Deuterated dextromethorphan salt, crystal form, preparation method therefor and use thereof

Abstract

The present invention provides a plurality of salt forms of deuterated dextromethorphan represented by formula (I), a preparation method therefor and a use thereof. The deuterated dextromethorphan salt comprise tartrate, citrate, hydrobromate and benzoate. Also provided are a plurality of crystal forms of the salt. The salt exhibits excellent stability, bioactivity, bioavailability, medicinal effect and the like, and is suitable for development of pharmaceutical formulations.

Description

Deuterated dextromethorphan salts, crystal forms, and methods of preparation and use thereof

[0001] This application claims the priority of the prior application filed with the China National Intellectual Property Office on May 24, 2024, application number CN202410656859.1, entitled "Deuterated dextromethorphan salts, crystal forms, and methods of preparation and use thereof", the contents of the above-mentioned application are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to different salts and crystal forms of a deuterated dextromethorphan compound, and methods of preparation and use thereof. BACKGROUND

[0003] Dextromethorphan (CAS: 125-71-3), chemically named as 3-methoxy-17-methyl-(9α, 13α, 14α)-morphinan, is clinically used as a drug in the form of its hydrobromide monohydrate, and the structural formula is as follows:

[0004] CN101687868A discloses a variety of deuterated dextromethorphan compounds and methods of preparation thereof. CN115322150A discloses a crystal form of deuterated dextromethorphan-d6 hydrobromide, and the structural formula is as shown below:

[0005] The marketed dextromethorphan drug can be used to treat non-productive dry cough, including frequent and severe cough. In 2022, the FDA approved Auvelity sustained-release tablets (containing 45 mg of dextromethorphan hydrobromide and 105 mg of bupropion hydrochloride) of Axsome Company, which is the first rapid-acting oral drug approved for the treatment of major depressive disorder (MDD). Currently, the combination of dextromethorphan (deuterated or non-deuterated) with other drugs such as quinidine, bupropion, etc. is still under research for the treatment of pseudobulbar affect, depression, agitation in Alzheimer's disease, and other diseases.

[0006] Different deuterated dextromethorphan drugs, different salt types, and crystal forms can significantly affect their physicochemical properties, biological effectiveness, etc., thereby affecting the stability, bioavailability, and efficacy of the drug, and such influence is particularly evident in oral formulations. Therefore, in-depth research on the crystal forms and salt types of dextromethorphan deuterated compounds is of great significance for the pharmaceutical development of dextromethorphan. SUMMARY

[0007] The purpose of the present application is to provide salts and crystal forms of deuterated dextromethorphan (chemical name: 3-(methoxy-d3)-17-methyl-(9α, 13α, 14α)-morphinan) represented by formula (I), and methods of preparation and use thereof.

[0008] According to a first aspect of the present application, there is provided a salt of a deuterated dextromethorphan compound of formula (I) as shown below,

[0009] In one embodiment, the acid is selected from an organic acid or an inorganic acid; preferably, the organic acid is selected from tartaric acid, citric acid, hydrobromic acid and benzoic acid. That is, the salt is selected from a tartaric acid salt, a citric acid salt, a hydrobromic acid salt monohydrate and a benzoic acid salt of the compound of formula (I).

[0010] In one embodiment, the organic acid includes any optical isomer, racemate, meso thereof. For example, the tartaric acid can be L-tartaric acid, D-tartaric acid or DL-tartaric acid.

[0011] In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) can have a molar ratio of the compound of formula (I) to the acid selected from 1:1, 1:2, 2:1 or 3:1, etc., in which the salt has a charge balance between the ion of the compound of formula (I) and the ion of the acid.

[0012] In one embodiment, the tartaric acid salt, the citric acid salt, the hydrobromic acid salt monohydrate and the benzoic acid salt of the compound of formula (I) can have a salt of the compound of formula (I) and the acid in a molar ratio of substantially 1:1.

[0013] In one embodiment, the pharmaceutically acceptable salt of the compound of formula (I) includes a salt in an anhydrous form, a solvate, a hydrate form, preferably, a salt monohydrate.

[0014] In one embodiment, the deuterated dextromethorphan tartaric acid salt has a structure as shown in formula (II) below:

[0015] In one embodiment, the deuterated dextromethorphan citric acid salt has a structure as shown in formula (III) below:

[0016] In one embodiment, the deuterated dextromethorphan hydrobromic acid salt monohydrate has a structure as shown in formula (IV) below:

[0017] In one embodiment, the deuterated dextromethorphan benzoic acid salt has a structure as shown in formula (V) below:

[0018] According to a second aspect of the present application, there is provided a polymorph of a salt of deuterated dextromethorphan of formula (I). Preferably, the salt is a tartaric acid salt, a citric acid salt, a hydrobromic acid salt monohydrate or a benzoic acid salt.

[0019] In one embodiment, the crystalline Form A of the compound of formula (II) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 7.9 ± 0.2°, 13.8 ± 0.2°, 15.3 ± 0.2°, 18.9 ± 0.2°, 19.8 ± 0.2°.

[0020] In one embodiment, the crystalline Form A of the compound of formula (II) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 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°, 28.3 ± 0.2°.

[0021] In one embodiment, the crystalline Form A of the compound of formula (II) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 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°, 29.2 ± 0.2°.

[0022] In one embodiment, the crystalline Form A of the compound of formula (II) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 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°, 29.2 ± 0.2°.

[0023] In one embodiment, the crystalline Form A of the compound of formula (II) has an XRPD pattern substantially as set out in Figure 1.

[0024] In one embodiment, the crystalline Form A of the compound of formula (II) has a DSC pattern with an endothermic peak in the range of about 196 ± 3 °C.

[0025] In one embodiment, the crystalline Form A of the compound of formula (II) has a DSC pattern substantially as set out in Figure 2.

[0026] In one embodiment, the crystalline Form A of the compound of formula (II) has a TGA pattern substantially as set out in Figure 3.

[0027] In one embodiment, the crystalline Form A of the compound of formula (II) is an anhydrate.

[0028] In an embodiment, the crystalline Form B of the compound of formula (II) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 5.3 ± 0.2°, 11.7 ± 0.2°, 15.6 ± 0.2°, 16.8 ± 0.2°, 20.9 ± 0.2°.

[0029] In an embodiment, the crystalline Form B of the compound of formula (II) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 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°, 23.9 ± 0.2°.

[0030] In an embodiment, the crystalline Form B of the compound of formula (II) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 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°, 26.3 ± 0.2°.

[0031] In an embodiment, the crystalline Form B of the compound of formula (II) has an XRPD pattern substantially as shown in Figure 4.

[0032] In an embodiment, the crystalline Form B of the compound of formula (II) has a DSC pattern with an endothermic peak in the range of about 189 ± 3 °C.

[0033] In an embodiment, the crystalline Form B of the compound of formula (II) has a DSC pattern substantially as shown in Figure 5.

[0034] In an embodiment, the crystalline Form B of the compound of formula (II) is an anhydrate.

[0035] In an embodiment, the crystalline Form A of the compound of formula (III) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 4.1 ± 0.2°, 8.1 ± 0.2°, 12.2 ± 0.2°, 16.2 ± 0.2°, 18.3 ± 0.2°.

[0036] In an embodiment, the crystalline Form A of the compound of formula (III) has an XRPD pattern, expressed in terms of 2 theta angles, with characteristic peaks at one or more of 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°, 24.3 ± 0.2°.

[0037] In one embodiment, crystalline Form A of the compound of formula (III) has an XRPD pattern, expressed in terms of 2 theta angles, with one or more peaks at one or more of 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°, 24.3 ± 0.2°.

[0038] In one embodiment, crystalline Form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6.

[0039] In one embodiment, crystalline Form A of the compound of formula (III) has a DSC pattern with an endothermic peak in the range of about 136 ± 3 °C.

[0040] In one embodiment, crystalline Form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7.

[0041] In one embodiment, crystalline Form A of the compound of formula (III) has a TGA pattern substantially as shown in Figure 8.

[0042] In one embodiment, crystalline Form A of the compound of formula (IV) has an XRPD pattern, expressed in terms of 2 theta angles, with one or more peaks at one or more of 6.5 ± 0.2°, 18.9 ± 0.2°, 21.7 ± 0.2°, 23.2 ± 0.2°, 26.0 ± 0.2°.

[0043] In one embodiment, crystalline Form A of the compound of formula (IV) has an XRPD pattern, expressed in terms of 2 theta angles, with one or more peaks at one or more of 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°, 26.0 ± 0.2°.

[0044] In one embodiment, crystalline Form A of the compound of formula (IV) has an XRPD pattern, expressed in terms of 2 theta angles, with one or more peaks at one or more of 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°, 32.6 ± 0.2°.

[0045] In one embodiment, crystalline Form A of the compound of formula (IV) has an XRPD pattern substantially as shown in Figure 9.

[0046] In one embodiment, Form A of the compound of formula (IV) has a DSC pattern substantially as shown in Figure 10.

[0047] In one embodiment, Form A of the compound of formula (IV) has a DSC pattern substantially as shown in Figure 10.

[0048] In one embodiment, Form A of the compound of formula (IV) has a TGA pattern substantially as shown in Figure 11.

[0049] In one embodiment, Form A of the compound of formula (V) has an XRPD pattern, expressed in terms of 2Θ angles, with one or more peaks at 14.0 ± 0.2°, 17.4 ± 0.2°, 19.4 ± 0.2°, 19.7 ± 0.2°, 21.2 ± 0.2°.

[0050] In one embodiment, Form A of the compound of formula (V) has an XRPD pattern, expressed in terms of 2Θ angles, with one or more peaks at 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°.

[0051] In one embodiment, Form A of the compound of formula (V) has an XRPD pattern, expressed in terms of 2Θ angles, with one or more peaks at 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°, 25.0 ± 0.2°.

[0052] In one embodiment, Form A of the compound of formula (V) has an XRPD pattern substantially as shown in Figure 12.

[0053] In one embodiment, Form A of the compound of formula (V) has a DSC pattern with an endothermic peak in the range of about 98 ± 3 °C.

[0054] In one embodiment, Form A of the compound of formula (V) has a DSC pattern substantially as shown in Figure 13.

[0055] In one embodiment, Form A of the compound of formula (V) has a TGA pattern substantially as shown in Figure 14.

[0056] According to a third aspect of the present application, there is provided a pharmaceutical composition comprising a salt of the compound of formula (I) in any of the forms described above, and at least one pharmaceutically acceptable carrier.

[0057] In one embodiment, the salt of the compound of formula (I) in the pharmaceutical composition is selected from the group consisting of tartrate, citrate, hydrobromide monohydrate, benzoate; preferably, the salt is selected from the group consisting of tartrate, citrate.

[0058] In one embodiment, the salt of the compound of formula (I) in the pharmaceutical composition is selected from the group consisting of crystalline form A of the compound of formula (II), crystalline form B of the compound of formula (II), crystalline form A of the compound of formula (III), crystalline form A of the compound of formula (IV), and form A of the compound of formula (V); preferably, the salt is selected from the group consisting of crystalline form A of the compound of formula (II), and crystalline form A of the compound of formula (III).

[0059] In one embodiment, the pharmaceutical composition optionally comprises a second therapeutic agent. For example, the second therapeutic agent can be selected from one or more of quinidine, quinidine sulfate, hydroxytetracycline, gabapentin, bupropion, bupropion hydrochloride, clomipramine, doxepin, fluoxetine, mianserin, imipramine, 2-chloroimipramine, amitriptyline, amoxapine, desipramine, protriptyline, trimipramine, nortriptyline, maprotiline, phenelzine, isocarboxazid, tranylcypromine, paroxetine, trazodone, citalopram, sertraline, aryloxyaminoindans, benactyzine, escitalopram, fluvoxamine, venlafaxine, desmethylvenlafaxine, nefazodone, selegiline, milnacipran, tetrabenazine, bostfenoxine, molindone, rasagiline, nialamide, isopropylhydrazine, iproclozide, toloxatone, butriptyline, duloxetine, dibenzoxepin, iprindole, lofepramine, opipramil, norfluoxetine, dapoxetine, and ketamine.

[0060] According to a fourth aspect of the present application, there is provided a method of preparing the deuterated dextromethorphan salt of the first aspect, and the polymorph of the deuterated dextromethorphan salt of the second aspect.

[0061] In one embodiment, there is provided a method of preparing a salt of the compound of formula (I), comprising reacting the compound of formula (I) with the acid to obtain the salt.

[0062] In one embodiment, the salt can be prepared by Preparation Method I, comprising the steps of dissolving the compound of Formula (I) and the acid in an organic solvent A; then adding an organic solvent B, and isolating the solid to obtain the salt of the compound of Formula (I). The acid has the definition as described above. Preferably, the organic solvent A is selected from one or more of an alcohol or a ketone. The alcohol can be selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, and the ketone can be selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone; the organic solvent B is selected from an ester. The ester can be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, isopropyl acetate. Preferably, the salt prepared by Preparation Method I is a tartrate salt, a citrate salt.

[0063] In one embodiment, when the acid is selected from hydrobromic acid, the salt can be prepared by Preparation Method II, comprising the steps of dissolving the compound of Formula (I) in an organic solvent C; then adding an aqueous solution of hydrobromic acid, and isolating the solid to obtain the salt of the compound of Formula (I). Preferably, the organic solvent C is selected from an ester. The ester can be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, isopropyl acetate. Preferably, the aqueous solution of hydrobromic acid has a concentration of 40-60 wt%, for example, 45, 48, 50, 55, 60 wt%.

[0064] In one embodiment, there is provided a Preparation Method I for preparing the crystalline Form A of the compound of Formula (II), comprising the steps of: dissolving the compound of Formula (II) in an organic solvent I, and isolating the solid. The organic solvent I is selected from one or more of an alcohol or a nitrile. The alcohol can be selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol, and the nitrile can be acetonitrile. Preferably, the ratio of the compound of Formula (II) to the organic solvent I is 100 mg: 0.5-10 mL. Preferably, when the organic solvent I is selected from a nitrile (e.g., acetonitrile), the ratio of the compound of Formula (II) to the organic solvent I is 100 mg: 0.5-3 mL, for example, 100 mg: 1 mL; when the organic solvent I is selected from an alcohol (e.g., ethanol), the ratio of the compound of Formula (II) to the organic solvent I is 100 mg: 6 mL.

[0065] In one embodiment, there is provided a method for preparing crystalline Form A of the compound of formula (II), comprising the steps of: dissolving the compound of formula (I) and L-tartaric acid in an organic solvent A; then adding an organic solvent B, and precipitating a solid. Preferably, the organic solvent A is selected from alcohols. The alcohols can be selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol; 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, isopropyl acetate. Preferably, the ratio of L-tartaric acid to the organic solvent A is 1 mmol: 0.5-2 mL, for example, 1 mmol: 1 mL; preferably, the ratio of L-tartaric acid to the organic solvent B is 1 mmol: 3-6 mL, for example, 1 mmol: 4 mL.

[0066] In one embodiment, there is provided a method for preparing crystalline Form B of the compound of formula (II), comprising the steps of: dissolving the compound of formula (II) in an organic solvent II, and precipitating a solid. The organic solvent II is selected from one or more of ketones, tetrahydrofuran, the ketones can be selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone.

[0067] In one embodiment, there is provided a method for preparing crystalline Form A of the compound of formula (III), comprising dissolving the compound of formula (I) and citric acid monohydrate in an organic solvent A; then adding an organic solvent B, and precipitating a solid. Preferably, the organic solvent A is selected from alcohols. The alcohols can be selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol; 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, isopropyl acetate.

[0068] In one embodiment, there is provided a method for preparing crystalline Form A of the compound of formula (IV), comprising dissolving the compound of formula (I) in an organic solvent C; then adding an aqueous solution of hydrobromic acid, and precipitating a solid. Preferably, the organic solvent C is selected from esters. The esters can be selected from one or more of methyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, isopropyl acetate. Preferably, the concentration of the aqueous solution of hydrobromic acid is 40-60 wt%, for example, 45, 48, 50, 55, 60 wt%.

[0069] In one embodiment, a method for preparing the crystalline form A of the compound of formula (V) is provided, which comprises dissolving the compound of formula (I) and benzoic acid in an organic solvent A; then adding an organic solvent B, and precipitating a solid. Preferably, the organic solvent A is selected from ketones. The ketone can be selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone; the organic solvent B is selected from esters. The ester can be selected from one or more of methyl formate, ethyl formate, ethyl acetate, isobutyl formate, ethyl propyl acetate, isopropyl acetate.

[0070] According to a fifth aspect of the present application, there is provided a 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 manufacture of a medicament. The medicament is for treating a subject suffering from or susceptible to a disease or condition selected from the group consisting of cough, pseudobulbar affect, depressive disorder, agitation in Alzheimer's disease, non-suicidal self-injury, post-traumatic stress disorder, schizophrenia, anxiety, 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, Rett's syndrome (RTT).

[0071] The salt of the deuterated dextromethorphan of the present application (especially the crystalline form of the specific salt) has excellent physicochemical stability, longer half-life, and significantly improved bioavailability, is expected to have better clinical therapeutic effect, and is easy to be mass-produced industrially, and is very suitable for the development of pharmaceutical preparations. BRIEF DESCRIPTION OF DRAWINGS

[0072] Figure 1. XRPD pattern of the crystalline form A of the deuterated dextromethorphan tartrate (compound of formula II);

[0073] Figure 2. DSC pattern of the crystalline form A of the deuterated dextromethorphan tartrate (compound of formula II);

[0074] Figure 3. TGA pattern of the crystalline form A of the deuterated dextromethorphan tartrate (compound of formula II);

[0075] Figure 4. XRPD pattern of the crystalline form B of the deuterated dextromethorphan tartrate (compound of formula II);

[0076] Figure 5. DSC pattern of the crystalline form B of the deuterated dextromethorphan tartrate (compound of formula II);

[0077] Figure 6. XRPD pattern of the crystalline form A of the deuterated dextromethorphan citrate (compound of formula III);

[0078] Figure 7. DSC pattern of crystalline Form A of deuterated dextromethorphan citrate (compound of Formula III);

[0079] Figure 8. TGA pattern of crystalline Form A of deuterated dextromethorphan citrate (compound of Formula III);

[0080] Figure 9. XRPD pattern of crystalline Form A of deuterated dextromethorphan hydrobromide monohydrate (compound of Formula IV);

[0081] Figure 10. DSC pattern of crystalline Form A of deuterated dextromethorphan hydrobromide monohydrate (compound of Formula IV);

[0082] Figure 11. TGA pattern of crystalline Form A of deuterated dextromethorphan hydrobromide monohydrate (compound of Formula IV);

[0083] Figure 12. XRPD pattern of crystalline Form A of deuterated dextromethorphan benzoate (compound of Formula V);

[0084] Figure 13. DSC pattern of crystalline Form A of deuterated dextromethorphan benzoate (compound of Formula V);

[0085] Figure 14. TGA pattern of crystalline Form A of deuterated dextromethorphan benzoate (compound of Formula V);

[0086] Figure 15. DSC comparison of deuterated dextromethorphan tartrate (compound of Formula II) before and after crystalline form conversion test. DETAILED DESCRIPTION

[0087] The present application is described in detail below by way of Examples. It should be understood that the methods in the Examples are for illustrative purposes only and do not constitute any limitation of the present application. The materials used in the Examples are commercially available or prepared according to known or conventional methods unless otherwise specified. The experimental methods used are conventional unless otherwise specified.

[0088] Experimental Materials:

[0089] The deuterated dextromethorphan used in the Examples refers to the compound as shown in Formula (I) which can be prepared according to the following method:

[0090] Synthetic Route:

[0091] Synthetic Steps:

[0092] Dextromethorphan hydrobromide (compound 1, 100.0 g, purchased from Shanghai Melin Biological Technology Co., Ltd.) was dissolved in dichloromethane (500 mL) and washed with aqueous NaOH (25.0 g, 400 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness to obtain dextromethorphan (compound 2, 74.6 g).

[0093] 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 reaction was heated to reflux for 16 h. The reaction was cooled to room temperature, diluted with dichloromethane (200 mL), and poured into ice water (700 mL). After stirring well, the mixture was allowed to stand and separate. 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 light yellow oil (Intermediate 3, 90.0 g).

[0094] Intermediate 3 (45.0 g) was dissolved in dichloromethane (450 mL), and a solution of boron tribromide in dichloromethane (1 M, 273 mL) was added dropwise at 0-5 °C under nitrogen. After the addition was complete, the reaction was stirred for 3 h. The reaction was diluted with dichloromethane (200 mL) and quenched by the dropwise addition of saturated aqueous sodium bicarbonate solution (800 mL). The mixture was separated, and the organic phase was washed with deionized water (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give crude light yellow solid (Intermediate 4, 46.2 g).

[0095] Intermediate 4 (46.2 g) was dissolved in N,N-dimethylformamide (150 mL), and deuterated methyl iodide (31.7 g) and potassium carbonate (37.8 g) were added. The reaction was stirred at 25 °C overnight until the reaction was complete. The reaction was added to methyl tert-butyl ether (350 mL) and water (700 mL), and the mixture was allowed to stand and separate. The aqueous phase was extracted with methyl tert-butyl ether (200 mL), and the combined organic phases were washed with saturated aqueous brine (2 x 300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give a light yellow oil (Intermediate 5, 45.2 g).

[0096] 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. The reaction was stirred at room temperature for 3 h, and quenched by the dropwise addition of water (22 mL) followed by the dropwise addition of 15% aqueous NaOH solution (8.0 mL) and then (7.7 mL). The reaction was filtered, the filter cake was washed with tetrahydrofuran (150 mL), and the filtrate was concentrated to dryness. The residue was dissolved in ethyl acetate (150 mL), filtered, and the filtrate was washed with a small amount of ethyl acetate. A 48% aqueous hydrobromic acid solution (22.7 g) was added, and the reaction was stirred at 40 °C for 1 h and then at 0-5 °C for 1 h. The reaction was filtered, the filter cake was washed with ethyl acetate (100 mL), and the filter cake was dried in a vacuum at 50 °C to give a white solid (Compound 6, 42.5 g).

[0097] Compound 6 (40.0 g) was dissolved in dichloromethane (350 mL), and the solution was washed with an aqueous NaOH solution (10.0 g in 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).

[0098] Instruments and Methods:

[0099] XRPD (X-ray powder diffraction): Instrument: Bruker D8 ADVANCE X-ray diffractometer; XRPD parameters: Light tube: Cu, k a, Light tube voltage: 40 kV, light tube current: 40 mA; scan range: 3-45 deg; step: 0.02 deg; step size: 0.12 seconds. Test method: About 10-20 mg sample was used for XRPD testing. The XRPD data 2 theta value error range is ±0.2°.

[0100] DSC (Differential Scanning Calorimetry): Instrument: METTLER TOLEDO DSC3+ Differential Scanning Calorimeter; DSC parameters: Temperature range: 25-300 °C; heating rate: 10 °C / min; nitrogen purge gas: 50 mL / min. Test method: The sample (3-5 mg) was placed in a DSC aluminum pan for testing.

[0101] TGA (Thermogravimetric Analysis): Instrument: USA TA TGA Q50; TGA parameters: Temperature range: 30-300 °C; heating rate: 10 °C / min; nitrogen purge gas: 25 mL / min. Test method: The sample (5-10 mg) was placed in a TGA platinum pan for testing.

[0102] Preparation of different salt forms of deuterated dextromethorphan

[0103] 1.1 Preparation of deuterated dextromethorphan tartrate salt

[0104] Into a reaction bottle, deuterated dextromethorphan (2.2 g, 8.0 mmol), L-tartaric acid (1.2 g, 8.0 mmol) and methanol (8 mL) were added in sequence, and stirred to dissolve at room temperature. Ethyl acetate (32 mL) was added dropwise, and stirred to crystallize for 2-3 h. Filtration was performed, the filter cake was eluted with ethyl acetate, and vacuum drying was performed at 40 °C to obtain deuterated dextromethorphan L-tartrate salt (3.28 g) in the form of white solid.

[0105] 1 H NMR (400 MHz, DMSO-d6) δ 7.11 (d, J = 8.3 Hz, 1H), 6.91 - 6.70 (m, 2H), 4.02 (s, 2H), 3.30 (m, 1H), 3.07 (d, J = 19.1 Hz, 1H), 2.94 - 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).

[0106] 1.2 Preparation of Deuterated dextromethorphan citrate

[0107] To a reaction flask was added deuterated dextromethorphan (2.2 g, 8.0 mmol), citric acid monohydrate (1.7 g, 8.0 mmol), and methanol (8 mL) sequentially and stirred to dissolve at room temperature. Ethyl acetate (64 mL) was added dropwise and stirred to crystallize for 2-3 hours. Filtered, the filter cake was rinsed with ethyl acetate, and dried under vacuum at 40 °C to give deuterated dextromethorphan citrate as a white solid (2.46 g).

[0108] 1 H NMR (400 MHz, Methanol-d4) δ 7.18 (d, J = 8.5 Hz, 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, 1.9 Hz, 2H), 2.79 - 2.73 (dd, J = 15.4, 1.9 Hz, 2H), 2.70 (m, 1H), 2.50 (d, J = 13.9 Hz, 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).

[0109] 1.3 Preparation of deuterated dextromethorphan hydrobromide

[0110] To a reaction flask was added deuterated dextromethorphan (3.7 g, 13.5 mmol) and ethyl acetate (370 mL) and stirred to dissolve at room temperature. 48% aqueous HBr (2.28 g, 13.5 mmol) was added and a white solid precipitated, the system was moved to a 40 °C water bath and stirred to crystallize for 1 hour, then stirred to crystallize for 1 hour in an ice water bath. Filtered, the filter cake was rinsed with ethyl acetate, and dried under vacuum at 50 °C to give deuterated dextromethorphan hydrobromide (monohydrate, 4.25 g) as a white solid.

[0111] 1 H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.83 (m, 2H), 3.62 (m, 1H), 3.23 - 2.87 (m, 4H), 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).

[0112] 1.4 Preparation of deuterated dextromethorphan benzoate

[0113] Into a reaction flask, deuterated dextromethorphan (2.2 g, 8.0 mmol), benzoic acid (0.98 g, 8.0 mmol) and acetone (8 mL) were added successively. The mixture was stirred to dissolve at room temperature. Then, the mixture was stirred to crystallize at 2-8°C. After the solid was precipitated, ethyl acetate (64 mL) was added dropwise to the mixture, and the mixture was stirred to crystallize for about 3 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate. The filter cake was dried at 40°C under vacuum to obtain deuterated dextromethorphan benzoate (1.8 g) in the form of white crystalline powder. 1 H NMR (400 MHz, DMSO-d6) δ 8.04 - 7.81 (m, 2H), 7.68 - 7.54 (m, 1H), 7.48 (dd, J = 8.3, 7.0 Hz, 2H), 7.04 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 2.7 Hz, 1H), 6.70 (dd, J = 8.3, 2.6 Hz, 1H), 2.94 (d, J = 18.2 Hz, 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).

[0114] 1.5 Preparation of other salts

[0115] About 200 mg of deuterated dextromethorphan (compound of formula (I)) and the acid in the molar ratio shown in Table 1 below were weighed into the solvent (about 2-4 mL) shown in the table below, heated to dissolve the system, and then left to stand at room temperature for 5 days to evaporate the solvent slowly to crystallize. It was found that the reaction products were all in the form of a gel, and no solid salt could be obtained.

[0116] Table 1: Experimental results of salt type preparation

[0117] Example 2: Study on the physicochemical properties of different salt types

[0118] This example investigates the solubility and stability of the different salt types of deuterated dextromethorphan obtained in Example 1.

[0119] 2.1 Solubility

[0120] The free base of deuterated dextromethorphan (i.e. the compound of formula (I)) and the tartrate, hydrobromide, citrate and benzoate salts prepared according to Example 1 of the present application were each added to 2 mL purified water at 25 °C to give suspensions, which were stirred for 24 h. The supernatant of each sample was taken and tested by HPLC to investigate the solubility in pH 1.0 (pH 1.0 hydrochloric acid solution), pH 4.5 (pH 4.5 acetic acid buffer) and pH 6.8 (pH 6.8 phosphate buffer) media. The HPLC test conditions are shown in Table 2. The results are shown in Table 3, in which the solubility values of the different salts are calculated as free base.

[0121] Table 2 HPLC test conditions

[0122] Table 3 Solubility data (25 °C)

[0123] The results show that the tartrate, citrate, hydrobromide and benzoate salts of deuterated dextromethorphan have significantly improved solubility compared to the free base; the solubility of the citrate and tartrate salts is particularly high.

[0124] 2.2 Stability

[0125] The tartrate, citrate, hydrobromide and benzoate salts of deuterated dextromethorphan prepared according to Example 1 of the present application were each placed under high temperature (60 ± 2 °C), high humidity (25 °C, RH 90% ± 5%) and light (4500 Lx ± 500 Lx) conditions for 30 days. Samples were taken at 0, 10 and 30 days to investigate the stability of the samples. The results are shown in Tables 4, 5 and 6.

[0126] Table 4 Results of the high temperature (60 ± 2 °C) test

[0127] Table 5 Results of the high humidity (25 °C, RH 90% ± 5%) test

[0128] Table 6 Results of the light (4500 Lx ± 500 Lx) test

[0129] The results show that the tartrate, citrate, hydrobromide and benzoate salts of deuterated dextromethorphan have significantly improved solubility compared to the free base; the solubility of the citrate and tartrate salts is particularly high.

[0130] Example 3. Polymorphs of different salt forms and salt form conversion studies

[0131] The present example further carried out polymorph screening test on different salt types, and obtained two crystal forms of the deuterated dextromethorphan tartrate, one crystal form of the deuterated dextromethorphan citrate, one crystal form of the deuterated dextromethorphan hydrobromide, and one crystal form of the deuterated dextromethorphan benzoate.

[0132] 3.1 Preparation of the deuterated dextromethorphan tartrate crystal form A

[0133] Method 1: 100 mg of the deuterated dextromethorphan tartrate sample prepared according to Example 1.1 was taken, 1 mL of acetonitrile was added, and the sample was heated to dissolve. After the solution was clear, the sample was moved to an ice water bath for stirring overnight. The solid was separated by filtration, and the solid was washed with a small amount of ice acetonitrile. The product was obtained by drying at 40°C under vacuum.

[0134] Method 2: 50 mg of the deuterated dextromethorphan tartrate sample prepared according to Example 1.1 was taken, 3 mL of ethanol was added, and the sample was heated to dissolve. After the solution was clear, the sample was moved to an ice water bath for stirring overnight. The solid was separated by filtration, and the solid was washed with a small amount of ice ethanol. The product was obtained by drying at 40°C under vacuum.

[0135] Method 3: The preparation of the deuterated dextromethorphan tartrate in Example 1.1 was repeated.

[0136] The obtained product was detected as the same crystal form, which was marked as crystal form A. The XRPD spectrum was substantially as shown in FIG. 1, and the diffraction angle data was substantially as shown in Table 7. The DSC spectrum was substantially as shown in FIG. 2, wherein the DSC spectrum had an endothermic peak at about 196°C. The crystal form was an anhydrous substance. The TGA spectrum was substantially as shown in FIG. 3.

[0137] Table 7 XRPD characteristic diffraction peaks of the deuterated dextromethorphan tartrate crystal form A

[0138] 3.2 Preparation of the deuterated dextromethorphan tartrate crystal form B

[0139] Method 1: 100 mg of the deuterated dextromethorphan tartrate sample prepared according to Example 1.1 was taken, 1 mL of acetonitrile was added, and the sample was heated to dissolve. After the solution was clear, the sample was moved to an ice water bath for stirring overnight. The solid was separated by filtration, and the solid was washed with a small amount of ice acetonitrile. The product was obtained by drying at 40°C under vacuum.

[0140] Method 2: 100 mg of the deuterated dextromethorphan tartrate sample prepared according to Example 1.1 was taken, 1 mL of tetrahydrofuran was added, and the sample was heated to dissolve. After the solution was clear, the sample was moved to an ice water bath for stirring overnight. The solid was separated by filtration, and the solid was washed with a small amount of ice tetrahydrofuran. The product was obtained by drying at 40°C under vacuum.

[0141] The resulting product was labeled Form B. The XRPD pattern was substantially as shown in Figure 4, and the diffraction angle data was substantially as shown in Table 8. The DSC pattern was substantially as shown in Figure 5, which had an endothermic peak at about 189 °C. This form was an anhydrate.

[0142] Table 8 XRPD characteristic diffraction peaks of deuterated dextromethorphan tartrate Form B

[0143] 3.3 Preparation of deuterated dextromethorphan citrate Form A

[0144] Preparation Method: Same as the preparation of deuterated dextromethorphan citrate in Example 1.2.

[0145] The XRPD pattern of the resulting product was substantially as shown in Figure 6, and the diffraction angle data was substantially as shown in Table 9. The DSC pattern was substantially as shown in Figure 7, which had an endothermic peak at about 136 °C. The TGA pattern was substantially as shown in Figure 8.

[0146] Table 9 XRPD characteristic diffraction peaks of deuterated dextromethorphan citrate Form B

[0147] 3.4 Preparation of deuterated dextromethorphan hydrobromide Form A

[0148] Preparation Method: Same as the preparation of deuterated dextromethorphan hydrobromide in Example 1.3.

[0149] The XRPD pattern of the resulting product was substantially as shown in Figure 9, and the diffraction angle data was substantially as shown in Table 10. The DSC pattern was substantially as shown in Figure 10, which had an endothermic peak at about 109 °C. This form was a monohydrate. The TGA pattern was substantially as shown in Figure 11.

[0150] Table 10 XRPD characteristic diffraction peaks of deuterated dextromethorphan hydrobromide Form B

[0151] 3.5 Preparation of deuterated dextromethorphan benzoate Form A

[0152] Preparation Method: Same as the preparation of deuterated dextromethorphan benzoate in Example 1.4.

[0153] The XRPD pattern of the resulting product was substantially as shown in Figure 12, and the diffraction angle data was substantially as shown in Table 11. The DSC pattern was substantially as shown in Figure 13, which had an endothermic peak at 98 °C. The TGA pattern was substantially as shown in Figure 14.

[0154] Table 11 XRPD characteristic diffraction peaks of deuterated dextromethorphan benzoate Form B

[0155] 3.6 Crystalline form conversion study of deuterated dextromethorphan tartrate

[0156] About 50 mg of the mixed crystal sample of deuterated dextromethorphan tartrate (crystal form A and B) was added to 1 mL of ethanol, acetone and toluene, respectively, and the mixture was stirred at room temperature for 24 hours. The solid was separated by centrifugation and dried under vacuum at 40 °C. The dried sample was subjected to DSC characterization test, and the experimental results are shown in Table 12. The DSC spectrum is substantially as shown in Figure 15.

[0157] Table 12 Crystal form conversion experiment results of tartrate salt

[0158] The experimental results show that crystal form A of deuterated dextromethorphan tartrate is more stable than crystal form B.

[0159] 3.7 Characterization data of different salt forms

[0160] The characterization data of the deuterated dextromethorphan different salt form products are shown in Table 13.

[0161] Table 13 Characterization data of different salt forms

[0162] Example 4. Human liver microsomal metabolic stability study

[0163] 4.1 Experimental materials

[0164] Liver microsomes: human liver microsomes were purchased from BioIVT in vitro biological technology company in the United States;

[0165] Test compounds: dextromethorphan hydrobromide (purchased from Shanghai Maikelin Biochemical Technology Co., Ltd.); deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan citrate, deuterated dextromethorphan benzoate (prepared according to Example 1 of the present application);

[0166] LC-MS / MS instrument: high performance liquid chromatograph: LC-20ADXR (Shimadzu); API5000 (AB SCIEX).

[0167] 4.2 Experimental method

[0168] 1) Phosphate buffer (pH 7.4): a 100 mM potassium dihydrogen phosphate and 100 mM dihydrogen potassium phosphate solution was prepared, and then mixed according to the ratio of dihydrogen potassium phosphate solution: potassium dihydrogen phosphate solution = 40.5:9.5 to obtain the phosphate buffer.

[0169] 2) Magnesium chloride solution: a 3 mM magnesium chloride solution was prepared using the phosphate buffer.

[0170] 3) Compound working solution: the above test compound was prepared as a 10 mM stock solution, and then diluted with 80% acetonitrile-water to a 100 μM working solution for use.

[0171] 4) NADPH solution: Take a certain amount of NADPH, add an appropriate amount of 3 mM magnesium chloride solution to prepare a 2 mM NADPH solution, and wait for use.

[0172] 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 compound working solution obtained in step 3, and vortex evenly.

[0173] 6) From the liver microsome mixture in step 5, 165 μL / tube was dispensed in parallel in two parts

[0174] ① 0 min sample: Take 30 μL / tube of liver microsome mixture working solution as 0 min sample, and immediately add 300 μL of carbamazepine (internal standard IS) acetonitrile termination solution (20 ng / mL), then add 30 μL of NADPH solution, and mix evenly.

[0175] ② The remaining liver microsome mixture (135 μL / tube) in each group was added with 135 μL of NADPH solution to start the reaction, and after incubation at 37°C water bath for 5, 15, 30, and 60 min, 60 μL was taken out and added with 300 μL of termination solution.

[0176] 7) From the liver microsome mixture in step 5, 45 μL / tube was dispensed in parallel in two parts, and 45 μL of magnesium chloride solution was added, and after incubation at 37°C water bath for 60 min, 60 μL was taken out and added with 300 μL of termination solution as the negative control of each test compound.

[0177] 8) Vortex and centrifuge all samples in steps 6 and 7, take 150 μL of supernatant, add 150 μL of water, vortex and mix evenly, and analyze by LC-MS / MS.

[0178] 4.3 Data analysis

[0179] Convert the peak area ratio of the analyte / internal standard to the remaining percentage (remaining rate %), and the formula is as follows:

[0180] Remaining rate % = peak area ratio of analyte to IS at each time point / peak area ratio of analyte to IS at t = 0 × 100;

[0181] Based on the remaining rate at each time point, the slope is calculated, and the half-life (T 1 / 2 ) of dextromethorphan hydrobromide, deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan benzoate, and deuterated dextromethorphan citrate is calculated.

[0182] In vitro clearance (CL int) = 0.693 / T 1 / 2 *Vd (Vd = 1 / protein content in liver microsomes).

[0183] 4.4 Experimental results: as shown in Table 14 below.

[0184] Table 14 Metabolic stability test results of human liver microsomes

[0185] The results show that the half-lives of the tartrate, benzoate and citrate salts of deuterated dextromethorphan are superior to those of dextromethorphan hydrobromide; and the half-lives of the tartrate, benzoate and citrate salts of deuterated dextromethorphan are equivalent to that of deuterated dextromethorphan hydrobromide, and all belong to moderate clearance rates (0.01≤CL int ≤0.1 mL / min / mg) in the in vitro human liver microsome system, among which the half-life of the tartrate salt of deuterated dextromethorphan is relatively longer.

[0186] Example 5. Pharmacokinetic study

[0187] 5.1 Experimental materials:

[0188] 15 male ICR mice, weighing 25-30 g, were purchased from Hunan Slike Jingda Experimental Animal Co., Ltd.

[0189] Test compounds: dextromethorphan hydrobromide (purchased from Shanghai Maikelin 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 application).

[0190] 5.2 Experimental method:

[0191] 1) Drug preparation: a certain amount of drug was weighed and dissolved in physiological saline, vortexed, and ultrasonicated to prepare a solution with a concentration of 6.8 mg / mL (free base concentration);

[0192] 2) 15 male ICR mice were randomly divided into 5 groups, and each group was administered with the solution of the above five test compounds by gavage, with a dose of 5 mL / kg (34 mg / kg). At 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration, about 100 mL of whole blood was collected from the tail vein of each mouse into a labeled EDTA-2K anticoagulant tube, and the plasma was separated by centrifugation at 4°C and 6800 rpm for 6 minutes. The blood drug concentration of dextromethorphan or deuterated dextromethorphan was detected by LC-MS.

[0193] 3) Data statistics: the blood concentration of three animals at the same time point was averaged, and WinNonlin was used to calculate the pharmacokinetic parameters of dextromethorphan or deuterated dextromethorphan.

[0194] 5.3 Experimental results: as shown in Table 15 below.

[0195] Table 15 Pharmacokinetic study results

[0196] The results show that, at the same dose, the AUC 0-t and C max of dextromethorphan hydrobromide, deuterated dextromethorphan hydrobromide and deuterated dextromethorphan benzoate are equivalent; the AUC 0-t and C max of deuterated dextromethorphan tartrate and deuterated dextromethorphan citrate are higher, among which deuterated dextromethorphan tartrate is the best, with an AUC 0-t about 3 times that of dextromethorphan hydrobromide.

[0197] Example 6. Cough suppression experiment in mice

[0198] 6.1 Experimental materials

[0199] ICR mice 60 (half male and half female), weighing 20-25 g, purchased from Wuxi Hengtai Experimental Animal Breeding Co., Ltd.

[0200] Test compounds: dextromethorphan hydrobromide (purchased from Shanghai Maikelin Biochemical Technology Co., Ltd.); deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan citrate, deuterated dextromethorphan benzoate (prepared according to Example 1 of the present application).

[0201] 6.2 Experimental method:

[0202] 1) Drug preparation: the above five test compounds were dissolved in physiological saline respectively, and prepared into a solution with a concentration of 2 mg / mL (calculated as free base).

[0203] 2) Dose groups: the design groups are blank solvent group, dextromethorphan hydrobromide group, deuterated dextromethorphan hydrobromide group, deuterated dextromethorphan tartrate group, deuterated dextromethorphan benzoate group, deuterated dextromethorphan citrate group.

[0204] 3) 60 ICR mice (half male and half female) were randomly divided into 6 groups, 10 mice in each group, which were 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 given intragastrically once, wherein the blank solvent group was given normal saline, and the rest of the groups were given the corresponding test compounds, and the dose was 10 mL / kg (20 mg / kg, calculated as free base). 60 min after administration, the mice were placed in an inverted 1000 mL beaker filled with concentrated ammonia water saturated vapor, and the time was counted for 10 s, then the mice were taken out and placed in another inverted 1000 mL beaker, and the frequency of cough was observed, and the total number of coughs within 3 min was recorded.

[0205] 4) Statistical method: all experimental data were expressed as mean. Graphad Prism 8.0 software was used for statistical analysis. One-way ANOVA test was used for comparison between groups, LSD was used for comparison between groups with equal variance, Dunnett's T3 was used for comparison between groups with unequal variance, and P<0.05 indicated statistical significance.

[0206] 6.3 Experimental results: as shown in Table 16.

[0207] Table 16 Results of mouse antitussive experiment

[0208] Note: *P<0.05 vs blank solvent group

[0209] The results showed that 60 min after administration, the antitussive effect of deuterated dextromethorphan hydrobromide, deuterated dextromethorphan tartrate, deuterated dextromethorphan benzoate, and deuterated dextromethorphan citrate on mice was better than that of dextromethorphan hydrobromide, and the antitussive effect of deuterated dextromethorphan tartrate was the best.

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 of claim 1, wherein The molar ratio of the compound of formula (I) to the acid in the tartrate salt, citrate salt, hydrobromide monohydrate or benzoate salt is 1 :

1.

3. The salt of claim 1 or 2, wherein said salt is crystalline Form A of the compound of formula (II) having an XRPD pattern, in terms of 2 theta angle, with one or more peaks at 7.9 ± 0.2°, 13.8 ± 0.2°, 15.3 ± 0.2°, 18.9 ± 0.2°, 19.8 ± 0.2°; Preferably, the XRPD pattern expressed in terms of 2-theta angle has a characteristic peak at one or more of 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°, 28.3 ± 0.2°; Preferably, the XRPD pattern expressed in terms of 2-theta angle has a characteristic peak at one or more of 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°, 28.3 ± 0.2°; Preferably, the crystalline Form A has an XRPD pattern substantially as shown in Figure 1 ; Preferably, the DSC pattern of the crystalline Form A of the compound of formula (II) has an endothermic peak in the range of about 196 ± 3 °C; Preferably, the crystalline Form A of the compound of formula (II) has a DSC pattern substantially as shown in Figure 2; Preferably, the crystalline Form A of the compound of formula (II) has a TGA pattern substantially as shown in Figure 3.

4. The salt of claim 1 or 2, wherein said salt is crystalline Form B of the compound of formula (II) having an XRPD pattern, in terms of 2 theta angles, with one or more peaks at 5.3 ± 0.2°, 11.7 ± 0.2°, 15.6 ± 0.2°, 16.8 ± 0.2°, 20.9 ± 0.2°, Preferably, the XRPD pattern expressed in terms of 2-theta angle has a characteristic peak at one or more of 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°, 23.9 ± 0.2°; Preferably, the XRPD pattern expressed in terms of 2-theta angle has a characteristic peak at one or more of 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°, 26.3 ± 0.2°; Preferably, the crystalline Form B has an XRPD pattern substantially as shown in Figure 4; Preferably, the DSC pattern of the crystalline Form B of the compound of formula (II) has an endothermic peak in the range of about 189 ± 3 °C; Preferably, the crystalline Form B of the compound of formula (II) has a DSC pattern substantially as shown in Figure 5; Preferably, the crystalline Form B of the compound of formula (II) is anhydrous.

5. The salt of claim 1 or 2, wherein said salt is crystalline Form A of the compound of formula (III) having an XRPD pattern, in terms of 2 theta angles, with one or more peaks at 4.1 ±0.2°, 8.1 ±0.2°, 12.2 ±0.2°, 16.2 ±0.2°, 18.3 ±0.2°, Preferably, the XRPD pattern expressed in terms of 2-theta angle has a characteristic peak at one or more of 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°, 24.3 ± 0.2°; Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a TGA pattern substantially as shown in Figure 8.

6. The salt of claim 1 or 2, wherein said salt is crystalline Form A of the compound of formula (IV) having an XRPD pattern, in terms of 2 theta angle, with one or more peaks at 6.5 ± 0.2°, 18.9 ± 0.2°, 21.7 ± 0.2°, 23.2 ± 0.2°, 26.0 ± 0.2°, Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a TGA pattern substantially as shown in Figure 8. Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; 7. The salt of claim 1 or 2, wherein said salt is crystalline Form A of the compound of formula (V) having an XRPD pattern, in terms of 2 theta angles, with one or more peaks at 14.0 ± 0.2°, 17.4 ± 0.2°, 19.4 ± 0.2°, 19.7 ± 0.2°, 21.2 ± 0.2°, Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a TGA pattern substantially as shown in Figure 8. Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a TGA pattern substantially as shown in Figure 8. Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; Preferably, the crystalline form A of the compound of formula (III) has an XRPD pattern substantially as shown in Figure 6; Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a DSC pattern substantially as shown in Figure 7. Preferably, the crystalline form A of the compound of formula (III) has a TGA pattern substantially as shown in Figure 8. Preferably, the DSC pattern of the crystalline Form A of the compound of formula (V) has an endothermic peak in the range of about 98±3°C; Preferably, the crystalline Form A of the compound of formula (V) has a DSC pattern substantially as shown in Figure 13; Preferably, the crystalline Form A of the compound of formula (V) has a TGA pattern substantially as shown in Figure 14.

8. The method for preparing the salt according to any one of claims 1-7, comprising reacting the compound of formula (I) with an acid to obtain the salt. Preferably, the method for preparing the salt, comprises: dissolving the compound of formula (I) and the acid in an organic solvent A; then adding an organic solvent B to precipitate a solid to obtain the salt of the compound of formula (I); preferably, the organic solvent A is selected from one or more of alcohols or ketones; the alcohols are selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol; the ketones are selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone; the 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, isopropyl acetate. Preferably, the method for preparing the crystalline Form A of the compound of formula (II) comprises the following steps: dissolving the compound of formula (II) in an organic solvent I to precipitate a solid; the organic solvent I is selected from one or more of alcohols or nitriles; the alcohols are selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol; the nitriles are selected from acetonitrile. Preferably, the method for preparing the crystalline Form A of the compound of formula (II) comprises the following steps: dissolving the compound of formula (I) and L-tartaric acid in an organic solvent A; then adding an organic solvent B to precipitate a solid; preferably, the organic solvent A is selected from alcohols; the alcohols are selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, neopentyl alcohol; the 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, isopropyl acetate. Preferably, the method for preparing the crystalline Form B of the compound of formula (II) comprises the following steps: dissolving the compound of formula (II) in an organic solvent II to precipitate a solid; the organic solvent II is selected from one or more of ketones or tetrahydrofuran; the ketones are selected from one or more of acetone, butanone, pentanone, methyl ethyl ketone, 4-methyl-2-pentanone.

9. A pharmaceutical composition comprising the salt according to 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 a salt according to any one of claims 1-7 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament; preferably the medicament is for the treatment of an individual suffering from or susceptible to a disease or condition selected from the group consisting of: cough, pseudobulbar affect, depressive disorders, agitation in Alzheimer's disease, non-suicidal self-injury, post-traumatic stress disorder, schizophrenia, anxiety, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADDH), bipolar disorder, mania, pain, autism, Parkinson's combined 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's syndrome (RTT).

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