Deuterated dextromethorphan salt, crystal form, preparation method and application thereof

Abstract

The invention provides various salt forms of deuterated dextromethorphan as shown in a formula (I) as well as a preparation method and application of the various salt forms. The various salt forms comprise tartrate, citrate, hydrobromide and benzoate. Also provided are various crystal forms of the above salts. The salt has excellent effects in the aspects of stability, biological activity, bioavailability, drug effect and the like, and is suitable for development of pharmaceutical preparations.

Description

[0001] This application claims priority to the prior application filed by the applicant with the China National Intellectual Property Administration on May 24, 2024, with application number CN202410656859.1 and invention title "Deuterated dextromethorphan salt, crystal form and preparation method and use thereof", the contents of which are incorporated herein by reference. Technical Field

[0002] This invention belongs to the pharmaceutical field, specifically relating to different salts and crystal forms of a deuterated dextromethorphan compound, as well as its preparation method and uses. Background Technology

[0003] Dextromethorphan (CAS: 125-71-3), chemically named 3-methoxy-17-methyl-(9α,13α,14α)-morphine, is clinically used primarily as its hydrobromide monohydrate. Its structural formula is as follows:

[0004]

[0005] CN101687868A discloses several deuterated dextromethorphan compounds and their preparation methods. CN115322150A discloses the crystal form of deuterated dextromethorphan-d6 hydrobromide, with the following structural formula:

[0006]

[0007] Marketed dextromethorphan is used to treat dry cough without phlegm, including frequent and severe coughs. In 2022, the FDA approved Axsome's Auvelity extended-release tablets (containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride), the first approved rapid-acting oral medication for the treatment of major depressive disorder (MDD). Currently, research is ongoing on combinations of dextromethorphan (deuterated or non-deuterated) with other drugs such as quinidine and bupropion for the treatment of pseudobulbar mood, depression, Alzheimer's disease agitation, and other conditions.

[0008] Different deuterated derivatives, salt forms, and crystal forms of dextromethorphan can significantly affect its physicochemical properties and bioavailability, thereby impacting its stability, bioavailability, and efficacy. This effect is particularly pronounced in oral formulations. Therefore, in-depth research into the crystal forms and salt forms of dextromethorphan deuterated derivatives is of great significance for the pharmaceutical development of dextromethorphan. Summary of the Invention

[0009] The purpose of this invention is to provide the salt, crystal form, preparation method and use of deuterated dextromethorphan (chemical name: 3-(methoxy-d3)-17-methyl-(9α,13α,14α)-morphine) as shown in formula (I).

[0010] According to a first aspect of the present invention, a salt of a deuterated dextromethorphan compound of formula (I) is provided, said salt being selected from salts formed by the compound of formula (I) and an acid.

[0011]

[0012] In one embodiment, the acid is selected from organic or inorganic acids; preferably, the organic acid is selected from tartaric acid, citric acid, hydrobromic acid, and benzoic acid. That is, the salt is selected from tartrate, citrate, hydrobromic acid monohydrate, and benzoate of compounds of formula (I).

[0013] In one embodiment, the organic acid includes any optical isomer, racemic mixture, or meso mixture thereof. For example, the tartaric acid may be L-tartaric acid, D-tartaric acid, or DL-tartaric acid.

[0014] In one embodiment, in a pharmaceutically acceptable salt of the compound of formula (I), the molar ratio of the compound of formula (I) to the acid may be selected from 1:1, 1:2, 2:1 or 3:1, etc., in which the ions of the compound of formula (I) and the ions of the acid form a charge balance.

[0015] In one embodiment, among the tartrate, citrate, hydrobromide monohydrate, and benzoate of the compound of formula (I), the compound of formula (I) forms a salt with an acid in a molar ratio of approximately 1:1.

[0016] In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) includes anhydrous salt, solvate, hydrate form, and preferably, monohydrate form of salt.

[0017] In one embodiment, the deuterated dextromethorphan tartrate has the structure shown in formula (II):

[0018]

[0019] In one embodiment, the deuterated dextromethorphan citrate has the structure shown in formula (III):

[0020]

[0021] In one embodiment, the deuterated dextromethorphan hydrobromide monohydrate has the structure shown in formula (IV):

[0022]

[0023] In one embodiment, the deuterated dextromethorphan benzoate has the structure shown in formula (V):

[0024]

[0025] According to a second aspect of the invention, a polymorph of a salt of deuterated dextromethorphan of formula (I) is provided. Preferably, the salt is a tartrate, citrate, hydrobromide monohydrate, or benzoate.

[0026] In one embodiment, the crystal form A of the compound of formula (II) has a characteristic peak at one or more of the following locations in XRPD plots expressed in 2θ angles: 7.9±0.2°, 13.8±0.2°, 15.3±0.2°, 18.9±0.2°, and 19.8±0.2°.

[0027] In one embodiment, the crystal form A of the compound of formula (II) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 7.9±0.2°, 12.8±0.2°, 13.8±0.2°, 15.3±0.2°, 18.9±0.2°, 19.8±0.2°, 22.9±0.2°, and 28.3±0.2°.

[0028] In one embodiment, the crystal form A of the compound of formula (II) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 7.9±0.2°, 11.2±0.2°, 12.8±0.2°, 13.8±0.2°, 15.3±0.2°, 18.9±0.2°, 19.8±0.2°, 21.3±0.2°, 22.9±0.2°, 28.3±0.2°, 28.7±0.2°, and 29.2±0.2°.

[0029] In one embodiment, the crystal form A of the compound of formula (II) has characteristic peaks in its XRPD pattern expressed in 2θ angles at 7.9±0.2°, 11.2±0.2°, 12.8±0.2°, 13.8±0.2°, 15.3±0.2°, 18.9±0.2°, 19.8±0.2°, 21.3±0.2°, 22.9±0.2°, 28.3±0.2°, 28.7±0.2°, and 29.2±0.2°.

[0030] In one embodiment, the crystal form A of the compound of formula (II) has essentially the following characteristics: Figure 1 The XRPD map shown.

[0031] In one embodiment, the DSC plot of crystal form A of compound (II) has an endothermic peak in the range of about 196 ± 3 °C.

[0032] In one embodiment, the crystal form A of the compound of formula (II) has essentially the following characteristics: Figure 2 The DSC spectrum shown.

[0033] In one embodiment, the crystal form A of the compound of formula (II) has essentially the following characteristics: Figure 3 The TGA spectrum shown.

[0034] In one embodiment, the crystal form A of the compound of formula (II) is anhydrous.

[0035] In one embodiment, the crystal form B of the compound of formula (II) has a characteristic peak at one or more of the following locations in XRPD plots expressed in 2θ angles: 5.3±0.2°, 11.7±0.2°, 15.6±0.2°, 16.8±0.2°, and 20.9±0.2°.

[0036] In one embodiment, the crystal form B of the compound of formula (II) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 5.3±0.2°, 10.5±0.2°, 11.7±0.2°, 15.0±0.2°, 15.6±0.2°, 16.8±0.2°, 20.9±0.2°, and 23.9±0.2°.

[0037] In one embodiment, the crystal form B of the compound of formula (II) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 5.3±0.2°, 10.5±0.2°, 11.7±0.2°, 12.9±0.2°, 15.0±0.2°, 15.6±0.2°, 16.8±0.2°, 19.1±0.2°, 21.0±0.2°, 22.3±0.2°, 23.9±0.2°, and 26.3±0.2°.

[0038] In one embodiment, the crystal form B of the compound of formula (II) has essentially the following characteristics: Figure 4 The XRPD map shown.

[0039] In one embodiment, the DSC plot of crystal form B of compound (II) has an endothermic peak in the range of about 189 ± 3 °C.

[0040] In one embodiment, the crystal form B of the compound of formula (II) has essentially the following characteristics: Figure 5 The DSC spectrum shown.

[0041] In one embodiment, the crystal form B of the compound of formula (II) is anhydrous.

[0042] In one embodiment, the crystal form A of the compound of formula (III) has a characteristic peak at one or more of the following locations in XRPD plots expressed in 2θ angles: 4.1±0.2°, 8.1±0.2°, 12.2±0.2°, 16.2±0.2°, and 18.3±0.2°.

[0043] In one embodiment, the crystal form A of the compound of formula (III) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 4.1±0.2°, 8.1±0.2°, 12.2±0.2°, 15.1±0.2°, 16.2±0.2°, 17.2±0.2°, 18.3±0.2°, and 24.3±0.2°.

[0044] In one embodiment, the crystal form A of the compound of formula (III) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 4.1±0.2°, 8.1±0.2°, 12.2±0.2°, 13.8±0.2°, 15.1±0.2°, 16.2±0.2°, 17.2±0.2°, 17.6±0.2°, 18.3±0.2°, 18.3±0.2°, 19.8±0.2°, 20.9±0.2°, and 24.3±0.2°.

[0045] In one embodiment, the crystal form A of the compound of formula (III) has essentially the following characteristics: Figure 6 The XRPD map shown.

[0046] In one embodiment, the DSC plot of crystal form A of compound (III) has an endothermic peak in the range of about 136 ± 3 °C.

[0047] In one embodiment, the crystal form A of the compound of formula (III) has essentially the following characteristics: Figure 7 The DSC spectrum shown.

[0048] In one embodiment, the crystal form A of the compound of formula (III) has essentially the following characteristics: Figure 8 The TGA spectrum shown.

[0049] In one embodiment, the crystal form A of the compound of formula (IV) has a characteristic peak in one or more of the following XRPD plots expressed in 2θ angles: 6.5±0.2°, 18.9±0.2°, 21.7±0.2°, 23.2±0.2°, and 26.0±0.2°.

[0050] In one embodiment, the crystal form A of the compound of formula (IV) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 6.5±0.2°, 15.9±0.2°, 17.1±0.2°, 18.1±0.2°, 18.9±0.2°, 21.7±0.2°, 23.2±0.2°, and 26.0±0.2°.

[0051] In one embodiment, the crystal form A of the compound of formula (IV) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 6.5±0.2°, 15.9±0.2°, 17.1±0.2°, 18.1±0.2°, 18.9±0.2°, 21.7±0.2°, 23.2±0.2°, 24.7±0.2°, 25.2±0.2°, 26.0±0.2°, 27.8±0.2°, and 32.6±0.2°.

[0052] In one embodiment, the crystal form A of the compound of formula (IV) has essentially the following characteristics: Figure 9 The XRPD map shown.

[0053] In one embodiment, the DSC plot of crystal form A of compound (IV) has an endothermic peak in the range of about 109 ± 3 °C.

[0054] In one embodiment, the crystal form A of the compound of formula (IV) has essentially the following characteristics: Figure 10 The DSC spectrum shown.

[0055] In one embodiment, the crystal form A of the compound of formula (IV) has essentially the following characteristics: Figure 11 The TGA spectrum shown.

[0056] In one embodiment, the crystal form A of the compound of formula (V) has a characteristic peak at one or more of the following locations in XRPD plots expressed in 2θ angles: 14.0±0.2°, 17.4±0.2°, 19.4±0.2°, 19.7±0.2°, and 21.2±0.2°.

[0057] In one embodiment, the crystal form A of the compound of formula (V) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 9.8±0.2°, 11.0±0.2°, 14.0±0.2°, 15.6±0.2°, 17.4±0.2°, 19.4±0.2°, 19.7±0.2°, and 21.2±0.2°.

[0058] In one embodiment, the crystal form A of the compound of formula (V) has a characteristic peak in one or more of the following XRPD patterns expressed in 2θ angles: 9.8±0.2°, 11.0±0.2°, 14.0±0.2°, 15.6±0.2°, 17.4±0.2°, 19.4±0.2°, 19.7±0.2°, 21.2±0.2°, 22.0±0.2°, 22.4±0.2°, 23.0±0.2°, and 25.0±0.2°.

[0059] In one embodiment, the crystal form A of the compound of formula (V) has essentially the following characteristics: Figure 12 The XRPD map shown.

[0060] In one embodiment, the DSC plot of crystal form A of compound (V) has an endothermic peak in the range of about 98 ± 3 °C.

[0061] In one embodiment, the crystal form A of the compound of formula (V) has essentially the following characteristics: Figure 13 The DSC spectrum shown.

[0062] In one embodiment, the crystal form A of the compound of formula (V) has essentially the following characteristics: Figure 14 The TGA spectrum shown.

[0063] According to a third aspect of the invention, a pharmaceutical composition is provided comprising a salt of any of the aforementioned compounds of formula (I), and at least one pharmaceutically acceptable carrier.

[0064] In one embodiment, the salt of the compound of formula (I) in the pharmaceutical composition is selected from tartrate, citrate, hydrobromide monohydrate, and benzoate; preferably tartrate or citrate.

[0065] In one embodiment, the salt of the compound of formula (I) in the pharmaceutical composition is selected from crystal form A of compound (II), crystal form B of compound (II), crystal form A of compound (III), crystal form A of compound (IV), and A of compound (V); preferably, the salt is selected from crystal form A of compound (II) and crystal form A of compound (III).

[0066] In one embodiment, the pharmaceutical composition optionally comprises a second therapeutic agent. For example, the second therapeutic agent may be selected from quinidine, quinidine sulfate, oxycodone, gabapentin, bupropion, bupropion hydrochloride, clomipramine, doxepin, fluoxetine, miancelin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, norimipramine, protriptyline, trimethamipramine, nortriptyline, maprotiline, phenelzine, isozolidine, transphenylcyclopropionamide, paroxetine, trazodone, citalopram, sertraline, etc. One or more of the following: aryloxyaminoindane, benatizine, escitalopram, fluvoxamine, venlafaxine, norvenlafaxine, nefazodone, selegiline, mirnaciline, tersofencin, butofencin, moclobemide, rasagiline, nialamine, isoniazid, isopropylchlorohydrin, toloxacin, butiline, duthiram, dibenzapine, iproindole, lofepramine, octopiol, norfluoxetine, dapoxetine, and ketamine.

[0067] According to a fourth aspect of the present invention, a method for preparing the polymorph of the deuterated dextromethorphan salt described in the first aspect and the deuterated dextromethorphan salt described in the second aspect is provided.

[0068] In one embodiment, a method for preparing a salt of a compound of formula (I) is provided, comprising reacting the compound of formula (I) with the acid to obtain the salt.

[0069] In one embodiment, the salt can be prepared by method one, comprising dissolving the compound of formula (I) and the acid in organic solvent A; then adding organic solvent B, precipitating a solid, and obtaining a salt of the compound of formula (I). The acid has the definition described above. Preferably, the organic solvent A is selected from one or two of alcohols or ketones. The alcohols can be selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and neopentyl alcohol; the ketones can be selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, and 4-methyl-2-pentanone; the organic solvent B is selected from esters. The esters can be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, and isopropyl acetate. Preferably, the salt prepared by method one is a tartrate or citrate.

[0070] In one embodiment, when the acid is selected from hydrobromic acid, preparation method two can be used, comprising dissolving the compound shown in formula (I) in organic solvent C; then adding an aqueous solution of hydrobromic acid, precipitating a solid, and obtaining a salt of the compound of formula (I). Preferably, the organic solvent C is selected from esters. The esters may be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, and isopropyl acetate. Preferably, the concentration of the aqueous solution of hydrobromic acid is 40-60 wt%, for example, 45, 48, 50, 55, or 60 wt%.

[0071] In one embodiment, a method for preparing crystal form A of compound (II) is provided, comprising the following steps: dissolving compound (II) in organic solvent I to precipitate a solid. The organic solvent I is selected from one or more alcohols and nitrile compounds. The alcohol may be selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and neopentyl alcohol. The nitrile may be selected from acetonitrile. Preferably, the ratio of compound (II) to organic solvent I is 100 mg: 0.5-10 mL. Preferably, when organic solvent I is selected from nitrile compounds (e.g., acetonitrile), the ratio of compound (II) to organic solvent I is 100 mg: 0.5-3 mL, for example, 100 mg: 1 mL; when organic solvent I is selected from alcohols (e.g., ethanol), the ratio of compound (II) to organic solvent I is 100 mg: 6 mL.

[0072] In one embodiment, a second method for preparing crystal form A of compound (II) is provided, comprising the following steps: dissolving compound (I) and L-tartaric acid in organic solvent A; then adding organic solvent B to precipitate a solid. Preferably, organic solvent A is selected from alcohols. The alcohol may be selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and neopentyl alcohol; organic solvent B is selected from esters. The ester may be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, and isopropyl acetate. Preferably, the ratio of L-tartaric acid to organic solvent A is 1 mmol:0.5-2 mL, for example, 1 mmol:1 mL; preferably, the ratio of L-tartaric acid to organic solvent B is 1 mmol:3-6 mL, for example, 1 mmol:4 mL.

[0073] In one embodiment, a method for preparing crystal form B of compound (II) is provided, comprising the steps of: dissolving compound (II) in organic solvent II to precipitate a solid. The organic solvent II is selected from one or more ketones and tetrahydrofurans, wherein the ketones may be selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, and 4-methyl-2-pentanone.

[0074] In one embodiment, a method for preparing crystal form A of the compound of formula (III) is provided, comprising dissolving the compound of formula (I) and citric acid monohydrate in organic solvent A; then adding organic solvent B to precipitate a solid. Preferably, the organic solvent A is selected from alcohols. The alcohol may be selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and neopentyl alcohol; the organic solvent B is selected from esters. The ester may be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, and isopropyl acetate.

[0075] In one embodiment, a method for preparing crystal form A of the compound of formula (IV) is provided, comprising dissolving the compound of formula (I) in an organic solvent C; then adding an aqueous solution of hydrobromic acid to precipitate a solid. Preferably, the organic solvent C is selected from esters. The ester may be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, and isopropyl acetate. Preferably, the concentration of the aqueous solution of hydrobromic acid is 40-60 wt%, for example, 45, 48, 50, 55, or 60 wt%.

[0076] In one embodiment, a method for preparing crystal form A of the compound of formula (V) is provided, comprising dissolving the compound of formula (I) and benzoic acid in organic solvent A; then adding organic solvent B to precipitate a solid. Preferably, the organic solvent A is selected from ketones. The ketone may be selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, and 4-methyl-2-pentanone; the organic solvent B is selected from esters. The ester may be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, and isopropyl acetate.

[0077] According to a fifth aspect of the invention, the use of the deuterated dextromethorphan salt of the first aspect, the polymorph of the deuterated dextromethorphan salt of the second aspect, or the pharmaceutical composition of the third aspect in the preparation of a medicament is provided. The medicament is intended to treat individuals suffering from or susceptible to a disease or condition selected from: cough, pseudobulbar mood, depressive disorder, Alzheimer's disease agitation, non-suicidal self-harm, post-traumatic stress disorder, schizophrenia, anxiety disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), bipolar disorder, mania, pain, autism, brain injury, disorders of consciousness, cardiovascular disease, glaucoma, tardive dyskinesia, cancer, rheumatoid arthritis, diabetic neuropathy, retinopathy, epilepsy, tinnitus, sexual dysfunction, addiction, nicotine addiction, dermatitis, and Rett syndrome (RTT).

[0078] The deuterated dextromethorphan salts of the present invention (especially specific salt crystal forms) have excellent physicochemical stability, longer half-life, and significantly improved bioavailability, and are expected to have better clinical therapeutic effects. They are also easy to mass-produce industrially and are very suitable for the development of pharmaceutical formulations. Attached Figure Description

[0079] Figure 1 XRPD spectrum of deuterated dextromethorphan tartrate (compound of formula II) crystal form A;

[0080] Figure 2 DSC spectrum of deuterated dextromethorphan tartrate (compound of formula II) crystal form A;

[0081] Figure 3TGA spectrum of deuterated dextromethorphan tartrate (compound of formula II) crystal form A;

[0082] Figure 4 XRPD pattern of deuterated dextromethorphan tartrate (compound of formula II) crystal form B;

[0083] Figure 5 DSC spectrum of deuterated dextromethorphan tartrate (compound of formula II) crystal form B;

[0084] Figure 6 XRPD spectrum of deuterated dextromethorphan citrate (compound of formula III) crystal form A;

[0085] Figure 7 DSC spectrum of deuterated dextromethorphan citrate (compound of formula III) crystal form A;

[0086] Figure 8 TGA spectrum of deuterated dextromethorphan citrate (compound of formula III) crystal form A;

[0087] Figure 9 XRPD spectrum of deuterated dextromethorphan hydrobromide monohydrate (compound of formula IV) crystal form A;

[0088] Figure 10 DSC spectrum of deuterated dextromethorphan hydrobromide monohydrate (compound of formula IV) crystal form A;

[0089] Figure 11 TGA spectrum of deuterated dextromethorphan hydrobromide monohydrate (compound of formula IV) crystal form A;

[0090] Figure 12 XRPD spectrum of deuterated dextromethorphan benzoate (compound of formula V) crystal form A;

[0091] Figure 13 DSC spectrum of deuterated dextromethorphan benzoate (compound of formula V) crystal form A;

[0092] Figure 14 TGA spectrum of deuterated dextromethorphan benzoate (compound of formula V) crystal form A;

[0093] Figure 15 Comparison of DSC diagrams before and after the crystal form transformation test of deuterated dextromethorphan tartrate (compound of formula II). Detailed Implementation

[0094] The present invention will be described in detail below through embodiments. It should be understood that the methods in the embodiments are for illustrative purposes only and do not constitute any limitation on the present invention. Unless otherwise specified, the materials used in the embodiments are commercially available or prepared by known or conventional methods. Unless otherwise specified, the experimental methods used are conventional methods.

[0095] Experimental materials:

[0096] The deuterated dextromethorphan used in the examples refers to the compound shown in formula (I), which can be prepared according to the following method:

[0097] Synthesis route:

[0098]

[0099] Synthesis steps:

[0100] Dextromethorphan hydrobromide (compound 1, 100.0 g, purchased from Shanghai Maclean Biochemical Technology Co., Ltd.) was dissolved in dichloromethane (500 mL) and washed with NaOH (25.0 g) aqueous solution (400 mL). The organic phase was dried with sodium sulfate, filtered, and concentrated to dryness to obtain dextromethorphan (compound 2, 74.6 g).

[0101] Dextromethorphan (74.6 g) was dissolved in dichloroethane (1.0 L), potassium carbonate (189.9 g) was added, and ethyl chloroformate (149.1 g) was added dropwise. The mixture was heated under reflux for 16 h. The reaction solution was cooled to room temperature, diluted with dichloromethane (200 mL), and then poured into ice water (700 mL). After thorough stirring, the mixture was allowed to stand and separated. The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness. The residue was dissolved in petroleum ether (500 mL) and ethyl acetate (50 mL), filtered, and the filtrate was concentrated to dryness to give a pale yellow oily substance (intermediate 3, 90.0 g).

[0102] Intermediate 3 (45.0 g) was dissolved in dichloromethane (450 mL), and a dichloromethane solution of boron tribromide (1 M, 273 mL) was added dropwise under nitrogen protection at 0-5 °C. The reaction was allowed to proceed for 3 h after the addition was complete. The reaction solution was diluted with dichloromethane (200 mL), and the reaction was quenched dropwise with a saturated sodium bicarbonate aqueous solution (800 mL). The mixture was separated, the organic phase was washed with deionized water (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a crude pale yellow solid (intermediate 4, 46.2 g).

[0103] Intermediate 4 (46.2 g) was dissolved in N,N-dimethylformamide (150 mL), and deuterated iodomethane (31.7 g) and potassium carbonate (37.8 g) were added. The mixture was stirred overnight at 25 °C until the reaction was complete. The reaction solution was then mixed with tertiary methyl ether (350 mL) and water (700 mL), allowed to stand, and separated. The aqueous phase was extracted with tertiary methyl ether (200 mL), the organic phases were combined, washed with saturated brine (2 x 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to obtain a pale yellow oil (intermediate 5, 45.2 g).

[0104] Intermediate 5 (45.2 g) was dissolved in anhydrous tetrahydrofuran (320 mL), and lithium aluminum hydride (7.7 g) was added in portions at 0–5 °C under nitrogen protection. The reaction was carried out at room temperature for 3 h, and the reaction was quenched by dropwise addition of (7.7 mL), 15% NaOH aqueous solution (8.0 mL), and water (22 mL). The reaction solution was filtered, the filter cake was washed with tetrahydrofuran (150 mL), concentrated to dryness, and the residue was dissolved in ethyl acetate (150 mL), filtered, and washed with a small amount of ethyl acetate. 48% hydrobromic acid aqueous solution (22.7 g) was added, and the mixture was stirred at 40 °C for 1 h, followed by stirring at 0–5 °C for 1 h. The mixture was filtered, the filter cake was washed with ethyl acetate (100 mL), and dried under vacuum at 50 °C to give a white solid (compound 6, 42.5 g).

[0105] Compound 6 (40.0 g) was dissolved in dichloromethane (350 mL) and washed with NaOH (10.0 g) aqueous solution (400 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give deuterated dextromethorphan (compound of formula I, 28.0 g).

[0106] Instruments and methods:

[0107] XRPD (X-ray Powder Diffraction): Instrument: Bruker D8 ADVANCE X-ray diffractometer; XRPD parameters: Tube: Cu, kα, Phototube voltage: 40kV; Phototube current: 40mA; Scan range: 3-45deg; Step size: 0.02deg; Step length: 0.12 seconds. Test method: Approximately 10-20mg of sample is used for XRPD detection. The error range of the 2θ value of XRPD data is ±0.2°.

[0108] DSC (Differential Scanning Calorimetry): Instrument: METTLER TOLEDO DSC3+ differential scanning calorimeter; DSC parameters: Temperature range: 25~300℃; Heating rate: 10℃ / min; Nitrogen purge gas: 50mL / min. Test method: Place the sample (3~5mg) in the DSC aluminum pot for testing.

[0109] Thermogravimetric Analysis (TGA): Instrument: TA TGA Q50 (USA); TGA parameters: Temperature range: 30–300℃; Heating rate: 10℃ / min; Nitrogen purging gas: 25 mL / min. Test method: Place the sample (5–10 mg) in a TGA platinum pot for testing.

[0110] Example 1: Preparation of different salt forms of deuterated dextromethorphan

[0111] 1.1 Preparation of deuterated dextromethorphan tartrate

[0112] Deuterated dextromethorphan (2.2 g, 8.0 mmol), L-tartaric acid (1.2 g, 8.0 mmol), and methanol (8 mL) were added sequentially to a reaction flask and stirred at room temperature to dissolve. Ethyl acetate (32 mL) was added dropwise, and the mixture was stirred to induce crystallization for 2–3 h. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum at 40 °C to obtain a white solid of dextromethorphan L-tartarate (3.28 g).

[0113] 1 H NMR (400MHz, DMSO-d6) δ7.11(d,J=8.3Hz,1H),6.91–6.70(m,2H),4.02(s,2H),3.30(m,1H),3.07(d,J=19.1Hz,1H),2.9 4–2.75(m,2H),2.65(s,3H),2.47–2.25(m,2H),1.95(m,1H),1.79(m,1H),1.67–1.23(m,6H),1.15(m,1H),0.97(m,1H).

[0114] 1.2 Preparation of deuterated dextromethorphan citrate

[0115] Deuterated dextromethorphan (2.2 g, 8.0 mmol), citrate monohydrate (1.7 g, 8.0 mmol), and methanol (8 mL) were added sequentially to a reaction flask and stirred at room temperature to dissolve. Ethyl acetate (64 mL) was added dropwise, and the mixture was stirred to induce crystallization for 2–3 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried under vacuum at 40 °C to obtain a white solid of dextromethorphan citrate (2.46 g).

[0116] 1H NMR(400MHz, Methanol-d4)δ7.18(d,J=8.5Hz,1H),6.95–6.78(m,2H),3.62(m,1H),3.24–3.09(m,3H),2.93(s,3H),2.85(dd,J=15.4,1.9Hz,2H),2.79– 2.73(dd,J=15.4,1.9Hz,2H),2.70(m,1H),2.50(d,J=13.9Hz,1H),2.13(m, 1H),2.00(m,1H),1.72(m,1H),1.65–1.41(m,5H),1.32(m,1H),1.15(m,1H).

[0117] 1.3 Preparation of deuterated dextromethorphan hydrobromide

[0118] Deuterated dextromethorphan (3.7 g, 13.5 mmol) and ethyl acetate (370 mL) were added to a reaction flask and dissolved at room temperature. 48% HBr aqueous solution (2.28 g, 13.5 mmol) was added, and a white solid precipitated. The system was transferred to a 40°C water bath and stirred for 1 hour to allow crystallization, followed by stirring in an ice-water bath for another 1 hour. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under vacuum at 50°C to obtain a white solid dextromethorphan hydrobromide (monohydrate, 4.25 g).

[0119] 1 H NMR(400MHz, DMSO-d6)δ9.70(s,1H),7.14(d,J=8.2Hz,1H),6.83(m,2H),3.62(m,1H),3.23–2.87(m,4 H),2.82(s,3H),2.45(m,1H),2.01(m,1H),1.81(m,1H),1.68–1.23(m,6H),1.14(m,1H),0.97(m,1H).

[0120] 1.4 Preparation of deuterated dextromethorphan benzoate

[0121] Deuterated dextromethorphan (2.2 g, 8.0 mmol), benzoic acid (0.98 g, 8.0 mmol), and acetone (8 mL) were added sequentially to a reaction flask and stirred at room temperature to dissolve. Crystallization was then carried out by stirring at 2-8 °C. After solid precipitate, ethyl acetate (64 mL) was added dropwise, and stirring continued for approximately 3 hours to allow crystallization. The mixture was filtered, the filter cake was washed with ethyl acetate, and dried under vacuum at 40 °C to obtain a white crystalline powder of dextromethorphan benzoate (1.8 g).

[0122] 1H NMR (400MHz, DMSO-d6) δ8.04–7.81(m,2H),7.68–7.54(m,1H),7.48(dd,J=8.3,7.0 Hz,2H),7.04(d,J=8.3Hz,1H),6.76(d,J=2.7Hz,1H),6.70(dd,J=8.3,2.6Hz,1H),2 .94(d,J=18.2Hz,1H),2.78(m,1H),2.59–2.53(m,1H),2.37(m,2H),2.31(s,3H),1 .97(m,1H),1.75(m,1H),1.62(m,2H),1.48(m,1H),1.41–1.10(m,5H),1.00(m,1H).

[0123] 1.5 Preparation of other salts

[0124] Approximately 200 mg of dextromethorphan (compound of formula (I)) and the molar ratios of acid shown in Table 1 below were weighed and added to the solvents (approximately 2–4 mL) shown in the table below. The mixture was heated until the system was completely dissolved, and then allowed to stand at room temperature for 5 days to slowly evaporate the solvent to induce crystallization. The results showed that the reaction products were all gel-like substances, and no solid salt could be obtained.

[0125] Table 1. Experimental results of salt form preparation

[0126]

[0127]

[0128] Example 2: Study on the physicochemical properties of different salt types

[0129] This embodiment examines the solubility and stability of different salt forms of deuterated dextromethorphan obtained in Example 1.

[0130] 2.1 Solubility

[0131] At 25°C, the free base of dextromethorphan (i.e., compound (I)) and the tartrate, hydrobromide, citrate, and benzoate salts prepared according to Example 1 of this invention were added to 2 mL of purified water to obtain suspensions, which were stirred for 24 h. The supernatant of each sample was then subjected to HPLC analysis to investigate its solubility in media at pH 1.0 (pH 1.0 hydrochloric acid solution), pH 4.5 (pH 4.5 acetate buffer), and pH 6.8 (pH 6.8 phosphate buffer). The HPLC test conditions are shown in Table 2. The experimental results are shown in Table 3, where the solubility values ​​of different salts are all calculated based on the free base.

[0132] Table 2 HPLC test conditions

[0133] Chromatographic column Waters XBridge C18 (4.6*150mm, 3.5μm) Flow rate 1.0 mL / min Column temperature 35℃ Mobile phase A 10 mmol / L potassium dihydrogen phosphate solution Mobile phase B Acetonitrile Isocratic elution A phase-B phase (65:35) for 10 minutes Sample tray Uncontrolled temperature Injection volume 10 μl Detection wavelength 280 nm Needle washing liquid 50% methanol

[0134] Table 3 Solubility data (25℃)

[0135] Salt type Water pH 1.0 medium pH 4.5 medium pH 6.8 medium Free base 12.50 ug / mL N / A N / A N / A Hydrobromide 16.91 mg / mL 17.46 mg / mL 16.82 mg / mL 18.23 mg / mL Tartrate 44.54 mg / mL 66.86 mg / mL 55.62 mg / mL 65.91 mg / mL Benzoate 7.40 mg / mL 15.78 mg / mL 7.18 mg / mL 7.27 mg / mL Citrate 131.10 mg / mL 77.09 mg / mL 192.8 mg / mL 149.58 mg / mL

[0136] Experimental results show that, compared with the free base, the tartrate, citrate, hydrobromide, and benzoate of deuterated dextromethorphan have significantly improved solubility; among them, the solubility of citrate and tartrate is particularly high.

[0137] 2.2 Stability

[0138] Tartrate, citrate, hydrobromide, and benzoate samples of deuterated dextromethorphan prepared according to Example 1 of this invention were placed under high temperature (60±2℃), high humidity (25℃, RH 90%±5%), and light (4500Lx±500Lx) conditions for 30 days, respectively. Samples were taken on day 0, day 10, and day 30 to examine the stability of the samples. The experimental results are shown in Tables 4, 5, and 6.

[0139] Table 4. High Temperature (60±2℃) Test Results

[0140]

[0141] Table 5 Results of High Humidity Test (25℃, RH 90% ± 5%)

[0142]

[0143] Table 6. Results of the light irradiation (4500 Lx ± 500 Lx) test

[0144]

[0145]

[0146] Experimental results showed that the tartrate, citrate, hydrobromide and benzoate salts of deuterated dextromethorphan did not show significant changes in appearance or related substances after being placed under high temperature (60±2℃), high humidity (25℃, RH90%±5%) and light (4500Lx±500Lx) conditions for 30 days, indicating that the four salt forms have good physical and chemical stability.

[0147] Example 3. Study on polymorphs of different salt types and crystal form transformation

[0148] This embodiment further conducted polymorph screening experiments on different salt forms, obtaining two crystal forms of deuterated dextromethorphan tartrate; and one crystal form each of deuterated dextromethorphan citrate, hydrobromide and benzoate.

[0149] 3.1 Preparation of tartrate crystal form A of deuterated dextromethorphan

[0150] Method 1: Take 100 mg of dextromethorphan tartrate sample prepared according to Example 1.1, add 1 mL of acetonitrile, heat to dissolve, after dissolution, transfer to an ice-water bath and stir overnight, precipitate solid, filter, wash the solid with a small amount of ice acetonitrile, and dry under vacuum at 40°C to obtain the product.

[0151] Method 2: Take 50 mg of dextromethorphan tartrate sample prepared according to Example 1.1, add 3 mL of ethanol, heat to dissolve, after clear dissolution, transfer to ice water bath and stir overnight, precipitate solid, filter, wash the solid with a small amount of ice ethanol, and dry under vacuum at 40 °C to obtain the product.

[0152] Method 3: Same as the preparation of deuterated dextromethorphan tartrate in Example 1.1.

[0153] The obtained product was tested and found to be of the same crystal form, labeled as crystal form A. The XRPD spectrum is basically as follows. Figure 1 As shown, the diffraction angle data are basically as shown in Table 7. The DSC spectrum is basically as shown in Table 7. Figure 2 As shown, the DSC spectrum exhibits an endothermic peak at approximately 196 °C. This crystal form is anhydrous. The TGA spectrum is basically as follows. Figure 3 As shown.

[0154] Table 7. XRPD characteristic diffraction peaks of deuterated dextromethorphan tartrate crystal form A

[0155] Serial number 2θ±0.2° d value Relative intensity Serial number 2θ±0.2° d value Relative intensity 1 7.89 11.20 7.6％ 7 19.80 4.48 100％ 2 11.22 7.88 0.9％ 8 21.33 4.16 1.3％ 3 12.82 6.90 4.4％ 9 22.93 3.88 4.4％ 4 13.76 6.43 3.5％ 10 28.33 3.15 6.3％ 5 15.30 5.79 2.5％ 11 28.74 3.10 2.6％ 6 18.91 4.69 2.7％ 12 29.24 3.05 3.4％

[0156] 3.2 Preparation of tartrate form B of deuterated dextromethorphan

[0157] Method 1: Take 100 mg of dextromethorphan tartrate sample prepared according to Example 1.1, add 1 mL of acetone, heat to dissolve, after clear dissolution, transfer to an ice-water bath and stir to crystallize overnight, filter after the solid is precipitated, wash with a small amount of ice acetone, dry under vacuum to obtain a wet sample, place in a vacuum dryer at 40℃ to obtain the product.

[0158] Method 2: Take 100 mg of dextromethorphan tartrate sample prepared according to Example 1.1, add 1 mL of tetrahydrofuran, heat to dissolve, after clear dissolution, transfer to an ice-water bath and stir to crystallize overnight, filter after the solid precipitates, wash with a small amount of ice tetrahydrofuran, dry under vacuum to obtain a wet sample, place in a vacuum dryer at 40℃ to obtain the product.

[0159] The obtained product is labeled as crystal form B. The XRPD pattern is basically as follows: Figure 4 As shown, the diffraction angle data are basically as shown in Table 8. The DSC spectrum is basically as shown in Table 8. Figure 5 As shown, the DSC spectrum exhibits an endothermic peak at approximately 189 °C. This crystal form is anhydrous.

[0160] Table 8. XRPD characteristic diffraction peaks of deuterated dextromethorphan tartrate crystal form B

[0161] Serial number 2θ±0.2° d value Relative intensity Serial number 2θ±0.2° d value Relative intensity 1 5.33 16.58 100％ 7 16.80 5.27 51.5％ 2 10.51 8.41 17.1％ 8 19.07 4.65 25.1％ 3 11.71 7.55 61.5％ 9 20.94 4.24 66.8％ 4 12.93 6.84 17.6％ 10 22.30 3.98 18.8％ 5 15.04 5.88 27.2％ 11 23.91 3.72 44.4％ 6 15.62 5.67 95.7％ 12 26.26 3.39 25.5％

[0162] 3.3 Preparation of citrate form A of deuterated dextromethorphan

[0163] Preparation method: Same as the preparation of deuterated dextromethorphan citrate in Example 1.2.

[0164] The XRPD spectrum of the obtained product is basically as follows: Figure 6 As shown, the diffraction angle data are basically as shown in Table 9. The DSC spectrum is basically as shown in Table 9. Figure 7 As shown, the DSC spectrum exhibits an endothermic peak at approximately 136℃. The TGA spectrum is basically as follows. Figure 8 As shown.

[0165] Table 9. XRPD characteristic diffraction peaks of deuterated dextromethorphan citrate crystal form

[0166] Serial number 2θ±0.2° d value Relative intensity Serial number 2θ±0.2° d value Relative intensity 1 4.08 21.62 100％ 7 17.17 5.16 2.1％ 2 8.10 10.90 44.3％ 8 17.61 5.03 1.6％ 3 12.17 7.27 10.0％ 9 18.26 4.86 3.9％ 4 13.80 6.41 1.1％ 10 19.77 4.49 1.9％ 5 15.12 5.85 2.8％ 11 20.90 4.25 1.9％ 6 16.22 5.46 3.6％ 12 24.33 3.66 2.7％

[0167] 3.4 Preparation of deuterated dextromethorphan hydrobromide crystal form A

[0168] Preparation method: Same as the preparation of deuterated dextromethorphan hydrobromide in Example 1.3.

[0169] The XRPD spectrum of the obtained product is basically as follows: Figure 9 As shown, the diffraction angle data are basically as shown in Table 10. The DSC spectrum is basically as shown in Table 10. Figure 10 As shown, the DSC spectrum exhibits an endothermic peak at approximately 109 °C. This crystal form is a monohydrate. The TGA spectrum is basically as follows. Figure 11 As shown.

[0170] Table 10. XRPD characteristic diffraction peaks of deuterated dextromethorphan hydrobromide crystal forms.

[0171] Serial number 2θ±0.2° d value Relative intensity Serial number 2θ±0.2° d value Relative intensity 1 6.49 13.61 100％ 7 23.19 3.83 15.1％ 2 15.87 5.58 7.4％ 8 24.72 3.60 7.6％ 3 17.11 5.18 6.4％ 9 25.15 3.54 5.7％ 4 18.06 4.91 9.1％ 10 26.00 3.42 72.1％ 5 18.87 4.70 19.8％ 11 27.80 3.21 9.7％ 6 21.73 4.09 14.6％ 12 32.65 2.74 12.0％

[0172] 3.5 Preparation of deuterated dextromethorphan benzoate crystal form A

[0173] Preparation method: Same as the preparation of deuterated dextromethorphan benzoate in Example 1.4.

[0174] The XRPD spectrum of the obtained product is basically as follows: Figure 12 As shown, the diffraction angle data are basically as shown in Table 11. The DSC spectrum is basically as shown in Table 11. Figure 13 As shown, the DSC spectrum exhibits an endothermic peak at 98℃. The TGA spectrum is basically as follows. Figure 14 As shown.

[0175] Table 11. XRPD characteristic diffraction peaks of deuterated dextromethorphan benzoic acid crystal forms

[0176] Serial number 2θ±0.2° d value Relative intensity Serial number 2θ±0.2° d value Relative intensity 1 9.76 9.05 8.3％ 7 19.73 4.50 63.8％ 2 10.98 8.05 9.9％ 8 21.19 4.19 32.7％ 3 13.96 6.34 100％ 9 21.98 4.04 12.0％ 4 15.60 5.68 7.4％ 10 22.42 3.96 11.5％ 5 17.41 5.09 64.3％ 11 23.01 3.86 13.7％ 6 19.38 4.58 13.2％ 12 24.98 3.56 7.6％

[0177] 3.6 Study on the crystal form transformation of deuterated dextromethorphan tartrate

[0178] Approximately 50 mg of a mixed crystal sample (crystal forms A and B) of dextromethorphan tartrate was added to 1 mL of ethanol, acetone, and toluene, respectively. The mixture was stirred at room temperature for 24 hours, centrifuged to obtain a solid, and dried under vacuum at 40 °C. The dried sample was then characterized by DSC analysis, and the results are shown in Table 12. The DSC spectra are basically as follows. Figure 15 As shown.

[0179] Table 12 Results of crystal form transformation experiments of tartrates

[0180] Serial number Initial crystal form Solvent Temperature Time Final crystal form 1 A+B Ethanol Room temperature 24h A 2 A+B Acetone Room temperature 24h A 3 A+B Toluene Room temperature 24h A

[0181] Experimental results show that deuterated dextromethorphan tartrate crystal form A is more stable than crystal form B.

[0182] 3.7 Characterization data of different salt types

[0183] Characterization data of different salt forms of deuterated dextromethorphan are shown in Table 13.

[0184] Table 13 Characterization data of different salt types

[0185] Salt type Salt formation ratio Crystal form Melting point PLM Tartrate 1:1 Crystal form A About 196±3℃ Long rod Tartrate 1:1 Crystal form B About 189±3℃ Long rod Citrate 1:1 Crystal form A About 136±3℃ Long rod Hydrobromide 1:1 Crystal form A About 109±3℃ Flaky Benzoate 1:1 Crystal form A About 98±3℃ Long rod

[0186] Example 4. Study on metabolic stability of human liver microsomes

[0187] 4.1 Experimental Materials

[0188] Liver microsomes: Human liver microsomes, purchased from BioIVT In Vitro Biotechnology, USA;

[0189] Test compounds: dextromethorphan hydrobromide (purchased from Shanghai Maclean Biochemical Technology Co., Ltd.); deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan citrate, deuterated dextromethorphan benzoate (prepared according to Example 1 of the present invention);

[0190] LC-MS / MS instruments: High performance liquid chromatograph: LC-20ADXR (Shimadzu); API5000 (AB SCIEX).

[0191] 4.2 Experimental Methods

[0192] 1) Phosphate buffer (pH 7.4): Prepare 100mM potassium dihydrogen phosphate and 100mM dipotassium hydrogen phosphate solutions, and then mix them in a ratio of dipotassium hydrogen phosphate solution: potassium dihydrogen phosphate solution = 40.5: 9.5 to obtain phosphate buffer.

[0193] 2) Magnesium chloride solution: Prepare a 3mM magnesium chloride solution using phosphate buffer.

[0194] 3) Compound working solution: Prepare a 10 mM stock solution of the above-mentioned test compound, and then dilute it with 80% acetonitrile-water to a 100 μM working solution for later use.

[0195] 4) NADPH solution: Take a certain amount of NADPH, add an appropriate amount of 3mM magnesium chloride solution, and prepare a 2mM NADPH solution for later use.

[0196] 5) Add 22.5 μL of human liver microsomes (21.3 mg protein / mL) to 448 μL of phosphate buffer, then add 9.6 μL of the compound working solution obtained in step 3, and vortex until homogeneous.

[0197] 6) Dispense 165 μL / tube from the liver microsome mixture from step 5 into two parallel aliquots.

[0198] ①0min sample: Take 30μL / tube of liver microsome mixed working solution as 0min sample, and immediately add 300μL of carbamazepine (internal standard IS) acetonitrile termination solution (20ng / mL), then add 30μL of NADPH solution and mix well.

[0199] ② Add 135 μL of NADPH solution to the remaining liver microsome mixture (135 μL / tube) in each group to start the reaction. After incubating in a water bath at 37°C for 5, 15, 30 and 60 min, take out 60 μL of each mixture and add 300 μL of the stop solution.

[0200] 7) Dispense 45 μL of the liver microsome mixture from step 5 into two parallel tubes, add 45 μL of magnesium chloride solution to each tube, incubate at 37°C for 60 min, and then take 60 μL of each tube and add 300 μL of stop solution as a negative control for each test compound.

[0201] 8) Vortex and centrifuge all samples from steps 6 and 7, take 150 μL of the supernatant, add 150 μL of water, vortex to mix, and analyze by LC-MS / MS.

[0202] 4.3 Data Analysis

[0203] Convert the analyte / internal standard peak area ratio to the remaining percentage (remaining percentage) using the following formula:

[0204] Residual rate % = Ratio of analyte to IS peak area at each time point / Ratio of analyte to IS peak area at t=0 × 100;

[0205] The slope was calculated based on the remaining rate at each time point, and the half-lives (T1) of dextromethorphan hydrobromide, deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan benzoate, and deuterated dextromethorphan citrate were calculated. 1 / 2 );

[0206] In vitro clearance rate (CL) int )=0.693 / T 1 / 2 *Vd (Vd = 1 / protein content in liver microsomes).

[0207] 4.4 Experimental results: as shown in Table 14 below.

[0208] Table 14 Results of Human Liver Microsomal Metabolic Stability Test

[0209] Final residual amount % T 1 / 2 (min)]]> In vitro clearance rate (mL / min / mg) Dextromethorphan hydrobromide 44.2 45.6 0.0304 Deuterated dextromethorphan hydrobromide 52.5 59.3 0.0230 Deuterated dextromethorphan tartrate 53.1 64.8 0.0214 Deuterated dextromethorphan benzoate 49.4 55.9 0.0248 Deuterated dextromethorphan citrate 47.9 51.7 0.0268

[0210] The results showed that the half-lives of dextromethorphan tartrate, benzoate, and citrate were superior to those of dextromethorphan hydrobromide; furthermore, the half-lives of dextromethorphan tartrate, benzoate, and citrate were comparable to those of dextromethorphan hydrobromide, and all exhibited moderate clearance rates (0.01 ≤ CL) in the in vitro human liver microsomal system. int (≤0.1mL / min / mg), among which dextromethorphan tartrate has a relatively longer half-life.

[0211] Example 5. Pharmacokinetic Study

[0212] 5.1 Experimental Materials:

[0213] Fifteen male ICR mice, weighing 25-30g, were purchased from Hunan Slack Jingda Experimental Animal Co., Ltd.

[0214] Test compounds: dextromethorphan hydrobromide (purchased from Shanghai Maclean Biochemical Technology Co., Ltd.); deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan citrate, and deuterated dextromethorphan benzoate (prepared according to Example 1 of the present invention).

[0215] 5.2 Experimental Methods:

[0216] 1) Drug preparation: Based on free base, weigh a certain amount of drug and dissolve it in physiological saline, vortex mix, sonicate, and prepare solutions with a concentration of 6.8 mg / mL (free base concentration);

[0217] 2) Fifteen male ICR mice were randomly divided into five groups and administered solutions of the five test compounds by gavage at a dose of 5 mL / kg (34 mg / kg). Approximately 100 mL of whole blood was collected from the tail vein of each mouse at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-administration. The blood was placed in labeled EDTA-2K anticoagulant tubes and centrifuged at 4°C and 6800 rpm for 6 minutes to separate the plasma. The blood concentrations of dextromethorphan or deuterated dextromethorphan were determined by LC-MS.

[0218] 3) Data statistics: WinNonlin calculated the pharmacokinetic parameters of dextromethorphan or deuterated dextromethorphan by averaging the blood drug concentrations of three animals at the same time point.

[0219] 5.3 Experimental results: as shown in Table 15 below.

[0220] Table 15 Results of Pharmacokinetic Studies

[0221]

[0222] The results showed that, at the same dose, the AUCs of dextromethorphan hydrobromide, deuterated dextromethorphan hydrobromide, and deuterated dextromethorphan benzoate were... 0-t and C max Equivalent; AUC of dextromethorphan tartrate and dextromethorphan citrate 0- t and C max The AUC was higher, with deuterated dextromethorphan tartrate showing the best performance. 0-t It is approximately three times that of dextromethorphan hydrobromide.

[0223] Example 6. Antitussive test in mice

[0224] 6.1 Experimental Materials

[0225] Sixty ICR mice (half male and half female), weighing 20-25g, were purchased from Wuxi Hengtai Experimental Animal Breeding Co., Ltd.

[0226] The compounds to be tested were: dextromethorphan hydrobromide (purchased from Shanghai Maclean Biochemical Technology Co., Ltd.); deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan citrate, and deuterated dextromethorphan benzoate (prepared according to Example 1 of the present invention).

[0227] 6.2 Experimental Methods:

[0228] 1) Drug preparation: Dissolve the five test compounds in physiological saline to prepare solutions with a concentration of 2 mg / mL (calculated as free base).

[0229] 2) Dosing groups: The groups were designed as blank solvent group, dextromethorphan hydrobromide group, deuterated dextromethorphan hydrobromide group, deuterated dextromethorphan tartrate group, deuterated dextromethorphan benzoate group, and deuterated dextromethorphan citrate group.

[0230] 3) Sixty ICR mice (half male and half female) were randomly divided into 6 groups of 10 mice each: blank solvent group, dextromethorphan hydrobromide group, deuterated dextromethorphan hydrobromide group, deuterated dextromethorphan tartrate group, deuterated dextromethorphan benzoate group, and deuterated dextromethorphan citrate group. Each group of mice was administered the drug once by gavage. The blank solvent group received physiological saline, while the other groups received the corresponding test compound at a dose of 10 mL / kg (20 mg / kg, calculated as free base). Sixty minutes after administration, the mice were placed in an inverted 1000 mL beaker filled with concentrated ammonia vapor for 10 seconds. The mice were then removed and placed in another inverted 1000 mL beaker. The frequency of coughing was observed, and the total number of coughs within 3 minutes was recorded.

[0231] 4) Statistical methods: All experimental data are expressed as means. Statistical analysis was performed using Graphad Prism 8.0 software. One-way ANOVA was used for comparisons between groups; LSD was used for comparisons between groups with homogeneous variances, and Dunnett's T3 was used for comparisons between groups with unequal variances. P < 0.05 was considered statistically significant.

[0232] 6.3 Experimental results: as shown in Table 16.

[0233] Table 16 Results of the antitussive experiment in mice

[0234]

[0235]

[0236] Note: *P < 0.05 vs. blank solvent group

[0237] The results showed that 60 minutes after administration, deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan benzoic acid, and deuterated dextromethorphan citrate all had better antitussive effects on mice than dextromethorphan hydrobromide, with deuterated dextromethorphan tartrate showing the best antitussive effect.

Claims

1. A salt of a deuterated dextromethorphan compound as shown in formula (I), said salt being selected from tartrate, citrate, hydrobromide monohydrate, and benzoate salts of the compound of formula (I).

2. The salt as described in claim 1, characterized in that, In the tartrate, citrate, hydrobromide monohydrate or benzoate, the molar ratio of the compound of formula (I) to the acid is 1:

1.

3. The salt as described in claim 1 or 2, characterized in that, The salt is crystal form A of the compound of formula (II), which has characteristic peaks at one or more of the following locations in the XRPD pattern expressed in 2θ angles: 7.9±0.2°, 13.8±0.2°, 15.3±0.2°, 18.9±0.2°, and 19.8±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 7.9±0.2°, 12.8±0.2°, 13.8±0.2°, 15.3±0.2°, 18.9±0.2°, 19.8±0.2°, 22.9±0.2°, and 28.3±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 7.9±0.2°, 11.2±0.2°, 12.8±0.2°, 13.8±0.2°, 15.3±0.2°, 18.9±0.2°, 19.8±0.2°, 21.3±0.2°, 22.9±0.2°, 28.3±0.2°, 28.7±0.2°, and 29.2±0.2°. Preferably, the crystal form A has an XRPD pattern as shown in Figure 1; Preferably, the DSC plot of crystal form A of compound (II) has an endothermic peak in the range of about 196±3 °C; Preferably, the crystal form A of the compound of formula (II) has a DSC spectrum as shown in Figure 2; Preferably, the crystal form A of the compound of formula (II) has a TGA spectrum as shown in Figure 3.

4. The salt as described in claim 1 or 2, characterized in that, The salt is crystal form B of compound (II), which has characteristic peaks at one or more of the following locations in its XRPD pattern expressed at 2θ angles: 5.3±0.2°, 11.7±0.2°, 15.6±0.2°, 16.8±0.2°, and 20.9±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 5.3±0.2°, 10.5±0.2°, 11.7±0.2°, 15.0±0.2°, 15.6±0.2°, 16.8±0.2°, 20.9±0.2°, and 23.9±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 5.3±0.2°, 10.5±0.2°, 11.7±0.2°, 12.9±0.2°, 15.0±0.2°, 15.6±0.2°, 16.8±0.2°, 19.1±0.2°, 21.0±0.2°, 22.3±0.2°, 23.9±0.2°, and 26.3±0.2°. Preferably, the crystal form B has an XRPD pattern as shown in Figure 4; Preferably, the DSC plot of crystal form B of compound (II) has an endothermic peak in the range of about 189±3 °C; Preferably, the crystal form B of compound (II) has a DSC spectrum as shown in Figure 5; Preferably, the crystal form B of the compound of formula (II) is anhydrous.

5. The salt as described in claim 1 or 2, characterized in that, The salt is crystal form A of compound of formula (III), which has characteristic peaks at one or more of the following locations in its XRPD pattern expressed in 2θ angles: 4.1±0.2°, 8.1±0.2°, 12.2±0.2°, 16.2±0.2°, and 18.3±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 4.1±0.2°, 8.1±0.2°, 12.2±0.2°, 15.1±0.2°, 16.2±0.2°, 17.2±0.2°, 18.3±0.2°, and 24.3±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 4.1±0.2°, 8.1±0.2°, 12.2±0.2°, 13.8±0.2°, 15.1±0.2°, 16.2±0.2°, 17.2±0.2°, 17.6±0.2°, 18.3±0.2°, 19.8±0.2°, 20.9±0.2°, and 24.3±0.2°. Preferably, the crystal form A of the compound of formula (III) has a basic XRPD pattern as shown in Figure 6; Preferably, the DSC plot of crystal form A of compound (III) has an endothermic peak in the range of about 136±3 °C; Preferably, the crystal form A of the compound of formula (III) has a DSC spectrum as shown in Figure 7; Preferably, the crystal form A of compound (III) has a TGA spectrum as shown in Figure 8.

6. The salt as described in claim 1 or 2, characterized in that, The salt is crystal form A of the compound shown in formula (IV), which has characteristic peaks at one or more of the following locations in its XRPD plot (expressed at 2θ angles): 6.5±0.2°, 18.9±0.2°, 21.7±0.2°, 23.2±0.2°, and 26.0±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 6.5±0.2°, 15.9±0.2°, 17.1±0.2°, 18.1±0.2°, 18.9±0.2°, 21.7±0.2°, 23.2±0.2°, and 26.0±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 6.5±0.2°, 15.9±0.2°, 17.1±0.2°, 18.1±0.2°, 18.9±0.2°, 21.7±0.2°, 23.2±0.2°, 24.7±0.2°, 25.2±0.2°, 26.0±0.2°, 27.8±0.2°, and 32.6±0.2°. Preferably, the crystal form A of the compound of formula (IV) has a basic XRPD pattern as shown in Figure 9; Preferably, the DSC plot of crystal form A of compound (IV) has an endothermic peak in the range of about 109±3 °C; Preferably, the crystal form A of the compound of formula (IV) has a DSC spectrum as shown in Figure 10; Preferably, the crystal form A of compound (IV) has a TGA spectrum as shown in Figure 11.

7. The salt as described in claim 1 or 2, characterized in that, The salt is crystal form A of compound of formula (V), which has characteristic peaks at one or more of the following locations in its XRPD pattern expressed at 2θ angles: 14.0±0.2°, 17.4±0.2°, 19.4±0.2°, 19.7±0.2°, and 21.2±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 9.8±0.2°, 11.0±0.2°, 14.0±0.2°, 15.6±0.2°, 17.4±0.2°, 19.4±0.2°, 19.7±0.2°, and 21.2±0.2°. Preferably, the XRPD plot expressed in 2θ angles has characteristic peaks at one or more of the following locations: 9.8±0.2°, 11.0±0.2°, 14.0±0.2°, 15.6±0.2°, 17.4±0.2°, 19.4±0.2°, 19.7±0.2°, 21.2±0.2°, 22.0±0.2°, 22.4±0.2°, 23.0±0.2°, and 25.0±0.2°. Preferably, the crystal form A of the compound of formula (V) has an XRPD pattern as shown in Figure 12; Preferably, the DSC plot of crystal form A of compound (V) has an endothermic peak in the range of about 98±3℃; Preferably, the crystal form A of the compound of formula (V) has a DSC spectrum as shown in Figure 13; Preferably, the crystal form A of compound (V) has a TGA spectrum as shown in Figure 14.

8. The method for preparing salt according to any one of claims 1-7, characterized in that, This includes reacting the compound of formula (I) with an acid to obtain the salt; Preferably, the method for preparing the salt includes: dissolving the compound of formula (I) and the acid in organic solvent A; then adding organic solvent B to precipitate a solid, thereby obtaining the salt of the compound of formula (I); preferably, the organic solvent A is selected from one or two of alcohols or ketones; the alcohol is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and neopentyl alcohol; the ketone is selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, and 4-methyl-2-pentanone; the organic solvent B is selected from esters; the ester is selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, and isopropyl acetate. Preferably, the method for preparing crystal form A of compound (II) includes the following steps: dissolving compound (II) in organic solvent I to precipitate a solid; wherein organic solvent I is selected from one or more alcohols and nitriles, wherein the alcohols are selected from one or more methanol, ethanol, n-propanol, isopropanol, n-butanol, and neopentyl alcohol, and the nitriles are selected from acetonitrile; Preferably, the second method for preparing crystal form A of compound (II) includes the following steps: dissolving compound (I) and L-tartaric acid in organic solvent A; then adding organic solvent B to precipitate a solid; preferably, organic solvent A is selected from alcohols; the alcohols are selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and neopentyl alcohol; organic solvent B is selected from esters; the esters are selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, and isopropyl acetate. Preferably, the method for preparing crystal form B of compound (II) includes the following steps: dissolving compound (II) in organic solvent II to precipitate a solid; wherein organic solvent II is selected from one or more of ketones and tetrahydrofuran, and wherein the ketones are selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, and 4-methyl-2-pentanone.

9. A pharmaceutical composition comprising the salt of any one of claims 1-7 and at least one pharmaceutically acceptable carrier; optionally, the pharmaceutical composition comprises a second therapeutic agent.

10. Use of the salt of any one of claims 1-7 or the pharmaceutical composition of claim 9 in the preparation of a medicament; preferably, the medicament is used to treat an individual suffering from or susceptible to a disease or condition selected from the following: cough, pseudobulbar mood, depressive disorder, Alzheimer's disease agitation, non-suicidal self-harm, post-traumatic stress disorder, schizophrenia, anxiety disorder, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), bipolar disorder, mania, pain, autism, Parkinson's disease with depression, brain injury, disorders of consciousness, cardiovascular disease, glaucoma, tardive dyskinesia, cancer, rheumatoid arthritis, diabetic neuropathy, retinopathy, epilepsy, tinnitus, sexual dysfunction, addiction, nicotine addiction, dermatitis, Rett syndrome (RTT).

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