powder diffraction data are shown in Table 2 as follows:

[0029] Table 2:

[0030]

[0031]

[0032] The hydrochloride salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one provided by the present invention, including hydrochloride crystal form I and hydrochloride crystal form II, can also be characterized by DSC, analyzed and identified by a differential scanning calorimeter at a scanning rate of 10 °C / minute. The hydrochloride crystal form I contains an endothermic peak with a peak temperature of 238.8 °C ± 3 °C; the hydrochloride crystal form II contains endothermic peaks with peak temperatures of 101.46 °C ± 3 °C and 219.39 °C ± 3 °C.

[0033] In one embodiment of the present invention, the molar ratio of salification of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to hydrochloric acid is 1:1 or 1:2.

[0034] In one embodiment of the present invention, an acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one is provided. The acid salt is p-toluenesulfonate, selected from p-toluenesulfonate crystal form I, and its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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 23.08° ± 0.2°.

[0035] Preferably, for the p-toluenesulfonate polymorph I, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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°, 23.08° ± 0.2° and 24.58 ± 0.2°.

[0036] Most preferably, for the p-toluenesulfonate polymorph I, its X-ray powder diffraction pattern is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 3 and its X-ray powder diffraction data are shown in Table 3 as follows:

[0037] Table 3:

[0038]

[0039]

[0040] The p-toluenesulfonate polymorph I of the present invention can also be characterized by DSC, identified by differential scanning calorimetry analysis with a scanning rate of 10 °C / minute, and the p-toluenesulfonate polymorph I contains an endothermic peak with a peak temperature of 203.15 °C ± 3 °C.

[0041] Further preferably, the molar ratio of salt formation of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to p-toluenesulfonic acid is 1:1.

[0042] In one embodiment of the present invention, there is provided an acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, and the acid salt is fumarate, including fumarate polymorph I or fumarate polymorph II, wherein,

[0043] for the fumarate polymorph I, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 7.90° ± 0.2°, 10.36° ± 0.2°, 11.89° ± 0.2°, 12.44° ± 0.2°, 15.89° ± 0.2°, 17.73° ± 0.2°, 19.91° ± 0.2°, 22.15° ± 0.2°, 23.98° ± 0.2° and 28.04° ± 0.2°.

[0044] Preferably, the fumarate polymorph I has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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°.

[0045] Most preferably, the fumarate polymorph I has an X-ray powder diffraction pattern substantially the same as the peaks at diffraction angles (2θ) shown in Figure 4 and its X-ray powder diffraction data are shown in Table 4 as follows:

[0046] Table 4:

[0047]

[0048]

[0049] The fumarate polymorph II has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 9.56° ± 0.2°, 12.50° ± 0.2°, 16.79° ± 0.2°, 21.60° ± 0.2°, 23.06° ± 0.2° and 25.79° ± 0.2°.

[0050] Preferably, the fumarate polymorph II has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.35° ± 0.2°, 9.56° ± 0.2°, 12.50° ± 0.2°, 16.79° ± 0.2°, 18.66° ± 0.2°, 20.40° ± 0.2°, 21.60° ± 0.2°, 23.06° ± 0.2° and 25.79° ± 0.2°.

[0051] More preferably, the fumarate polymorph II has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 8.35° ± 0.2°, 9.56° ± 0.2°, 12.50° ± 0.2°, 13.40 ± 0.2°, 15.52 ± 0.2°, 16.79° ± 0.2°, 18.66° ± 0.2°, 20.40° ± 0.2°, 21.60° ± 0.2°, 23.06° ± 0.2° and 25.79° ± 0.2°.

[0052] Most preferably, the fumarate polymorph II has an X-ray powder diffraction pattern substantially the same as the peaks at diffraction angles (2θ) shown in Figure 5 and its X-ray powder diffraction data are shown in Table 5 as follows:

[0053] Table 5:

[0054]

[0055]

[0056] The fumarate polymorph I or fumarate polymorph II of the present invention can also be characterized by DSC, analyzed and identified by a differential scanning calorimeter, with a scanning rate of 10 °C / minute.

[0057] The fumarate polymorph I includes endothermic peaks with peak temperatures of 115.47 ± 3 °C and 157.84 °C ± 3 °C.

[0058] The fumarate polymorph II includes an endothermic peak with a peak temperature of 180.03 °C ± 3 °C.

[0059] Further preferably, the acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one is fumarate, including fumarate polymorph I or fumarate polymorph II, wherein the molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to fumaric acid for salt formation is 1:1.

[0060] In one embodiment of the present invention, there is provided an acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, and the acid salt is maleate, selected from maleate polymorph I.

[0061] The maleate polymorph I has an X-ray powder diffraction pattern including peaks at diffraction angles (2θ) of 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° ± 0.2° and 28.68° ± 0.2°.

[0062] Preferably, the maleate polymorph I has an X-ray powder diffraction pattern comprising peaks at diffraction angles (2θ) of 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°, 28.21 ± 0.2° and 28.68° ± 0.2°.

[0063] Most preferably, the maleate polymorph I has an X-ray powder diffraction pattern that is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 6 and its X-ray powder diffraction data are shown in Table 6 as follows:

[0064] Table 6:

[0065]

[0066]

[0067] Further preferably, the acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one in crystalline form is maleate, selected from maleate polymorph I, wherein the molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin- or 2(1H)-one to maleic acid for salt formation is 1:1.

[0068] As used herein, the term "substantially the same" with respect to the position of X-ray diffraction peaks means considering typical peak position and intensity variability. For example, those skilled in the art will understand that the peak position (2θ) will vary due to different XRPD instruments, sometimes by up to 0.2°. In addition, those skilled in the art will understand that factors such as XRPD sample preparation methods, XRPD instruments, sample crystallinity, sample amount, and crystal preferred orientation will result in changes in the relative peak intensities in the XRPD diffraction pattern of the sample.

[0069] On the other hand, the present invention also provides a method for preparing an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, comprising:

[0070] Dissolve or disperse 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one free base in an organic solvent, and then add a liquid of an inorganic acid or an organic acid, or add a solid of an inorganic acid or an organic acid, or a solution of an acid to prepare an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one; or,

[0071] Add 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to a solution of an acid to prepare an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one; wherein the molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to the acid in the feed is 1:1 to 2.5. The molar ratio of the acid in the feed is related to the content of the acid in the prepared acid salt. For example, when preparing an acid salt with a molar ratio of 1:1, the molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to the acid in the feed is 1:1 to 1.1;

[0072] When preparing an acid salt with a molar ratio of 1:2, the molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to the acid in the feed is 1:2 to 2.5, preferably 1:2 to 2.1.

[0073] On the other hand, the present invention also provides a method for preparing a crystalline acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, comprising:

[0074] Prepare an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to the aforementioned method;

[0075] Collect the solid product precipitated during the above salt formation reaction, or obtain the solid product by creating a supersaturated solution in the salt formation system. The methods for creating a supersaturated solution include: evaporating the solvent, adding an antisolvent, or cooling, to obtain crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one acid salt;

[0076] And / or, by means of crystal form transformation, transform one crystal form of the acid salt into another crystal form of the salt. The crystal form transformation methods include: heating or suspension crystal transformation in a suitable solvent.

[0077] In the above methods, the suitable organic solvents used in the salt formation process include alcohols (such as methanol, ethanol, isopropanol), chloroalkanes (such as dichloromethane), ketones (such as acetone), ethers (such as diethyl ether), esters (such as ethyl acetate), alkanes (such as n-hexane, n-heptane), acetonitrile, benzenes, amides or mixtures thereof, preferably methanol, ethanol, ethyl acetate, acetonitrile or mixtures thereof; the solution of the acid is an ethyl acetate solution of the acid or an acetonitrile solution of the acid.

[0078] For example, the preparation method of hydrochloride crystal form I includes:

[0079] Add 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to dichloromethane and dissolve it completely, then add an ethyl acetate solution of hydrochloric acid, precipitate a solid, concentrate under reduced pressure and dry to obtain a dark green solid;

[0080] Among them, the molar feeding ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to hydrochloric acid is 1:1 to 2.5, preferably 1:2 to 2.1.

[0081] For example, the preparation method of compound I hydrochloride crystal form II includes:

[0082] Dissolve 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one in ethanol, preferably add ethyl acetate dropwise for dilution, then add concentrated hydrochloric acid, stir at room temperature, after the reaction is completed, centrifuge, and dry the solid under vacuum; among them, the molar feeding ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to hydrochloric acid is 1:1 to 2.5, preferably 1:1 to 1.1.

[0083] For example, the preparation method of compound I p-toluenesulfonate crystal form I includes:

[0084] Dissolve 5 - ((2-(cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one in ethanol, then add an acetonitrile solution of p - toluenesulfonic acid, stir at room temperature, after the reaction is completed, centrifuge, and dry the solid under vacuum;

[0085] Among them, the molar feeding ratio of 5 - ((2-(cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one to p - toluenesulfonic acid is 1:1 to 2.5, preferably 1:1 to 1.1.

[0086] For example, the preparation method of Compound I fumarate polymorph I includes:

[0087] Dissolve 5 - ((2-(cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one in ethanol, then add an acetonitrile solution of fumaric acid, stir at room temperature, after the reaction is completed, centrifuge, and dry the solid under vacuum; Among them, the molar feeding ratio of 5 - ((2-(cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one to fumaric acid is 1:1 to 2.5, preferably 1:1 to 1.1.

[0088] For example, the preparation method of Compound I fumarate polymorph II includes:

[0089] Dissolve 5 - ((2-(cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one in ethanol, then add an ethyl acetate solution of fumaric acid, stir at room temperature, after the reaction is completed, centrifuge, and dry the solid under vacuum;

[0090] Among them, the molar feeding ratio of 5 - ((2-(cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one to fumaric acid is 1:1 to 2.5, preferably 1:1 to 1.1.

[0091] For example, the preparation method of Compound I maleate polymorph I includes:

[0092] Dissolve 5 - ((2-(cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one in ethanol, then add an acetonitrile solution of maleic acid, stir at room temperature, after the reaction is completed, centrifuge, and dry the solid under vacuum for 10 hours;

[0093] Among them, the molar feeding ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to maleic acid is 1:1 to 2.5, preferably 1:1 to 1.1.

[0094] Another aspect of the present invention provides a pharmaceutical composition comprising an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one described in the present invention and a pharmaceutically acceptable carrier or excipient. Preferably, the acid salt is the hydrochloride, fumarate, maleate or p-toluenesulfonate of Compound I. More preferably, the acid salt is the hydrochloride of Compound I.

[0095] In another embodiment of the present invention, a pharmaceutical composition is provided, comprising the crystalline acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one described in the present invention and a pharmaceutically acceptable carrier or excipient; preferably, the crystalline acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one is hydrochloride crystal form I, hydrochloride crystal form II, fumarate crystal form I, fumarate crystal form II, p-toluenesulfonate crystal form I or maleate crystal form I.

[0096] Another aspect of the present invention provides the use of the acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, or the crystalline acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, or the pharmaceutical composition in the preparation of a drug for treating neuropsychiatric diseases; preferably, the neuropsychiatric diseases are selected from any one of depression and anxiety.

[0097] The present invention also provides a method for treating and / or preventing sigma-1 receptor-related diseases or disease states, which comprises administering to an individual in need thereof the acid salt of Compound I described in the present invention or the crystalline acid salt of Compound I, or a pharmaceutical composition comprising the acid salt of Compound I or its crystal form.

[0098] In another embodiment of the present invention, the acid salt of compound I of the present invention or the acid salt of the crystalline form of compound I, or a 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 mental diseases such as depression, anxiety, Alzheimer's disease, etc., preferably depression.

[0099] Beneficial effects: Compared with the prior art, the acid salt of compound I provided by the present invention, especially the hydrochloride salt, has significant improvements in physical and chemical properties. For example, it 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 active pharmaceutical ingredient can be maintained stable under conventional humidity storage conditions, and it can be better used in clinical treatment. In addition, the acid salt of compound I provided by the present invention has good sigma-1 affinity and shows good pharmacodynamic effects in mice. Compared with the free base of the compound, the acid salts of compound I provided by the present invention are all in solid crystal form or powder form, which is beneficial for storage, weighing, and subsequent formulation development. Description of the Drawings

[0100] The technical solutions of the present application will be further described below in conjunction with the drawings and embodiments.

[0101] Figure 1 is the XRPD pattern of crystalline form I of the hydrochloride salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one;

[0102] Figure 2 is the XRPD pattern of crystalline form II of the hydrochloride salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one;

[0103] Figure 3 is the XRPD pattern of crystalline form I of the p-toluenesulfonate salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one;

[0104] Figure 4 is the XRPD pattern of crystalline form I of the fumarate salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one;

[0105] Figure 5XRPD pattern of fumarate polymorph II of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one;

[0106] Figure 6 XRPD pattern of maleate polymorph I of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one;

[0107] Figure 7 XRPD comparative pattern of the hydrochloride salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one after being placed for 5 days and 10 days respectively at room temperature and room humidity;

[0108] Figure 8 XRPD comparative pattern of the hydrochloride salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one after being placed for 5 days and 10 days respectively at 40 °C and 75% RH;

[0109] Figure 9 XRPD comparative pattern of the hydrochloride salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one before and after being placed for 5 days at 25 °C ± 1 °C and 80% ± 4% RH humidity. Detailed implementation mode

[0110] 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.

[0111] The words "preferred", "preferably", "more preferably", "most preferably", 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 case 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 occasions where the event or circumstance occurs or does not occur. The sources of components not mentioned in the present invention are all commercially available.

[0112] As used in this specification, the term "crystalline form" means a crystal having a certain crystal form and formed by the regular arrangement of atoms, ions, molecules, etc. that make up a solid. Unless otherwise specified, "crystallization", "crystalline form" and "crystal form" in this specification are synonymous. The crystallinity of the crystalline form can be measured by various techniques such as, for example, X-ray powder diffraction measurement, water adsorption and desorption measurement, differential scanning calorimetry, solution colorimetry, dissolution characteristics, etc.

[0113] The crystalline solid of the present invention can be a single crystal, a twin crystal, a polycrystal, etc., and is usually a single crystal or a mixed crystal thereof. The form (outer shape) of the crystal is not particularly limited. 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 crystal, needle crystal (such as whisker crystal), etc. The size of the crystal is not particularly limited. For example, based on the laser diffraction method, the average particle diameter of the crystal can be 0.5 μm to 1 mm, preferably about 1 to 500 μm.

[0114] In addition, the acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one in crystalline form can also adsorb water due to the change in relative humidity, that is, the water molecules in the air can easily enter and exit the crystal lattice in the form of crystal water due to the change in external humidity; regarding such crystalline solids, even when the X-ray powder diffraction pattern shows some changes with the change 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 water can be any one of crystal water, adsorbed water and other residual solvents; in a preferred embodiment of the present invention, the acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one in crystalline form is anhydrous.

[0115] The "Compound I" and "5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one" described in the present invention refer to the same compound and can be replaced with each other, and both refer to the compound having the following structure:

[0116]

[0117] The crystal forms of the acid salts of Compound I according to the present invention are characterized by their X-ray powder diffraction patterns. That is, using Cu-Kα radiation, an X-ray powder diffraction pattern is obtained, expressed in terms of the diffraction angle 2θ. The "2θ or 2θ angle" refers to the diffraction angle, where θ is the Bragg angle, in units of ° or degrees; 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.

[0118] 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 degree of crystallization 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.

[0119] In addition to determining the crystal forms of the acid salts of Compound I 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.

[0120] The "differential scanning calorimetry" or "DSC" as 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 consecutive analyses, the thermal transition temperature and 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 that DSC peak or melting point ±5°C. "Substantially" also takes into account such temperature variations.

[0121] The X-ray powder diffraction patterns in the following examples were collected on a PANalytical Aeris X-ray powder diffractometer at a conventional temperature, such as 25°C. The method parameters for the X-ray powder diffraction are as follows:

[0122] X-ray reflection parameter: Cu, Kα

[0123] Wavelength:

[0124] Tube voltage: 40 KV

[0125] Tube current: 15 mA

[0126] Step size: 0.0110°

[0127] Time per scan step: 18.87 s

[0128] Scan range: from 3.0 to 40.0 degrees

[0129] Differential scanning calorimetry (DSC) curves were collected on a TA DSC25 differential scanning calorimeter. The method parameters were as follows: heating rate: 10 °C / min; protective gas: nitrogen.

[0130] Preparation of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one:

[0131] The preparation protocol of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one refers to the methods described in Examples 1 and 4 of PCT / CN2021 / 103543. The reaction equation is as follows:

[0132]

[0133] (1) Synthesis of 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline

[0134] 7-Bromo-1,2,3,4-tetrahydroisoquinoline (4.71 g, 22.2 mmol) and bromomethylcyclopropane (3.15 g, 23.13 mmol) were dissolved in 150 mL of acetonitrile and stirred magnetically overnight. After the reaction was completed, it was 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 (yield 98.3%).

[0135] (2) Synthesis of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one

[0136] The reactants 7-bromo-2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinoline (266 mg, 1.0 mmol), 5-(isopropylamino)-1-methylpyridin-2(1H)-one (182.8 mg, 1.1 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (48 mg, 0.10 mmol), Pd2(dba)3 (92 mg, 0.10 mmol), Cs2CO3 (630 mg, 1.9 mmol) and xylene (10 ml) were successively added into a reaction flask, and the reaction was carried out at 100 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with EA (30 ml x 2) and DCM (50 ml x 2). The organic phases were combined, concentrated, and purified by column chromatography (DCM / MeOH = 10:1) to obtain 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, which was a dark green gelatinous and viscous substance.

[0137] 1 H NMR (400 MHz, Methanol-d4) δ 7.65 (d, J = 2.8 Hz, 1H), 7.47 (d, J = 2.8 Hz, 0.5H), 7.44 (d, J = 2.9 Hz, 0.5H), 7.20 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 9.4 Hz, 2H), 6.74 (d, J = 2.1 Hz, 1H), 4.60 (d, J = 15.4 Hz, 1H), 4.38–4.25 (m, 2H), 3.86 (d, J = 16.4 Hz, 1H), 3.78 (s, 3H), 3.42 (d, J = 6.2 Hz, 1H), 3.27–3.05 (m, 4H), 1.24 (s, 1H), 1.18 (d, J = 6.5 Hz, 6H), 0.81 (d, J = 8.1 Hz, 2H), 0.50 (q, J = 4.8 Hz, 2H). MS (ESI) m / z 352.3 ([M+H] + )。

[0138] Example 1 Preparation of hydrochloride crystal form I of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one

[0139] In a 200 ml single-necked flask, 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one (4.9 g, 13.94 mmol) and dichloromethane (50 ml) were added. After complete dissolution, an ethyl acetate solution of hydrochloric acid (15 ml, 2 mol / L) was added, and obvious solids precipitated. After ultrasonic treatment for 10 min, it was concentrated under reduced pressure and dried to obtain dark green solids. HPLC: 98.24%. Identified by Aeris X-ray powder diffraction (XRPD) analysis, its XRPD data is shown in Table 1, and the XRPD pattern is as shown in Figure 1 shown, which is Form I of the hydrochloride of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

[0140] 1 1H NMR (400 MHz, Methanol-d4): δ 7.64 (d, J = 2.7 Hz, 1H), 7.45 (dd, J = 9.5, 2.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 9.3 Hz, 2H), 6.73 (d, J = 2.4 Hz, 1H), 4.60 (d, J = 15.3 Hz, 1H), 4.37–4.24 (m, 2H), 3.86 (d, J = 11.7 Hz, 1H), 3.76 (s, 3H), 3.45 - 3.34 (m, 5.2 Hz, 1H), 3.29–3.14 (m, 3H), 3.13 - 3.04 (m, 1H), 1.30–1.22 (m, 1H), 1.17 (d, J = 6.5 Hz, 6H), 0.85–0.77 (m, 2H), 0.50 (t, J = 5.0 Hz, 2H).

[0141] Determined by chlorine content titration, the salt-forming chemical ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to hydrochloric acid is 1:2.

[0142] Identified by differential scanning calorimetry analysis, the scanning rate is 10 °C / min, and there is an endothermic peak at 238.8 °C (peak temperature) with an error tolerance of ±3 °C. This Form I of the hydrochloride is a water-free crystal form.

[0143] Example 2: Preparation of Form II of the hydrochloride of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one

[0144] Dissolve 5 - ((2 - (cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one (1.5 g, 4.268 mmol) in ethanol (7 mL). Take 100 μL of the above - mentioned solution, dilute it by adding 0.5 mL of ethyl acetate, then add 37% hydrochloric acid (4.7 μL), stir and react at room temperature for 72 hours, centrifuge, and vacuum - dry the solid for 4 hours. Identified by Aeris X - ray powder diffraction (XRPD) analysis, its XRPD data is shown in Table 2, and the XRPD pattern is as Figure 2 shown, which is the hydrochloride crystal form II of 5 - ((2 - (cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one.

[0145] 1 1H NMR (400 MHz, Methanol - d4): δ 7.55 (d, J = 2.7 Hz, 1H), 7.30 (dd, J = 9.5, 2.8 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.68 (dd, J = 8.6, 2.6 Hz, 1H), 6.61 (d, J = 9.5 Hz, 1H), 6.50 (d, J = 2.6 Hz, 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).

[0146] Identified by differential scanning calorimetry analysis, the scanning rate is 10 °C / min, and endothermic peaks at 101.46 and 219.39 °C (peak temperatures) are present, with an error tolerance of ±3 °C.

[0147] Example 3: Preparation of the p - toluenesulfonate crystal form I of 5 - ((2 - (cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one

[0148] Dissolve 5 - ((2 - (cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one (1.5 g, 4.268 mmol) in ethanol (7 mL). Weigh 10.3 mg of p - toluenesulfonic acid and add it to 0.5 mL of acetonitrile. Then continue to add 100 μL of the above - mentioned solution, stir and react at room temperature for 60 hours, centrifuge, and vacuum - dry the solid for 10 hours. Identified by Aeris X - ray powder diffraction (XRPD) analysis, its XRPD data is shown in Table 3, and the XRPD pattern is asFigure 3 As shown, it is p-toluenesulfonate crystal form I of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

[0149] 1 1H NMR (400 MHz, Methanol-d4): δ 7.67 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 2.7 Hz, 1H), 7.30 (dd, J = 9.5, 2.8 Hz, 1H), 7.22 (d, J = 7.9 Hz, 2H), 7.06 (d, J = 8.6 Hz, 1H), 6.69 (dd, J = 8.6, 2.6 Hz, 1H), 6.61 (d, J = 9.5 Hz, 1H), 6.50 (d, J = 2.5 Hz, 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 = 6.5 Hz, 6H), 0.83–0.76 (m, 2H), 0.47 (d, J = 4.9 Hz, 2H). Through 1H NMR analysis, the salt-forming chemical ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to p-toluenesulfonic acid is 1:1.

[0150] Identified by differential scanning calorimetry analysis, the scanning rate is 10 °C / min, with an endothermic peak at 203.15 °C (peak temperature) and an error tolerance of ±3 °C. This p-toluenesulfonate is an anhydrous crystal form.

[0151] Example 4: Preparation of fumarate crystal form I of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one

[0152] Dissolve 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one (1.5 g, 4.268 mmol) in ethanol (7 mL), weigh 6.2 mg of fumaric acid and add it to 0.5 ml of acetonitrile, then continue to add 100 μL of the above solution dropwise, stir and react at room temperature for 60 hours, centrifuge, and dry the solid under vacuum for 10 hours. Identified by Aeris X-ray powder diffraction (XRPD) analysis, its XRPD data are shown in Table 4, and the XRPD pattern is as Figure 4As shown, it is Form I of the fumarate salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

[0153] 1 1H NMR (400 MHz, Methanol-d4): δ 7.56 (d, J = 2.8 Hz, 1H), 7.30 (dd, J = 9.5, 2.8 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.70–6.65 (m, 1H), 6.65 (s, 2H), 6.61 (d, J = 9.5 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 4.36 (s, 2H), 3.60 (s, 3H), 3.57–3.53 (m, 1H), 3.13 (d, J = 7.3 Hz, 2H), 3.07 (t, J = 6.4 Hz, 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 1H NMR analysis, the salt-forming chemical ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to fumaric acid is 1:1.

[0154] Identified by differential scanning calorimetry analysis, the scanning rate is 10 °C / min, with endothermic peaks at 115.47 and 157.84 °C (peak temperatures), and there is an error tolerance of ±3 °C. This fumarate salt is an amorphous crystal form.

[0155] Example 5: Preparation of Form II of the fumarate salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one

[0156] Dissolve 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one (1.5 g, 4.268 mmol) in ethanol (7 mL). Weigh 6.3 mg of fumaric acid and add it to 0.5 ml of ethyl acetate. Then continue to add 100 μL of the above solution and stir the reaction at room temperature for 60 hours. Centrifuge and dry the solid under vacuum for 10 hours. Identified by Aeris X-ray powder diffraction (XRPD) analysis, its XRPD data are shown in Table 5, and the XRPD pattern is as Figure 5 As shown, it is Form II of the fumarate salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

[0157] 1 1H NMR (400 MHz, Methanol-d4): δ 7.56 (d, J = 2.8 Hz, 1H), 7.30 (dd, J = 9.5, 2.8 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 6.69–6.65 (m, 1H), 6.64 (s, 2H), 6.61 (d, J = 9.5 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 4.36 (s, 2H), 3.59 (s, 3H), 3.56–3.52 (m, 1H), 3.12 (d, J = 7.3 Hz, 2H), 3.07 (t, J = 6.4 Hz, 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 = 5.2 Hz, 2H).

[0158] By 1H NMR analysis, the salt-forming chemical ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to fumaric acid is 1:1.

[0159] Identified by differential scanning calorimetry analysis, the scanning rate is 10 °C / min, there is an endothermic peak at 180.03 °C (peak temperature), with an error tolerance of ±3 °C. This fumarate is an anhydrous crystal form.

[0160] Example 6: Preparation of Crystal Form I of the Maleate Salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one

[0161] Dissolve 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one (1.5 g, 4.268 mmol) in ethanol (7 mL). Weigh 6.3 mg of maleic acid and add it to 0.5 ml of acetonitrile. Then continue to dropwise add 100 μL of the above solution, stir and react at room temperature for 60 hours, centrifuge, and vacuum dry the solid for 10 hours. Identified by Aeris X-ray powder diffraction (XRPD) analysis, its XRPD data are shown in Table 6, and the XRPD pattern is as Figure 6 shown, which is Crystal Form I of the maleate salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one.

[0162] 11H NMR (400 MHz, Methanol-d4): δ 7.28 (d, J = 2.7 Hz, 1H), 7.02 (dd, J = 9.5, 2.8 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.39 (dd, J = 8.6, 2.6 Hz, 1H), 6.32 (d, J = 9.5 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 5.93 (s, 2H), 4.11 (s, 2H), 3.31 (s, 3H), 3.06 - 2.99 (m, 1H), 2.88 (d, J = 7.3 Hz, 2H), 2.80 (t, J = 6.5 Hz, 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).

[0163] By 1H NMR analysis, the chemical ratio of the salt formation of 5 - ((2 - (cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one with maleic acid is 1:1.

[0164] Test Example

[0165] Test Example 1: Study on Properties

[0166] The appearance of the raw material of 5 - ((2 - (cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one is dark green jelly - like and viscous, which is not conducive to use in the subsequent formulation development process.

[0167] After being made into the acid salt, the appearance is crystal or powdery solid, which is convenient for storage, weighing and subsequent formulation processing.

[0168] Test Example 2: Hygroscopicity Test of the Salt Form of 5 - ((2 - (cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one

[0169] Take appropriate amounts of different salt - type samples of 5 - ((2 - (cyclopropylmethyl)-1,2,3,4 - tetrahydroisoquinolin - 7 - yl)(isopropyl)amino)-1 - methylpyridin - 2(1H)-one, spread them flat in a glass bottle with a thickness of about 1 mm, and place the glass bottle with the mouth open 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 the hydrochloride salt are shown in Table 7 and Figure 9 as follows.

[0170] Table 7:

[0171]

[0172] XRPD detection showed that, as Figure 9 shown, the crystal form of hydrochloride salt Form I did not change after being placed at 80% ± 4% RH for 5 days. The results showed that the acid salt of Compound I provided by the present invention has little or low hygroscopicity.

[0173] Test Example 3: Stability test of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one salt forms

[0174] Take appropriate amounts of different salt form samples of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, spread them flat in a glass bottle with a thickness of about 1.5 mm, and place the glass bottle with an open mouth in environments of 25°C ± 3°C and relative humidity of 60% ± 5% (i.e., room temperature and room humidity) and 40°C and relative humidity of 75% respectively. Sampling is carried out at 5 days and 10 days for XRPD detection, and at the same time, HPLC content (w / w, %) determination is carried out, and the results are compared with those at 0 day to evaluate the stability of the salt form.

[0175] Taking hydrochloride salt as an example, under the conditions of room temperature, room humidity and 40°C 75% RH, the physical and chemical stabilities of the hydrochloride salt are both good, and the test results are shown in Table 8.

[0176] Table 8:

[0177]

[0178] As Figure 7 and 8 shown, the crystal form of hydrochloride salt Form I did not change after 10 days under the conditions of room temperature, room humidity and 40°C 75% RH.

[0179] Test Example 4: sigma-1 agonist function test

[0180] According to the literature report ([J]. Synapse, 2005, 55(3): 192-195.), phenytoin can change the conformation of the sigma-1 receptor. In the presence of phenytoin, the Ki value of the agonist becomes smaller compared with the normal Ki value, and the Ki value of the inhibitor becomes larger compared with the normal Ki value.

[0181] For the specific operations in the reference ([J]. Synapse, 2005, 55(3): 192-195.), taking compound I hydrochloride as an example, the Ki value of the compound of the present invention was detected. The detection method for the Ki value of the phenytoin group was to additionally add phenytoin to the test substance tube and detect the Ki value after adding phenytoin. If the normal Ki value / Ki value of the phenytoin group > 1, it can be determined as an agonist.

[0182] Table 9 Experimental results showed that the ratio of compound I hydrochloride (normal Ki / Ki of the phenytoin group) > 1, which was an agonist.

[0183] Table 9. Ki values and ratios of the normal group and the phenytoin group

[0184] Ki value (nM) Sigma-1 (normal Ki) 49.62 Sigma-1 (Ki of phenytoin group) 47.88 Ratio 1.04

[0185] Test Example 5: In vivo pharmacodynamic test in mice

[0186] Mouse forced swimming test (FST): Male ICR mice weighing 18 - 22 g were divided into a vehicle control group, a positive control group (duloxetine, 15 mg / kg), and a test group (acid salt of compound I, 30, 60, 90 mg / kg). The test group, the vehicle group, and the positive control group were intraperitoneally injected with the test substance or the vehicle 30 minutes before the formal swimming, and then the mouse forced swimming test was carried out. The mice were placed in a transparent glass cylinder (water depth 15 cm, water temperature 23 - 25 °C) for 6 minutes, and the activity status of the mice was video-recorded. After the experiment, the cumulative immobility time results of the mice in the last 4 minutes during the 6-minute forced swimming were analyzed using Forced Swim ScanTM 2.0 software.

[0187] Taking compound I hydrochloride as an example, in the mouse forced swimming model, the duloxetine group (positive control) showed extremely significant pharmacodynamic effects (p < 0.0001). Compound I hydrochloride had no pharmacodynamic effects at 30 mg / kg, significant pharmacodynamic effects at 60 mg / kg (p < 0.05), and extremely significant pharmacodynamic effects at 90 mg / kg (p < 0.0001).

Claims

1. An acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, characterized in that, The acid salt is selected from hydrochloride, p-toluenesulfonate, fumarate, or maleate.

2. The acid addition salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 1, characterized in that, The acid salt is hydrochloride or p-toluenesulfonate.

3. The acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 1, characterized in that, The molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to the acid is 1:1 to 2.

4. The acid addition salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 1, characterized in that, The molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to the acid is 1:

1.

5. An acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, characterized in that, The acid salt is selected from hydrochloride crystal form I or hydrochloride crystal form II. For the hydrochloride crystal form I, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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°. For the hydrochloride crystal form II, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.17° ± 0.2°, 15.33° ± 0.2°, 16.17° ± 0.2°, 18.24° ± 0.2°, 18.77° ± 0.2°, 22.58° ± 0.2°, and 24.10° ± 0.2°.

6. The acid salt of the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 5, wherein For the hydrochloride crystal form I, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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 26.58° ± 0.2°. For the hydrochloride crystal form II, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.17° ± 0.2°, 11.18° ± 0.2°, 14.75° ± 0.2°, 15.33° ± 0.2°, 16.17° ± 0.2°, 18.24° ± 0.2°, 18.77° ± 0.2°, 22.58° ± 0.2°, 24.10° ± 0.2°, and 29.52° ± 0.2°.

7. The acid salt of the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 5, wherein For the hydrochloride crystal form I, its X-ray powder diffraction pattern is substantially the same as the peaks at the diffraction angles (2θ) shown in Figure 1. For the hydrochloride crystal form II, its X-ray powder diffraction pattern is substantially the same as the peaks at the diffraction angles (2θ) shown in Figure 2; and / or The acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, when characterized by DSC, is identified by differential scanning calorimeter analysis with a scanning rate of 10 °C / minute. The hydrochloride crystal form I contains an endothermic peak with a peak temperature of 238.8 °C ± 3 °C. The hydrochloride crystal form II contains endothermic peaks with peak temperatures of 101.46 ± 3 °C and 219.39 °C ± 3 °C.

8. An acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, characterized in that, The acid salt is selected from p-toluenesulfonate crystal form I, and its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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 23.08° ± 0.2°.

9. The acid addition salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 8, characterized in that, The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I includes peaks at diffraction angles (2θ) of 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°, 23.08° ± 0.2° and 24.58 ± 0.2°.

10. The acid addition salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 8, characterized in that, The X-ray powder diffraction pattern of the p-toluenesulfonate crystal form I is substantially the same as the peaks at the diffraction angles (2θ) shown in Figure 3; and / or, The acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, when characterized by DSC, is identified by differential scanning calorimeter analysis with a scanning rate of 10 °C / minute. The p-toluenesulfonate crystal form I contains an endothermic peak with a peak temperature of 203.15 °C ± 3 °C.

11. An acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, 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 peaks at diffraction angles (2θ) of 7.90° ± 0.2°, 10.36° ± 0.2°, 11.89° ± 0.2°, 12.44° ± 0.2°, 15.89° ± 0.2°, 17.73° ± 0.2°, 19.91° ± 0.2°, 22.15° ± 0.2°, 23.98° ± 0.2° and 28.04° ± 0.2°. The fumarate polymorph II, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 9.56° ± 0.2°, 12.50° ± 0.2°, 16.79° ± 0.2°, 21.60° ± 0.2°, 23.06° ± 0.2° and 25.79° ± 0.2°.

12. The acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 11, characterized in that The fumarate polymorph I, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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°; The fumarate polymorph II, whose X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 8.35° ± 0.2°, 9.56° ± 0.2°, 12.50° ± 0.2°, 16.79° ± 0.2°, 18.66° ± 0.2°, 20.40° ± 0.2°, 21.60° ± 0.2°, 23.06° ± 0.2° and 25.79° ± 0.2°.

13. The acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3, \alpha -tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 11, characterized in that The X-ray powder diffraction pattern of the fumarate polymorph I is substantially the same as the peaks at the diffraction angles (2θ) shown in Figure 4; The X-ray powder diffraction pattern of the fumarate polymorph II is substantially the same as the peaks at the diffraction angles (2θ) shown in Figure 5; and / or, The acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin- \alpha -yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, when characterized by DSC, is identified by differential scanning calorimetry analysis with a scanning rate of 10 °C / minute, The fumarate polymorph I contains endothermic peaks with peak temperatures of 115.47 ± \alpha °C and 157.84 °C ± \alpha °C; The fumarate polymorph II contains an endothermic peak with a peak temperature of 180.03 °C ± \alpha °C.

14. An acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one, characterized in that, The acid salt is selected from maleate crystal form I, and for the maleate crystal form I, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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° ± 0.2° and 28.68° ± 0.2°.

15. The acid addition salt of the crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 14, characterized in that, For the maleate crystal form I, its X-ray powder diffraction pattern includes peaks at diffraction angles (2θ) of 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°, 28.21 ± 0.2° and 28.68° ± 0.2°.

16. The acid addition salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to claim 14, characterized in that, For the maleate crystal form I, its X-ray powder diffraction pattern is substantially the same as the peaks at diffraction angles (2θ) shown in Figure 6.

17. A method for preparing an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to any one of claims 1 to 4, comprising: dissolving or dispersing the free base of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one in an organic solvent, and then adding a liquid of an inorganic acid or an organic acid, or adding a solid of an inorganic acid or an organic acid, or a solution of an acid, to prepare an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one; or adding 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to a solution of an acid to prepare an acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one; wherein the molar ratio of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one to the acid in the feed is 1:1 to 2.

5.

18. The preparation method according to claim 17, wherein the organic solvent used in the salt formation process is methanol, ethanol, isopropanol, dichloromethane, acetone, ether, ethyl acetate, n-hexane, n-heptane, acetonitrile or a mixture thereof.

19. The preparation method according to claim 17, wherein the organic solvent used in the salt formation process is ethanol, ethyl acetate, acetonitrile or a mixture thereof.

20. The preparation method according to claim 17, characterized in that, The solution of the acid is an ethyl acetate solution of the acid or an acetonitrile solution of the acid.

21. Process for preparing the acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to any one of claims 5 to 16, comprising: (1) Preparing the acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one by the method described in claim 17; (2) Collecting the solid product precipitated during the salt formation reaction in step (1), or obtaining the solid product by creating a supersaturated solution in the salt formation system, and the methods for creating the supersaturated solution include: evaporating the solvent, or adding an antisolvent, or by cooling, to obtain crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one acid salt; and / or, by the method of crystal form transformation, transforming one crystal form of the acid salt into another crystal form of the salt.

22. The preparation method according to claim 21, wherein the organic solvent used in the salt formation process is methanol, ethanol, isopropanol, dichloromethane, acetone, ether, ethyl acetate, n-hexane, n-heptane, acetonitrile or a mixture thereof.

23. The preparation method according to claim 22, wherein the organic solvent used in the salt formation process is ethanol, ethyl acetate, acetonitrile or a mixture thereof.

24. The preparation method according to claim 21, wherein, The solution of the acid is an ethyl acetate solution of the acid or an acetonitrile solution of the acid.

25. A pharmaceutical composition, characterized in that, Comprising the acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to any one of claims 1 to 4, or the acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to any one of claims 5 to 16 and a pharmaceutically acceptable carrier or excipient.

26. Use of the acid salt of 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to any one of claims 1 to 4, or the acid salt of crystalline 5-((2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)(isopropyl)amino)-1-methylpyridin-2(1H)-one according to any one of claims 5 to 16, or the pharmaceutical composition according to claim 25 in the preparation of a medicament for treating neuropsychiatric diseases.

27. The application according to claim 26, wherein The neuropsychiatric diseases are selected from any one of depression and anxiety.

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