Crystal forms of xanomeline pamoate or deuterated xanomeline pamoate, preparation method therefor, and use thereof

Abstract

The present disclosure belongs to the technical field of medicinal chemistry, and relates to novel crystal forms of xanomeline pamoate or deuterated xanomeline pamoate, a preparation method therefor, and the use thereof in the field of medicine. The present disclosure particularly relates to two novel crystal forms B3 and E of xanomeline pamoate represented by formula I and a novel crystal form d-B3 of deuterated xanomeline pamoate represented by formula II. The crystal form B3 exhibits good physical and chemical stabilities, can maintain an effective concentration for long time in vivo while maintaining the crystal form unchanged, has obviously relieved medicinal toxicity and side effects and possesses good druggability. Applying the crystal forms of the present disclosure by various routes of administration (e.g. intramuscular injection, subcutaneous injection, oral administration, etc.) can all achieve an expected sustained-release effect. Furthermore, the crystal forms of the present disclosure involve a simple preparation process and have a small inter-batch difference and thus are suitable for industrial production.

Description

Pamoate salt crystal form of xanomeline or deuterated xanomeline and preparation method and use thereof

[0001] Reference of Related Applications

[0002] The present disclosure claims priority to the invention patent application filed in China on June 28, 2024, entitled “Pamoate salt crystal form of xanomeline or deuterated xanomeline and preparation method and use thereof”, application number 202410855946.X, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure belongs to the technical field of pharmaceutical chemistry, and relates to a new pamoate salt crystal form of xanomeline or deuterated xanomeline, a preparation method thereof, and a use thereof in the medical field. BACKGROUND

[0004] Muscarinic cholinergic receptors (referred to as muscarinic receptors) are G protein-coupled receptors with five different receptor subtypes (M1-M5), which are widely expressed in the brain and peripheral tissues and play many key physiological roles in cognitive, behavioral, sensory, motor, and autonomic nervous processes. Activation of the muscarinic system through muscarinic receptor agonists can treat a variety of diseases or symptoms, such as schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegeneration.

[0005] Xanomeline (also known as Xanomeline) is a selective muscarinic type 1 and type 4 (M1 / M4) receptor agonist, developed by Novo Nordisk and Eli Lilly in the 1990s for the treatment of schizophrenia and Alzheimer's disease. Its chemical name is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine, and the chemical structure is shown below. Due to the side effects observed in clinical trials, Eli Lily stopped the research and development of xanomeline.

[0006] Developing xanomeline and its salts and crystal forms with better pharmacokinetic parameters, smaller toxic side effects, and better efficacy and the corresponding administration routes has great significance and value in clinical applications. SUMMARY

[0007] Problems to be solved

[0008] Although oral xanomeline tartrate was found to improve memory impairment and cognitive impairment in clinical trials, xanomeline can bind to peripheral muscarinic receptors, causing many serious peripheral side effects (including gastrointestinal side effects, cardiac side effects, and salivation), resulting in a high discontinuation rate of xanomeline in clinical studies, with a discontinuation rate of 56% in a 26-week Alzheimer's disease study (Bodick N.C., et al., The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease [J], Alzheimer Dis. Assoc. Disord., 1997, 11 Suppl. 4: S16-22).

[0009] Karuna Therapeutics developed KarXT drug (a combination of oral xanomeline tartrate and trospium), which uses the antagonistic effect of trospium on peripheral muscarinic receptors to offset or weaken the agonistic effect of xanomeline on peripheral muscarinic receptors, thereby reducing adverse reactions. However, KarXT also faces a challenge of extremely low oral bioavailability. In oral administration, well-absorbed xanomeline tartrate has a bioavailability of only about 1% due to severe first-pass effect, resulting in large individual differences in patient blood drug concentrations (Bymaster F.P., et al., Xanomeline: A selective muscarinic agonist for the treatment of Alzheimer's disease [J], Drug Development Research, 1997, 40(2): 158-170). And for patients with schizophrenia, daily oral administration of KarXT also brings certain inconvenience to patients.

[0010] US Pat. No. 5,980,933 discloses a transdermal preparation of xanomeline. Although the transdermal preparation can solve the gastrointestinal side effects caused by oral xanomeline tartrate, the severe skin irritation still hinders the development of the xanomeline transdermal preparation (Guan Y., Statistical analysis on adverse events of clinical trials [D], Master Thesis, University of Delaware, 2019).

[0011] The problem to be solved by the present disclosure is to provide zanomeline and its salt forms and crystal forms and the corresponding administration routes thereof with better pharmacokinetic characteristics, smaller side effects and better efficacy.

[0012] Although the salt forms and administration routes of common drugs can be designed in theory, it is difficult to accurately predict the behavior of drug salt forms in vivo and the risk of other toxic side reactions in practice. At the same time, the salt forms often have large differences in physicochemical properties between different crystal forms, and the results of in vivo pharmacokinetic parameters and safety are also unable to be obtained by theoretical calculation, and ultimately still need to be generated by experiments (for example, see He Rui, Yang Jinbo, Shallow discussion on possible problems in consistency evaluation of different salt drugs of the same API [J], China Food and Drug Supervision, 2019, 1: 50-55 or Wu, T., et al. Burger's Medicinal Chemistry and Drug Discovery (8th ed.) [M], WILEY, 2021, Vol. 3, Chapt. 6 Salt Screening and Selection: 1-31).

[0013] Solution for solving the problem

[0014] The present disclosure conducts crystal form research on the pamoate salt of zanomeline or its deuterated product, and unexpectedly obtains a new crystal form of the pamoate salt of zanomeline or its deuterated product, which has good thermodynamic stability, can be prepared into suitable pharmaceutical preparations, achieves long-term drug sustained release, reduces toxic side effects, and improves drug administration compliance.

[0015] In a first aspect, the present disclosure provides a zanomeline pamoate salt as shown in formula I,

[0016] The zanomeline pamoate salt has a crystal form B3, and the X-ray powder diffraction (XRPD) pattern of the crystal form B3 has characteristic diffraction peaks at the following 2θ angles: 14.06±0.2°, 17.48±0.2°, 20.86±0.2° and 22.42±0.2°.

[0017] In some embodiments of the disclosure, the XRPD pattern of the Form B3 further comprises at least one (e.g., any one, two, three, four, five, six, or seven, or all eight) of the following characteristic diffraction peaks: 7.80 ± 0.2°, 7.96 ± 0.2°, 10.38 ± 0.2°, 12.88 ± 0.2°, 13.74 ± 0.2°, 14.06 ± 0.2°, 17.48 ± 0.2°, 17.78 ± 0.2°, 20.56 ± 0.2°, 20.86 ± 0.2°, 21.04 ± 0.2°, 22.42 ± 0.2°, 23.32 ± 0.2°, 23.64 ± 0.2°, 24.12 ± 0.2°, 26.36 ± 0.2°, 28.56 ± 0.2°, 28.96 ± 0.2°, and 29.98 ± 0.2°.

[0018] In some embodiments of the disclosure, the XRPD pattern of the Form B3 further comprises at least one (e.g., any one, two, three, four, five, six, or seven, or all eight) of the following characteristic diffraction peaks: 7.80 ± 0.2°, 7.96 ± 0.2°, 10.38 ± 0.2°, 12.88 ± 0.2°, 13.74 ± 0.2°, 14.06 ± 0.2°, 17.48 ± 0.2°, 17.78 ± 0.2°, 20.56 ± 0.2°, 20.86 ± 0.2°, 21.04 ± 0.2°, 22.42 ± 0.2°, 23.32 ± 0.2°, 23.64 ± 0.2°, 24.12 ± 0.2°, 26.36 ± 0.2°, 28.56 ± 0.2°, 28.96 ± 0.2°, and 29.98 ± 0.2°.

[0019] In some embodiments of the disclosure, the XRPD pattern of the Form B3 further comprises at least one (e.g., any one, two, three, four, or five, or all of the following) characteristic diffraction peaks at the following 2Θ angles: 8.70 ± 0.2°, 15.62 ± 0.2°, 16.10 ± 0.2°, 24.84 ± 0.2°, and 27.34 ± 0.2°; for example, the XRPD pattern of the Form B3 can comprise characteristic diffraction peaks at the following 2Θ angles: 7.80 ± 0.2°, 7.96 ± 0.2°, 8.70 ± 0.2°, 10.38 ± 0.2°, 12.88 ± 0.2°, 13.74 ± 0.2°, 14.06 ± 0.2°, 15.62 ± 0.2°, 16.10 ± 0.2°, 17.48 ± 0.2°, 17.78 ± 0.2°, 20.56 ± 0.2°, 20.86 ± 0.2°, 21.04 ± 0.2°, 22.42 ± 0.2°, 23.32 ± 0.2°, 23.64 ± 0.2°, 24.12 ± 0.2°, 24.84 ± 0.2°, 26.36 ± 0.2°, 27.34 ± 0.2°, 28.56 ± 0.2°, 28.96 ± 0.2°, and 29.98 ± 0.2°.

[0020] In some embodiments of the disclosure, the XRPD pattern of the Form B3 further comprises at least one (e.g., any one, two, three, four, or five, or all of the following) characteristic diffraction peaks at the following 2Θ angles: 8.70 ± 0.2°, 15.62 ± 0.2°, 16.10 ± 0.2°, 24.84 ± 0.2°, and 27.34 ± 0.2°; for example, the XRPD pattern of the Form B3 can comprise characteristic diffraction peaks at the following 2Θ angles: 7.80 ± 0.2°, 7.96 ± 0.2°, 8.70 ± 0.2°, 10.38 ± 0.2°, 12.88 ± 0.2°, 13.74 ± 0.2°, 14.06 ± 0.2°, 15.62 ± 0.2°, 16.10 ± 0.2°, 17.48 ± 0.2°, 17.78 ± 0.2°, 20.56 ± 0.2°, 20.86 ± 0.2°, 21.04 ± 0.2°, 22.42 ± 0.2°, 23.32 ± 0.2°, 23.64 ± 0.2°, 24.12 ± 0.2°, 24.84 ± 0.2°, 26.36 ± 0.2°, 27.34 ± 0.2°, 28.56 ± 0.2°, 28.96 ± 0.2°, and 29.98 ± 0.2°.

[0021] In some embodiments of this disclosure, the error value of the 2θ angle corresponding to the characteristic diffraction peak in the XRPD pattern of crystal form B3 can be ±0.1°.

[0022] In some embodiments of this disclosure, the XRPD pattern of the crystal form B3 is basically as shown in Figure 1.

[0023] In some embodiments of this disclosure, the differential scanning calorimetry (DSC) spectrum of the crystal form B3 has an endothermic peak at 211.0 ± 10 °C.

[0024] In some embodiments of this disclosure, the differential scanning calorimetry (DSC) spectrum of the crystal form B3 has an endothermic peak at 211.0 ± 5 °C.

[0025] In some embodiments of this disclosure, the differential scanning calorimetry (DSC) spectrum of the crystal form B3 has an endothermic peak at 211.0 ± 2 °C.

[0026] In some embodiments of this disclosure, the differential scanning calorimetry (DSC) spectrum of the crystal form B3 has an endothermic peak at 211.0 ± 1 °C.

[0027] In some embodiments of this disclosure, the DSC spectrum of the crystal form B3 is basically as shown in Figure 2.

[0028] In some embodiments of this disclosure, the thermogravimetric analysis (TGA) spectrum of the B3 crystal form is basically as shown in Figure 3.

[0029] In some embodiments of this disclosure, the Raman spectrum of crystal form B3 has a characteristic peak at the following shift: 1685 ± 0.5 cm⁻¹ -1 1652±0.5cm -1 1577±0.5cm -1 1448±0.5cm -1 1400±0.5cm -1 1371±0.5cm -1 1355±0.5cm -1 1310±0.5cm -1 1270±0.5cm -1 1027±0.5cm -1 858±0.5cm -1 790±0.5cm -1 736±0.5cm -1 688±0.5cm -1 646±0.5cm -1 550±0.5cm -1 457±0.5cm -1, 436 ± 0.5 cm -1 , 425 ± 0.5 cm -1 , 336 ± 0.5 cm -1 , 240 ± 0.5 cm -1 , 166 ± 0.5 cm -1 , 146 ± 0.5 cm -1 and 100 ± 0.5 cm -1 .

[0030] In some embodiments of the present disclosure, the Raman spectrum of the Form B3 is substantially as shown in Figure 4.

[0031] In a second aspect, the present disclosure provides a xanomeline pamoate salt of Formula I, which has a crystalline Form E having an XRPD pattern with characteristic diffraction peaks at the following 2Θ angles: 7.94 ± 0.2°, 10.34 ± 0.2°, 25.48 ± 0.2° and 26.44 ± 0.2°.

[0032] In some embodiments of the present disclosure, the XRPD pattern of the Form E further has characteristic diffraction peaks at at least one (e.g., any one or two or all three) of the following 2Θ angles: 6.28 ± 0.2°, 8.70 ± 0.2° and 22.40 ± 0.2°; for example, the XRPD pattern of the Form E can have characteristic diffraction peaks at the following 2Θ angles: 6.28 ± 0.2°, 7.94 ± 0.2°, 8.70 ± 0.2°, 10.34 ± 0.2°, 22.40 ± 0.2°, 25.48 ± 0.2° and 26.44 ± 0.2°.

[0033] In some embodiments of the present disclosure, the XRPD pattern of the Form E further has characteristic diffraction peaks at at least one (e.g., any one, two or three or all four) of the following 2Θ angles: 11.44 ± 0.2°, 12.96 ± 0.2°, 15.92 ± 0.2° and 16.68 ± 0.2°; for example, the XRPD pattern of the Form E can have characteristic diffraction peaks at the following 2Θ angles: 6.28 ± 0.2°, 7.94 ± 0.2°, 8.70 ± 0.2°, 10.34 ± 0.2°, 11.44 ± 0.2°, 12.96 ± 0.2°, 15.92 ± 0.2°, 16.68 ± 0.2°, 22.40 ± 0.2°, 25.48 ± 0.2° and 26.44 ± 0.2°.

[0034] In some embodiments of the present disclosure, the XRPD pattern of the crystalline Form E further has at least one (e.g., any one, two, three, or four out of) characteristic diffraction peaks at 2-theta values of 14.54±0.2°, 18.92±0.2°, 20.38±0.2°, 20.78±0.2°, and 21.78±0.2°; for example, the XRPD pattern of the crystalline Form E can have characteristic diffraction peaks at 2-theta values of 6.28±0.2°, 7.94±0.2°, 8.70±0.2°, 10.34±0.2°, 11.44±0.2°, 12.96±0.2°, 14.54±0.2°, 15.92±0.2°, 16.68±0.2°, 18.92±0.2°, 20.38±0.2°, 20.78±0.2°, 21.78±0.2°, 22.40±0.2°, 25.48±0.2°, and 26.44±0.2°.

[0035] In some embodiments of the present disclosure, the XRPD pattern of the crystalline Form E further has at least one (e.g., any one, two, three, or four out of) characteristic diffraction peaks at 2-theta values of 14.54±0.2°, 18.92±0.2°, 20.38±0.2°, 20.78±0.2°, and 21.78±0.2°; for example, the XRPD pattern of the crystalline Form E can have characteristic diffraction peaks at 2-theta values of 6.28±0.2°, 7.94±0.2°, 8.70±0.2°, 10.34±0.2°, 11.44±0.2°, 12.96±0.2°, 14.54±0.2°, 15.46±0.2°, 15.92±0.2°, 16.68±0.2°, 17.38±0.2°, 18.92±0.2°, 20.04±0.2°, 20.38±0.2°, 20.78±0.2°, 21.20±0.2°, 21.78±0.2°, 22.40±0.2°, 25.48±0.2°, and 26.44±0.2°.

[0036] In some embodiments of the present disclosure, the XRPD pattern of the crystalline Form E further has at least one (e.g., any one, two, three, or four out of) characteristic diffraction peaks at 2-theta values of 14.54±0.2°, 18.92±0.2°, 20.38±0.2°, 20.78±0.2°, and 21.78±0.2°; for example, the XRPD pattern of the crystalline Form E can have characteristic diffraction peaks at 2-theta values of 6.28±0.2°, 7.94±0.2°, 8.70±0.2°, 10.34±0.2°, 11.44±0.2°, 12.96±0.2°, 14.54±0.2°, 15.46±0.2°, 15.92±0.2°, 16.68±0.2°, 17.38±0.2°, 18.92±0.2°, 20.04±0.2°, 20.38±0.2°, 20.78±0.2°, 21.20±0.2°, 21.78±0.2°, 22.40±0.2°, 25.48±0.2°, and 26.44±0.2°.

[0037] In some embodiments of the present disclosure, the XRPD pattern of the crystalline Form E is substantially as shown in Figure 5.

[0038] In some embodiments of the present disclosure, the DSC pattern of the crystalline Form E has an endothermic peak at 149.1±10 °C.

[0039] In some embodiments of the present disclosure, the DSC pattern of the crystalline Form E has an endothermic peak at 149.1±5 °C.

[0040] In some embodiments of the present disclosure, the DSC pattern of the crystalline Form E has an endothermic peak at 149.1±2 °C.

[0041] In some embodiments of the present disclosure, the DSC pattern of the crystalline Form E has an endothermic peak at 149.1±1 °C.

[0042] In some embodiments of the present disclosure, the DSC pattern of the crystalline Form E is substantially as shown in Figure 6.

[0043] In some embodiments of the present disclosure, the TGA pattern of the crystalline Form E is substantially as shown in Figure 7.

[0044] In a third aspect, the present disclosure provides a method for preparing the ranolazine palmitate of Formula I having crystalline Form B3, comprising the following steps:

[0045] 1) preparation of crude ranolazine palmitate; and

[0046] 2) recrystallization of the crude ranolazine palmitate.

[0047] In some embodiments of the present disclosure, the preparation of the crude ranolazine palmitate in step 1) comprises the following steps:

[0048] 1-1) dissolving a water-soluble salt of ranolazine in a solvent A to obtain a solution of the water-soluble salt of ranolazine;

[0049] 1-2) dissolving a palmitate salt in a solvent B to obtain a solution of the palmitate salt; and

[0050] 1-3) mixing the solution of the water-soluble salt of ranolazine with the solution of the palmitate salt, and optionally stirring to precipitate a solid.

[0051] In some embodiments of the present disclosure, the water-soluble salt of ranolazine in step 1-1) and / or the palmitate salt in step 1-2) can each independently exist in the form of a solvate; if in the form of a solvate, it is preferably in the form of a hydrate (e.g. monohydrate).

[0052] In some embodiments of the present disclosure, the molar ratio of the water-soluble salt of ranolazine in step 1-1) to the palmitate salt in step 1-2) can be 1:0.9-1:1.3, for example 1:0.9, 1:1.0, 1:1.1, 1:1.2 or 1:1.3 or a range value determined by any two point values thereof, preferably 1:1.

[0053] In some embodiments of the present disclosure, in step 1-1), the water-soluble salt of ranolazine can be a salt obtained by reacting ranolazine with a pharmaceutically acceptable water-soluble acid.

[0054] In some embodiments of the present disclosure, the pharmaceutically acceptable water-soluble acid can be hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, nitric acid, tartaric acid, oxalic acid, citric acid, maleic acid, lactic acid, malic acid, fumaric acid, gluconic acid, glutamic acid, ethanesulfonic acid, isethionic acid, mandelic acid, methanesulfonic acid, mucic acid, pantothenic acid, saccharinic acid, or succinic acid.

[0055] In some embodiments of the present disclosure, the pharmaceutically acceptable water-soluble acid can be hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, nitric acid, oxalic acid, citric acid, maleic acid, lactic acid, malic acid, fumaric acid, gluconic acid, glutamic acid, ethanesulfonic acid, isethionic acid, mandelic acid, methanesulfonic acid, mucic acid, pantothenic acid, saccharinic acid, or succinic acid.

[0056] In some embodiments of the present disclosure, the pharmaceutically acceptable water-soluble acid can be hydrochloric acid, i.e., the water-soluble salt of zanomeline can be zanomeline hydrochloride.

[0057] In some embodiments of the present disclosure, the pharmaceutically acceptable water-soluble acid can be tartaric acid (e.g., L-tartaric acid), i.e., the water-soluble salt of zanomeline can be zanomeline tartrate (e.g., L-tartrate).

[0058] In some embodiments of the present disclosure, in step 1-1), the solvent A can be one or more than two combinations of methanol, isopropanol, N,N-dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane, and water, preferably one or more than two combinations of methanol, tetrahydrofuran, and water, more preferably methanol, water, or a combination thereof.

[0059] In some embodiments of the present disclosure, in step 1-1), the ratio of the amount of the water-soluble salt of zanomeline to the solvent A can be 1 g:10-20 ml, such as 1 g:10 ml, 1 g:11 ml, 1 g:12 ml, 1 g:13 ml, 1 g:14 ml, 1 g:15 ml, 1 g:16 ml, 1 g:17 ml, 1 g:18 ml, 1 g:19 ml, or 1 g:20 ml, or a range value determined by any two point values thereof, preferably 1 g:12-18 ml.

[0060] In some embodiments of the present disclosure, in step 1-2), the pamoate salt can be a salt obtained by reacting pamoic acid with a pharmaceutically acceptable water-soluble base.

[0061] In some embodiments of the present disclosure, the pharmaceutically acceptable water-soluble base can be sodium hydroxide, potassium hydroxide, lithium hydroxide, or ammonia, preferably sodium hydroxide.

[0062] In some embodiments of the present disclosure, in step 1-2), the pamoate salt can be a disodium pamoate salt, a dipotassium pamoate salt, a dilithium pamoate salt, or a diammonium pamoate salt, preferably a disodium pamoate salt.

[0063] In some embodiments of the present disclosure, in step 1-2), the pamoate salt can be in the form of a solvate; if in the form of a solvate, it is preferably in the form of a hydrate (e.g., monohydrate).

[0064] In some embodiments of the present disclosure, in step 1-2), the solvent B can be one or a combination of two or more of methanol, isopropanol, tetrahydrofuran, and water, preferably water.

[0065] In some embodiments of the present disclosure, in step 1-2), the ratio of the amount of the pamoate salt to the solvent B can be 1 g: 20-70 ml, such as 1 g: 20 ml, 1 g: 25 ml, 1 g: 30 ml, 1 g: 35 ml, 1 g: 40 ml, 1 g: 45 ml, 1 g: 50 ml, 1 g: 55 ml, 1 g: 60 ml, 1 g: 65 ml, or 1 g: 70 ml, or a range value determined by any two point values therefrom, preferably 1 g: 40-60 ml.

[0066] In some embodiments of the present disclosure, in step 1-3), the mixing time can be 6-24 hours, such as 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours, or a range value determined by any two point values therefrom, preferably 12-24 hours.

[0067] In some embodiments of the present disclosure, in step 1-3), the mixing temperature can be room temperature; preferably, the room temperature can be 20-25 °C.

[0068] In some embodiments of the present disclosure, the preparation of the crude zanomeline pamoate salt in step 1) further comprises the following steps:

[0069] 1-4) filtering, optionally washing, and drying the solid.

[0070] In some embodiments of the present disclosure, the recrystallization of the crude zanomeline pamoate salt in step 2) comprises the following steps:

[0071] 2-1) suspending the crude zanomeline pamoate salt in a solvent C, optionally stirring, and precipitating crystals.

[0072] In some embodiments of the present disclosure, in step 2-1), the solvent C can be one or a combination of two or more of methanol, acetone, ethyl acetate, acetonitrile, dichloromethane, trichloromethane, tetrahydrofuran, methyl tert-butyl ether, or water.

[0073] In some embodiments of the present disclosure, in step 2-1), the solvent C can be a mixture of tetrahydrofuran and ethyl acetate, wherein the volume ratio of tetrahydrofuran to ethyl acetate is 1:1-3:1, for example 1.0:1, 1.5:1, 2.0:1, 2.5:1 or 3.0:1 or a range value defined by any two point values among them, preferably 3:1.

[0074] In some embodiments of the present disclosure, in step 2-1), the solvent C can be tetrahydrofuran.

[0075] In some embodiments of the present disclosure, in step 2-1), the solvent C can be a mixture of acetonitrile and dichloromethane, wherein the volume ratio of acetonitrile to dichloromethane is 1:1-3:1, for example 1.0:1, 1.5:1, 2.0:1, 2.5:1 or 3.0:1 or a range value defined by any two point values among them, preferably 1:1.

[0076] In some embodiments of the present disclosure, in step 2-1), the solvent C can be a mixture of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 1:1-3:1, for example 1.0:1, 1.5:1, 2.0:1, 2.5:1 or 3.0:1 or a range value defined by any two point values among them, preferably 1:1.

[0077] In some embodiments of the present disclosure, in step 2-1), the solvent C can be methanol.

[0078] In some embodiments of the present disclosure, in step 2-1), the solvent C can be acetone.

[0079] In some embodiments of the present disclosure, in step 2-1), the solvent C can be a mixture of acetone and water, wherein the volume ratio of acetone to water is 5:1-1:2, for example 5.0:1, 4.0:1, 3.0:1, 2.0:1, 1.0:1 or 1.0:2, preferably 1:1.

[0080] In some embodiments of the present disclosure, in step 2-1), the solvent C can be a mixture of acetone and diethyl ether, wherein the volume ratio of acetone to water is 5:1-1:2, for example 5.0:1, 4.0:1, 3.0:1, 2.0:1, 1.0:1 or 1.0:2, preferably 1:1.

[0081] In some embodiments of the present disclosure, in step 2-1), the solvent C can be ethyl acetate.

[0082] In some embodiments of the present disclosure, in step 2-1), the solvent C can be a mixture of acetone and ethyl acetate, wherein the volume ratio of acetone to ethyl acetate is 5:1-1:5, for example, 5.0:1, 4.0:1, 3.0:1, 2.0:1, 1.0:1, 1.0:2, 1.0:3, 1.0:4 or 1.0:5, preferably 3:1-1:3, for example, 3.0:1, 2.5:1, 2.0:1, 1.0:1, 1.0:2, 1.0:2.5 or 1.0:3, more preferably 3:1.

[0083] In some embodiments of the present disclosure, in step 2-1), the ratio of the amount of use of the crude pamoate salt of xanomeline to the solvent C can be 1 g:5-20 ml, for example, 1 g:5 ml, 1 g:6 ml, 1 g:8 ml, 1 g:9 ml, 1 g:10 ml, 1 g:12 ml, 1 g:14 ml, 1 g:16 ml, 1 g:18 ml or 1 g:20 ml or a range value determined by any two point values, preferably 1 g:10 mL.

[0084] In some embodiments of the present disclosure, in step 2-1), the suspension time can be 6-72 hours, for example, 6, 8, 12, 16, 17, 18, 24, 30, 32, 36, 40, 42, 48, 54, 56, 64 or 72 hours or a range value determined by any two point values, preferably 8-48 hours.

[0085] In some embodiments of the present disclosure, in step 2-1), the suspension temperature can be 10-60℃, for example, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60℃ or a range value determined by any two point values, preferably 20-60℃, for example, room temperature (20-25℃).

[0086] In some embodiments of the present disclosure, in step 2-1), when the suspension temperature is 40-60℃ (for example, 50℃), the suspension and the precipitated crystals can further comprise a cooling step.

[0087] In some embodiments of the present disclosure, the target temperature of the cooling can be 0-30℃, for example, 0, 2, 5, 8, 10, 12, 15, 18, 20, 22, 25, 28 or 30℃ or a range value determined by any two point values (for example, 0-25℃), preferably 10-25℃, for example, room temperature (20-25℃).

[0088] In some embodiments of the present disclosure, the cooling can be carried out under stirring. When the target temperature is reached, the stirring can be stopped.

[0089] In some embodiments of the present disclosure, the recrystallization of the crude zanomeline pamoate salt in step 2) further comprises the following steps:

[0090] 2-2) filtering, optionally washing, and drying the crystals.

[0091] In the fourth aspect, the present disclosure provides a preparation method of zanomeline pamoate salt of formula I with crystal form E, comprising the following steps:

[0092] 1') preparation of crude zanomeline pamoate salt; and

[0093] 2') recrystallization of the crude zanomeline pamoate salt.

[0094] In some embodiments of the present disclosure, step 1') is the same as step 1) in the preparation method of zanomeline pamoate salt of formula I with crystal form B3 described above.

[0095] In some embodiments of the present disclosure, the recrystallization of the crude zanomeline pamoate salt in step 2') comprises the following steps:

[0096] 2'-1) suspending the crude zanomeline pamoate salt in solvent D, optionally stirring, and precipitating crystals.

[0097] In some embodiments of the present disclosure, in step 2'-1), the solvent D can be one or a combination of two or more of methanol, acetone, ethyl acetate, acetonitrile, dichloromethane, trichloromethane, tetrahydrofuran, methyl tert-butyl ether, or water.

[0098] In some embodiments of the present disclosure, in step 2'-1), the solvent D can be acetonitrile, dichloromethane, or a combination thereof, preferably a combination of acetonitrile and dichloromethane.

[0099] In some embodiments of the present disclosure, in step 2'-1), the solvent D can be a mixture of acetonitrile and dichloromethane, wherein the volume ratio of acetonitrile to dichloromethane is 1:1-3:1, for example 1.0:1, 1.5:1, 2.0:1, 2.5:1, or 3.0:1 or a range value determined by any two point values, preferably 2:1.

[0100] In some embodiments of the present disclosure, in step 2'-1), the ratio of the amount of the crude zanomeline pamoate salt to the solvent D can be 1g:5-20mL, for example 1g:5ml, 1g:6ml, 1g:8ml, 1g:9ml, 1g:10ml, 1g:12ml, 1g:14ml, 1g:16ml, 1g:18ml, or 1g:20ml or a range value determined by any two point values, preferably 1g:10mL.

[0101] In some embodiments of the present disclosure, in step 2'-1), the time for the suspension can be 1-48 hours, such as 1, 2, 4, 5, 6, 8, 10, 12, 15, 16, 18, 20, 24, 30, 32, 36, 40, or 48 hours or a range determined by any two of the point values, preferably 6-24 hours.

[0102] In some embodiments of the present disclosure, in step 2'-1), the temperature for the suspension can be 10-70°C, such as 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, or 70°C or a range determined by any two of the point values, preferably 20-60°C, such as 40-60°C or room temperature (20-25°C).

[0103] In some embodiments of the present disclosure, in step 2'-1), when the temperature for the suspension is 40-60°C (such as 50°C), the suspension and the precipitated crystals can further comprise a cooling step.

[0104] In some embodiments of the present disclosure, the target temperature for the cooling can be 0-30°C, such as 0, 2, 5, 8, 10, 12, 15, 18, 20, 22, 25, 28, or 30°C or a range determined by any two of the point values (such as 0-20°C), preferably 10-25°C, such as room temperature (20-25°C).

[0105] In some embodiments of the present disclosure, the cooling can be performed under stirring. The stirring can be stopped when the target temperature is reached.

[0106] In some embodiments of the present disclosure, the recrystallization of the crude canabimitrilat palmitate in step 2') further comprises the following steps:

[0107] 2'-2) filtering, optionally washing, and drying the crystals.

[0108] In a fifth aspect, the present disclosure provides a deuterated canabimitrilat palmitate as shown in Formula II,

[0109] The deuterated canabimitrilat palmitate has a crystal form d-B3, which has an XRPD pattern with characteristic diffraction peaks at 2θ angles of 14.06±0.2°, 17.48±0.2°, 20.86±0.2°, and 22.42±0.2°.

[0110] In some embodiments of the disclosure, the XRPD pattern of the crystalline Form d-B3 further comprises at least one (e.g., any one, two, three, four, five, six, or seven, or all eight) of the following characteristic diffraction peaks: 7.80 ± 0.2°, 7.96 ± 0.2°, 10.38 ± 0.2°, 12.88 ± 0.2°, 13.74 ± 0.2°, 14.06 ± 0.2°, 17.48 ± 0.2°, 17.78 ± 0.2°, 20.56 ± 0.2°, 20.86 ± 0.2°, 21.04 ± 0.2°, 22.42 ± 0.2°, 23.32 ± 0.2°, 23.64 ± 0.2°, 24.12 ± 0.2°, 26.36 ± 0.2°, 28.56 ± 0.2°, 28.96 ± 0.2°, and 29.98 ± 0.2°.

[0111] In some embodiments of the disclosure, the XRPD pattern of the crystalline Form d-B3 further comprises at least one (e.g., any one, two, three, four, five, six, or seven, or all eight) of the following characteristic diffraction peaks: 7.80 ± 0.2°, 7.96 ± 0.2°, 10.38 ± 0.2°, 12.88 ± 0.2°, 13.74 ± 0.2°, 14.06 ± 0.2°, 17.48 ± 0.2°, 17.78 ± 0.2°, 20.56 ± 0.2°, 20.86 ± 0.2°, 21.04 ± 0.2°, 22.42 ± 0.2°, 23.32 ± 0.2°, 23.64 ± 0.2°, 24.12 ± 0.2°, 26.36 ± 0.2°, 28.56 ± 0.2°, 28.96 ± 0.2°, and 29.98 ± 0.2°.

[0112] In some embodiments of the disclosure, the XRPD pattern of the crystalline Form d-B3 further comprises at least one (e.g., any one, two, three, four, or five, or all six) of the following characteristic diffraction peaks, in terms of 2Θ angle: 11.00±0.2°, 17.06±0.2°, 18.88±0.2°, 22.02±0.2°, 25.30±0.2°, and 26.00±0.2°; for example, the XRPD pattern of the crystalline Form d-B3 can comprise the characteristic diffraction peaks, in terms of 2Θ angle, at 7.80±0.2°, 7.96±0.2°, 8.70±0.2°, 10.38±0.2°, 11.00±0.2°, 12.88±0.2°, 13.74±0.2°, 14.06±0.2°, 15.62±0.2°, 16.10±0.2°, 17.06±0.2°, 17.48±0.2°, 17.78±0.2°, 18.88±0.2°, 20.56±0.2°, 20.86±0.2°, 21.04±0.2°, 22.02±0.2°, 22.42±0.2°, 23.32±0.2°, 23.64±0.2°, 24.12±0.2°, 24.84±0.2°, 25.30±0.2°, 26.00±0.2°, 26.36±0.2°, 27.34±0.2°, 28.56±0.2°, 28.96±0.2°, and 29.98±0.2°.

[0113] In some embodiments of the disclosure, the XRPD pattern of the crystalline Form d-B3 further comprises at least one (e.g., any one, two, three, four, or five, or all six) of the following characteristic diffraction peaks, in terms of 2Θ angle: 11.00±0.2°, 17.06±0.2°, 18.88±0.2°, 22.02±0.2°, 25.30±0.2°, and 26.00±0.2°; for example, the XRPD pattern of the crystalline Form d-B3 can comprise the characteristic diffraction peaks, in terms of 2Θ angle, at 7.80±0.2°, 7.96±0.2°, 8.70±0.2°, 10.38±0.2°, 11.00±0.2°, 12.88±0.2°, 13.74±0.2°, 14.06±0.2°, 15.62±0.2°, 16.10±0.2°, 17.06±0.2°, 17.48±0.2°, 17.78±0.2°, 18.88±0.2°, 20.56±0.2°, 20.86±0.2°, 21.04±0.2°, 22.02±0.2°, 22.42±0.2°, 23.32±0.2°, 23.64±0.2°, 24.12±0.2°, 24.84±0.2°, 25.30±0.2°, 26.00±0.2°, 26.36±0.2°, 27.34±0.2°, 28.56±0.2°, 28.96±0.2°, and 29.98±0.2°.

[0114] In some embodiments of this disclosure, the error value of the 2θ angle corresponding to the characteristic diffraction peak in the XRPD pattern of the crystal form d-B3 can be ±0.1°.

[0115] In some embodiments of this disclosure, the XRPD pattern of the crystal form d-B3 is basically as shown in Figure 8.

[0116] In some embodiments of this disclosure, the DSC spectrum of the crystal form d-B3 has an endothermic peak at 206.6 ± 10 °C.

[0117] In some embodiments of this disclosure, the DSC spectrum of the crystal form d-B3 has an endothermic peak at 206.6±5℃.

[0118] In some embodiments of this disclosure, the DSC spectrum of the crystal form d-B3 has an endothermic peak at 206.6±2℃.

[0119] In some embodiments of this disclosure, the DSC spectrum of the crystal form d-B3 has an endothermic peak at 206.6±1℃.

[0120] In some embodiments of this disclosure, the DSC spectrum of the crystal form d-B3 is basically as shown in Figure 9.

[0121] In some embodiments of this disclosure, the TGA spectrum of the crystal form d-B3 is basically as shown in Figure 10.

[0122] Sixthly, this disclosure provides a method for preparing deuterated d-B3 pamoate of Formula II, comprising the following steps:

[0123] 1”) Preparation of crude deuterated pamoate; and

[0124] 2”) recrystallization of the crude deuterated pamoate.

[0125] In some embodiments of this disclosure, except that a deuterated zanomeline water-soluble salt is used instead of a zanomeline water-soluble salt as the starting material, the preparation method of the deuterated zanomeline pamoate with crystal form d-B3 as shown in Formula II is the same as the preparation method of the zanomeline pamoate with crystal form B3 described above.

[0126] In a seventh aspect, this disclosure provides a pharmaceutical composition comprising one or more of the following pharmaceutical active ingredients:

[0127] A) The above-mentioned zonomelin pamoate with crystal form B3 as shown in Formula I;

[0128] B) The above-mentioned zonomelin pamoate having crystal form E as shown in Formula I; and

[0129] C) the above deuterated zanolimine pamoate salt of Formula II having crystalline Form d-B3.

[0130] In some aspects of the disclosure, the pharmaceutical composition can comprise the above zanolimine pamoate salt of Formula I having crystalline Form B3 as the only pharmaceutically active ingredient.

[0131] In some aspects of the disclosure, the pharmaceutical composition can comprise the above zanolimine pamoate salt of Formula I having crystalline Form E as the only pharmaceutically active ingredient.

[0132] In some aspects of the disclosure, the pharmaceutical composition can comprise the above deuterated zanolimine pamoate salt of Formula II having crystalline Form d-B3 as the only pharmaceutically active ingredient.

[0133] In some aspects of the disclosure, the pharmaceutical composition can further comprise one or more pharmaceutically acceptable excipients.

[0134] In some aspects of the disclosure, the pharmaceutically acceptable excipients can include, but are not limited to, diluents (or fillers), lubricants, binders, disintegrants, stabilizers, surfactants, flavoring agents, odorizing agents, solvents, co-solvents, pH adjusting agents, osmotic pressure adjusting agents, and the like.

[0135] In some aspects of the disclosure, the various components in the pharmaceutical composition can be physically mixed.

[0136] In some aspects of the disclosure, the various components in the pharmaceutical composition can be physically isolated.

[0137] In some aspects of the disclosure, the zanolimine pamoate salt (e.g., the salt of Formula I having crystalline Form B3 or crystalline Form E), the deuterated zanolimine pamoate salt (e.g., the salt of Formula II having crystalline Form d-B3), or the pharmaceutical composition comprising the same can be administered to an individual in need thereof by an oral mode of administration.

[0138] In some aspects of the disclosure, the zanolimine pamoate salt (e.g., the salt of Formula I having crystalline Form B3 or crystalline Form E), the deuterated zanolimine pamoate salt (e.g., the salt of Formula II having crystalline Form d-B3), or the pharmaceutical composition comprising the same can be administered to an individual in need thereof by a non-oral mode of administration.

[0139] In some aspects of the disclosure, the zanolimine pamoate salt (e.g., the salt of Formula I having crystalline Form B3 or crystalline Form E), the deuterated zanolimine pamoate salt (e.g., the salt of Formula II having crystalline Form d-B3), or the pharmaceutical composition comprising the same can be administered to an individual in need thereof by an injection mode of administration.

[0140] In some embodiments of the present disclosure, the zanomeline pamoate salt (e.g., a salt of Formula I having Form B3 or Form E), deuterated zanomeline pamoate salt (e.g., a salt of Formula II having Form d-B3), or a pharmaceutical composition comprising the same can be administered by intramuscular injection.

[0141] In some embodiments of the present disclosure, the zanomeline pamoate salt of Formula I having Form B3 or a pharmaceutical composition comprising the same can be administered by intramuscular injection.

[0142] In some embodiments of the present disclosure, the zanomeline pamoate salt of Formula I having Form E or a pharmaceutical composition comprising the same can be administered by intramuscular injection.

[0143] In some embodiments of the present disclosure, the deuterated zanomeline pamoate salt of Formula II having Form d-B3 or a pharmaceutical composition comprising the same can be administered by intramuscular injection.

[0144] In some embodiments of the present disclosure, the zanomeline pamoate salt (e.g., a salt of Formula I having Form B3 or Form E), deuterated zanomeline pamoate salt (e.g., a salt of Formula II having Form d-B3), or a pharmaceutical composition comprising the same can be administered by subcutaneous injection.

[0145] In some embodiments of the present disclosure, the zanomeline pamoate salt of Formula I having Form B3 or a pharmaceutical composition comprising the same can be administered by subcutaneous injection.

[0146] In some embodiments of the present disclosure, the zanomeline pamoate salt of Formula I having Form E or a pharmaceutical composition comprising the same can be administered by subcutaneous injection.

[0147] In some embodiments of the present disclosure, the deuterated zanomeline pamoate salt of Formula II having Form d-B3 or a pharmaceutical composition comprising the same can be administered by subcutaneous injection.

[0148] In an eighth aspect, the present disclosure provides a pharmaceutical preparation comprising one or a combination of two or more of the following components:

[0149] A) the zanomeline pamoate salt of Formula I having Form B3 described above;

[0150] B) the zanomeline pamoate salt of Formula I having Form E described above;

[0151] C) the deuterated zanolimine pamoate salt having crystalline Form d-B3 as shown in Formula II above; and

[0152] D) the pharmaceutical composition described above.

[0153] In some embodiments of the present disclosure, the pharmaceutical preparation can be made from the zanolimine pamoate salt (e.g., the salt as shown in Formula I having crystalline Form B3 or crystalline Form E), the deuterated zanolimine pamoate salt (e.g., the salt as shown in Formula II having crystalline Form d-B3), or the pharmaceutical composition comprising the same.

[0154] In some specific embodiments of the present disclosure, the pharmaceutical preparation can be made from the zanolimine pamoate salt as shown in Formula I having crystalline Form B3 or the pharmaceutical composition comprising the same.

[0155] In some specific embodiments of the present disclosure, the pharmaceutical preparation can be made from the zanolimine pamoate salt as shown in Formula I having crystalline Form E or the pharmaceutical composition comprising the same.

[0156] In some specific embodiments of the present disclosure, the pharmaceutical preparation can be made from the deuterated zanolimine pamoate salt as shown in Formula II having crystalline Form d-B3 or the pharmaceutical composition comprising the same.

[0157] In some embodiments of the present disclosure, the pharmaceutical preparation can include (but not limited to) tablets, capsules, granules, lozenges, suppositories, ointments, creams, injections (e.g., injection solutions, lyophilized powder injections, etc.), suspensions, mixtures, tinctures, liniments, lotions, inhalants, aerosols, etc.

[0158] In some embodiments of the present disclosure, the pharmaceutical preparation can be a pharmaceutical preparation suitable for injection.

[0159] In some specific embodiments of the present disclosure, the pharmaceutical preparation can be a pharmaceutical preparation suitable for intramuscular injection.

[0160] In some specific embodiments of the present disclosure, the pharmaceutical preparation can be a pharmaceutical preparation suitable for subcutaneous injection.

[0161] In some embodiments of the present disclosure, the pharmaceutical preparation suitable for injection can include (but not limited to) aqueous solution injection, oil solution injection, suspension, emulsion, lyophilized powder injection, colloidal solution, etc.

[0162] In some specific embodiments of the present disclosure, the pharmaceutical preparation suitable for injection can be a lyophilized powder injection.

[0163] In some specific embodiments of the present disclosure, the pharmaceutical preparation suitable for injection can be a suspension.

[0164] In some embodiments of the present disclosure, the administration of the pharmaceutical preparation can include, but is not limited to, oral administration, injection (e.g., intravenous injection, intramuscular injection, subcutaneous injection, etc.), topical administration (e.g., skin administration, mucosal administration, etc.), inhalation administration, etc.

[0165] In some embodiments of the present disclosure, the pharmaceutical preparation can be administered to an individual in need thereof by oral administration.

[0166] In some embodiments of the present disclosure, the pharmaceutical preparation can be administered to an individual in need thereof by oral administration.

[0167] In some embodiments of the present disclosure, the pharmaceutical composition can be administered to an individual in need thereof by non-oral administration.

[0168] In some embodiments of the present disclosure, the pharmaceutical preparation can be administered to an individual in need thereof by injection.

[0169] In some embodiments of the present disclosure, the pharmaceutical preparation can be administered to an individual in need thereof by intramuscular injection.

[0170] In some embodiments of the present disclosure, the pharmaceutical preparation can be administered to an individual in need thereof by subcutaneous injection.

[0171] In some embodiments of the present disclosure, the pharmaceutical preparation can comprise a prophylactically and / or therapeutically effective amount of zanomeline pamoate salt (e.g., a salt of Formula I having crystalline Form B3 or crystalline Form E), deuterated zanomeline pamoate salt (e.g., a salt of Formula II having crystalline Form d-B3), or a pharmaceutical composition comprising the same, so as to exert an effect consistent with the prophylactic and / or therapeutic purpose or achieve a corresponding effect.

[0172] In some embodiments of the present disclosure, the administration dose of the pharmaceutical composition or pharmaceutical preparation (e.g., the administration dose by injection, in particular the administration dose by intramuscular injection or subcutaneous injection) can be set based on factors such as the age, body weight, gender, disease type and degree, administration mode, etc. of the individual in need thereof.

[0173] For example, the pharmaceutical composition or pharmaceutical formulation can have a dosage of from about 1 mg to about 3000 mg, or from about 1 mg to about 2000 mg, or from about 1 mg to 1000 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 30 mg, or from about 1 mg to about 20 mg, or from about 1 mg to about 10 mg, or from about 1 mg to about 8 mg, or from about 1 mg to about 5 mg, or from about 1 mg to about 3 mg, or from about 1 mg to about 2 mg, per administration of the drug, based on the weight of the free base of the above xanomeline pamoate salt of Formula I having crystalline Form B3, the above xanomeline pamoate salt of Formula I having crystalline Form E, or the above deuterated xanomeline pamoate salt of Formula II having crystalline Form d-B3.

[0174] In some embodiments of the present disclosure, the pharmaceutical composition or pharmaceutical preparation can be administered in a dose of 1-3000 mg, 1-2000 mg, 1-1000 mg, 1-300 mg, 1-200 mg, 1-100 mg, 1-30 mg, 1-20 mg, 1-10 mg, 2-3000 mg, 2-2000 mg, 2-1000 mg, 2-300 mg, 2-200 mg, 2-100 mg, 2-30 mg, 2-20 mg, 2-10 mg, 3-3000 mg, 3-2000 mg, 3-1000 mg, 3-300 mg, 3-200 mg, 3-100 mg, 3-30 mg, 3-20 mg, 3-10 mg, 5-3000 mg, 5-2000 mg, 5-1000 mg, 5-300 mg, 5-200 mg, 5-100 mg, 5-30 mg, 5-20 mg, 5-10 mg, 8-3000 mg, 8-2000 mg, 8-1000 mg, 8-300 mg, 8-200 mg, 8-100 mg, 8-30 mg, 8-20 mg, 8-10 mg, 10-3000 mg, 10-2000 mg, 10-1000 mg, 10-300 mg, 10-200 mg, 10-100 mg, 10-30 mg, 10-20 mg, 30-3000 mg, 30-2000 mg, 30-1000 mg, 30-300 mg, 30-200 mg, 30-100 mg, 50-3000 mg, 50-2000 mg, 50-1000 mg, 50-300 mg, 50-200 mg, 50-100 mg, 80-3000 mg, 80-2000 mg, 80-1000 mg, 80-300 mg, 80-200 mg, 80-100 mg, 100-3000 mg, 100-2000 mg, 100-1000 mg, 100-300 mg, 100-200 mg, 200-3000 mg, 200-2000 mg, 200-1000 mg, 200-300 mg, 300-3000 mg, 300-2000 mg, 300-1000 mg, 1000-3000 mg, 1000-2000 mg, or 2000-3000 mg per administration.

[0175] For example, based on the weight of the free base in the above-mentioned zanmolin pamoate of Formula I having crystal form B3, the above-mentioned zanmolin pamoate of Formula I having crystal form E, or the above-mentioned deuterated zanmolin pamoate of Formula II having crystal form d-B3, the dosage of the pharmaceutical composition or pharmaceutical preparation suitable for intramuscular injection may be from about 30 mg to about 3000 mg, or from about 30 mg to about 2000 mg, or from about 30 mg to about 1000 mg, or from about 30 mg to about 300 mg, or from about 30 mg to about 200 mg, or from about 30 mg to about 100 mg.

[0176] In some embodiments of this disclosure, the dosage of the pharmaceutical composition or pharmaceutical preparation suitable for intramuscular injection may be 30-3000 mg, 30-2000 mg, 30-1000 mg, 30-300 mg, 30-200 mg, 30-100 mg, 50-3000 mg, 50-2000 mg, 50-1000 mg, 50-300 mg, 50-200 mg, 50-100 mg, 80-3000 mg, 80-2000 mg, 80-1000 mg, 80-3 00mg, 80-200mg, 80-100mg, 100-3000mg, 100-2000mg, 100-1000mg, 100-300mg, 100-200mg, 200-3000mg, 200-2000mg, 200-1000mg, 200-300mg, 300-3000mg, 300-2000mg, 300-1000mg, 1000-3000mg, 1000-2000mg or 2000-3000mg.

[0177] For example, based on the weight of the free base in the above-mentioned zanmolin pamoate of Formula I having crystal form B3, the above-mentioned zanmolin pamoate of Formula I having crystal form E, or the above-mentioned deuterated zanmolin pamoate of Formula II having crystal form d-B3, the dosage of the pharmaceutical composition or pharmaceutical preparation suitable for subcutaneous injection may be from about 10 mg to 1000 mg, or from about 10 mg to about 300 mg, or from about 10 mg to about 200 mg, or from about 10 mg to about 100 mg, or from about 10 mg to about 30 mg, or from about 10 mg to about 20 mg.

[0178] In some embodiments of the present disclosure, the pharmaceutical composition or the pharmaceutical preparation suitable for subcutaneous injection can have a dose of 10-1000 mg, 10-300 mg, 10-200 mg, 10-100 mg, 10-30 mg, 10-20 mg, 20-1000 mg, 20-300 mg, 20-200 mg, 20-100 mg, 20-30 mg, 30-1000 mg, 30-300 mg, 30-200 mg, 30-100 mg, 50-1000 mg, 50-300 mg, 50-200 mg, 50-100 mg, 80-1000 mg, 80-300 mg, 80-200 mg, 80-100 mg, 100-1000 mg, 100-300 mg, 100-200 mg, 200-1000 mg, or 200-300 mg per administration.

[0179] In some embodiments of the present disclosure, the pharmaceutical preparation (e.g., the pharmaceutical preparation suitable for injection, in particular, the pharmaceutical preparation suitable for intramuscular injection or subcutaneous injection) can have a frequency of administration (e.g., the frequency of administration under the condition of the single dose described above) of 4 times per day (qid), or 3 times per day (tid), or 2 times per day (bid), or 1 time per day (qd), or 1 time every two days (qod), or 2 times per week (biw), or 1 time per week (qw), or 1 time every two weeks (q2w), or 1 time per month (qm), or 1 time every two months (q2m), or 1 time every three months (q3m).

[0180] In a ninth aspect, the present disclosure provides use of the above-mentioned nalmefene palmoate of formula I having crystal form B3, the above-mentioned nalmefene palmoate of formula I having crystal form E, the above-mentioned deuterated nalmefene palmoate of formula II having crystal form d-B3, the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation in the preparation of a medicament for preventing and / or treating central nervous system disorder diseases.

[0181] In a ninth aspect, the present disclosure provides use of the above-mentioned nalmefene palmoate of formula I having crystal form B3, the above-mentioned nalmefene palmoate of formula I having crystal form E, the above-mentioned deuterated nalmefene palmoate of formula II having crystal form d-B3, the above-mentioned pharmaceutical composition or the above-mentioned pharmaceutical preparation in the preparation of a medicament for preventing and / or treating central nervous system disorder diseases.

[0182] In an eleventh aspect, the present disclosure provides a method for preventing and / or treating a central nervous system disorder, comprising administering to an individual in need thereof a zanomeline pamoate salt of Formula I having a crystal form B3 described above, a zanomeline pamoate salt of Formula I having a crystal form E described above, a deuterated zanomeline pamoate salt of Formula II having a crystal form d-B3 described above, a pharmaceutical composition described above, or a pharmaceutical preparation described above.

[0183] In some embodiments of the present disclosure, the method can comprise administering to an individual in need thereof a zanomeline pamoate salt (e.g., a salt of Formula I having a crystal form B3 or a crystal form E), a deuterated zanomeline pamoate salt (e.g., a salt of Formula II having a crystal form d-B3), or a pharmaceutical composition or a pharmaceutical preparation comprising the same by oral administration.

[0184] In some embodiments of the present disclosure, the method can comprise administering to an individual in need thereof a zanomeline pamoate salt (e.g., a salt of Formula I having a crystal form B3 or a crystal form E), a deuterated zanomeline pamoate salt (e.g., a salt of Formula II having a crystal form d-B3), or a pharmaceutical composition or a pharmaceutical preparation comprising the same by oral administration.

[0185] In some embodiments of the present disclosure, the method can comprise administering to an individual in need thereof a zanomeline pamoate salt (e.g., a salt of Formula I having a crystal form B3 or a crystal form E), a deuterated zanomeline pamoate salt (e.g., a salt of Formula II having a crystal form d-B3), or a pharmaceutical composition or a pharmaceutical preparation comprising the same by non-oral administration.

[0186] In some embodiments of the present disclosure, the method can comprise administering to an individual in need thereof a zanomeline pamoate salt (e.g., a salt of Formula I having a crystal form B3 or a crystal form E), a deuterated zanomeline pamoate salt (e.g., a salt of Formula II having a crystal form d-B3), or a pharmaceutical composition or a pharmaceutical preparation comprising the same by injection.

[0187] In some embodiments of the present disclosure, the method can comprise administering to an individual in need thereof a zanomeline pamoate salt (e.g., a salt of Formula I having a crystal form B3 or a crystal form E), a deuterated zanomeline pamoate salt (e.g., a salt of Formula II having a crystal form d-B3), or a pharmaceutical composition or a pharmaceutical preparation comprising the same by intramuscular injection.

[0188] In some embodiments of the present disclosure, the method can comprise administering to an individual in need thereof a zanomeline pamoate salt of Formula I having a crystal form B3 described above or a pharmaceutical composition or a pharmaceutical preparation comprising the same by intramuscular injection.

[0189] In some more particular aspects of the present disclosure, the method can administer to an individual in need thereof a cannabimimetic agent, such as a cannabinoid, or a pharmaceutical composition or pharmaceutical formulation comprising the same, as described above.

[0190] In some more particular aspects of the present disclosure, the method can administer to an individual in need thereof a deuterated cannabimimetic agent, such as a cannabinoid, or a pharmaceutical composition or pharmaceutical formulation comprising the same, as described above.

[0191] In some particular aspects of the present disclosure, the method can administer to an individual in need thereof a cannabimimetic agent, such as a cannabinoid, or a pharmaceutical composition or pharmaceutical formulation comprising the same, as described above, by intramuscular injection.

[0192] In some more particular aspects of the present disclosure, the method can administer to an individual in need thereof a cannabimimetic agent, such as a cannabinoid, or a pharmaceutical composition or pharmaceutical formulation comprising the same, as described above, by intramuscular injection.

[0193] In some more particular aspects of the present disclosure, the method can administer to an individual in need thereof a cannabimimetic agent, such as a cannabinoid, or a pharmaceutical composition or pharmaceutical formulation comprising the same, as described above, by intramuscular injection.

[0194] In some more particular aspects of the present disclosure, the method can administer to an individual in need thereof a deuterated cannabimimetic agent, such as a cannabinoid, or a pharmaceutical composition or pharmaceutical formulation comprising the same, as described above.

[0195] In some aspects of the present disclosure, the central nervous system disorder disease can include, but is not limited to, schizophrenia, Alzheimer's disease, Parkinson's disease, depression, dyskinesia, drug addiction, pain, and neurodegeneration (e.g., tauopathy or synucleinopathy).

[0196] In some aspects of the present disclosure, the central nervous system disorder disease can be schizophrenia or Alzheimer's disease. Advantages

[0197] The present disclosure first obtains two new crystal forms of zanomeline pamoate salt as shown in Formula I, crystal form B3 and crystal form E, and one new crystal form of deuterated zanomeline pamoate salt as shown in Formula II, crystal form d-B3. Among them, the crystal form B3 has good physicochemical stability, can maintain an effective concentration for a long time while keeping the crystal form unchanged in vivo, and the drug toxicity side effects are obviously improved, and has good drug prospects; the crystal form E also has good stability and in vitro slow release effect; on the basis of the excellent physicochemical stability and pharmacokinetic properties of the crystal form B3, the crystal form d-B3 should also have satisfactory effects. The expected slow release effect can be achieved by administering the various crystal forms of the present disclosure through different administration routes (for example, intramuscular injection, subcutaneous injection, oral administration, etc.). In addition, the preparation process of the crystal form of the present disclosure is simple, the batch difference is small, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0198] Figure 1 is an XRPD spectrum of zanomeline pamoate salt crystal form B3.

[0199] Figure 2 is a DSC spectrum of zanomeline pamoate salt crystal form B3.

[0200] Figure 3 is a TGA spectrum of zanomeline pamoate salt crystal form B3.

[0201] Figure 4 is a Raman spectrum of zanomeline pamoate salt crystal form B3.

[0202] Figure 5 is an XRPD spectrum of zanomeline pamoate salt crystal form E.

[0203] Figure 6 is a DSC spectrum of zanomeline pamoate salt crystal form E.

[0204] Figure 7 is a TGA spectrum of zanomeline pamoate salt crystal form E.

[0205] Figure 8 is an XRPD spectrum of deuterated zanomeline pamoate salt crystal form d-B3.

[0206] Figure 9 is a DSC spectrum of deuterated zanomeline pamoate salt crystal form d-B3.

[0207] Figure 10 is a TGA spectrum of deuterated zanomeline pamoate salt crystal form d-B3.

[0208] Figure 11A is a schematic diagram of the connection mode of zanomeline and pamoic acid molecules in zanomeline pamoate salt crystal form B3 single crystal, and Figure 11B is a fitted XRPD spectrum of zanomeline pamoate salt crystal form B3 single crystal.

[0209] Figure 12 is the stability test results of zanomeline pamoate salt crystal form B3.

[0210] Fig. 13 is a result of stability test of zanomeline pamoate salt crystalline form E.

[0211] Fig. 14 is an IDR test curve of zanomeline pamoate salt crystalline form B3.

[0212] Fig. 15 is an IDR test curve of zanomeline pamoate salt crystalline form E.

[0213] Fig. 16 is a concentration-time curve of zanomeline in rat plasma after intramuscular administration of zanomeline sesame oil solution.

[0214] Fig. 17 is a concentration-time curve of zanomeline in rat plasma after intramuscular administration of zanomeline pamoate salt having crystalline form B3.

[0215] Fig. 18 is a comparison chart of Raman spectra of zanomeline pamoate salt having crystalline form B3, in which the upper graph is a Raman spectrum of a crystalline form B3 reference substance, and the lower graph is a Raman spectrum of a residue taken out 216 hours after intramuscular administration of crystalline form B3. DETAILED DESCRIPTION

[0216] The embodiments of the present disclosure will be described in detail below with reference to various example embodiments, but it will be understood by those skilled in the art that the following examples are for the purpose of illustration only and should not be construed as limiting the scope of the present disclosure. In this specification, the term "exemplary" means "serving as an example or illustration" and any embodiment described as "exemplary" is not necessarily construed as being superior to or preferable over other embodiments.

[0217] In this specification, unless otherwise specified, the operations are performed under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are all conventional products that can be commercially available. Those skilled in the art will understand that the present disclosure can be implemented without certain specific details. In some embodiments, methods, means, apparatuses, and steps that are well known to those skilled in the art are not described in detail in order to highlight the main idea of the present disclosure.

[0218] Unless otherwise specified, the units used in this specification are international standard units. In this specification, the numerical range expressed as "numerical value A to numerical value B" means a range including the end point values A and B, and the numerical values or numerical ranges appearing in the present disclosure should be understood to include systematic errors that are inevitably generated in actual production.

[0219] In this specification, the term "may" means both the meaning of performing a certain process and the meaning of not performing a certain process.

[0220] As used in this specification, the terms "scheme / embodiment", "some schemes / embodiments", "other schemes / embodiments", and the like, mean that the particular element (e.g., feature, structure, property, and / or characteristic) described is included in at least one scheme / embodiment described herein, and can or can not be present in other schemes / embodiments. In addition, it is to be understood that the described element can be present in any suitable manner in the various schemes / embodiments.

[0221] As used in this specification, the following abbreviations have the following meanings:

[0222] ACN stands for acetonitrile;

[0223] DCM stands for dichloromethane;

[0224] THF stands for tetrahydrofuran;

[0225] MeOH stands for methanol;

[0226] EtOH stands for ethanol;

[0227] IPA stands for isopropyl alcohol;

[0228] DSC stands for differential scanning calorimetry;

[0229] TGA stands for thermogravimetric analysis;

[0230] 1 H-NMR stands for nuclear magnetic resonance hydrogen spectrum;

[0231] XRPD stands for X-ray powder diffraction;

[0232] XRSCD stands for X-ray single crystal diffraction;

[0233] eq stands for molar equivalent;

[0234] SDS stands for sodium dodecyl sulfate;

[0235] PBS stands for phosphate buffered saline;

[0236] CMCNa stands for sodium carboxymethylcellulose;

[0237] EA stands for ethyl acetate.

[0238] In this specification, the instruments and methods used for characterizing the xanomeline salt forms and crystalline forms are as follows:

[0239] Differential scanning calorimetry (DSC): Differential scanning calorimeter, instrument model TA Q2000; specific operation mode: 1-3 mg sample was weighed in a non-sealed aluminum crucible, and the temperature was raised to the test temperature at a rate of 10 ℃ / min, the instrument was calibrated with metal indium, high-purity (> 99.99%) nitrogen protection, nitrogen flow rate was 50 ml / min, and the analysis software was TA Universal Analysis.

[0240] In the specification, DSC is used to determine the melting point of the crystal, and the transition temperature when the crystal absorbs or releases heat due to the change of its crystal structure or the melting of the crystal can also be determined. For the same crystal form of the same compound, the error of the transition temperature or the melting point is usually within about 5°C. When a certain compound has a certain specific DSC peak or melting point, it is expressed as the DSC peak or melting point ± 5°C. DSC provides an auxiliary method for distinguishing different crystal forms of the same compound. Different crystal forms can be identified according to their different transition temperatures.

[0241] Thermogravimetric analysis (TGA): Thermogravimetric analyzer, instrument model TA Q500; specific operation mode: 5-15 mg sample was placed in a platinum pan, and the temperature was raised to the test temperature at a rate of 20 ℃ / min, high-purity (99.99%) nitrogen protection, nitrogen flow rate was 40 ml / min, and the analysis software was TA Universal Analysis.

[0242] Nuclear magnetic resonance (NMR): Nuclear magnetic resonance spectrometer, instrument model Bruker 500 MHz, test solvent is deuterated reagent (such as deuterated chloroform, deuterated dimethyl sulfoxide, etc.); specific operation: 5-10 mg sample was dissolved in 0.6 ml deuterated reagent, and the sample was measured.

[0243] X-ray powder diffraction, also known as powder X-ray diffraction (PXRD): X-ray diffractometer, instrument model Japan Rigaku Smart;

[0244] The specific parameters are as follows:

[0245] Target: Cu-Kα ray

[0246] Voltage: copper palladium 40KV;

[0247] Current: 40 mA;

[0248] Temperature: room temperature;

[0249] Sample: not ground;

[0250] 2θ angle range: 3-40°;

[0251] Scan rate: 10° / min.

[0252] X-ray single crystal diffraction, also referred to as single-crystal X-ray diffraction (SCXRD): X-ray diffractometer, instrument model: Bruker D8, USA;

[0253] The specific operation mode is as follows:

[0254] The light source is Mo-Ka target;

[0255] Temperature: 100 K;

[0256] The determination of single crystal unit, the collection, integration and refinement of diffraction data are realized by SAINT program;

[0257] The data are corrected for absorption using the multi-scan method of SADABS;

[0258] The anisotropic refinement is performed on non-hydrogen atoms, and the hydrogen atoms are positioned on the geometric calculation position of the riding model.

[0259] High performance liquid chromatography (HPLC): high performance liquid chromatograph, instrument model: Shimadzu LC-20AT;

[0260] The specific parameters are as follows:

[0261] Chromatographic column: Agilent Zorbax SB C-18 (4.6x250mm, 5μm);

[0262] Mobile phase: A phase: 0.1% v / v trifluoroacetic acid acetonitrile solution / B phase: 0.1% v / v trifluoroacetic acid aqueous solution;

[0263] Elution mode: gradient elution as shown in the following table;

[0264] Column temperature: 40℃;

[0265] Flow rate: 1 ml / min;

[0266] Injection volume: 30μl;

[0267] Detection wavelength: 220nm.

[0268] Preparation example 1: preparation of zanamivir soluble salt (hydrochloride)

[0269] A 4M solution of hydrochloric acid in 1,4-dioxane (1.78 mL, containing 7.1 mmol of HC1, 1 eq) was added dropwise to a solution of 2 g of zanamivir (7.1 mmol) in DCM (20 mL) and stirred at 25 °C for 12 h. The reaction was added dropwise to THF and stirred, crystallized, filtered, and dried to give white to off-white zanamivir hydrochloride salt solids (30% yield). The zanamivir to hydrochloride salt molar ratio was 1:1 as tested by HPLC.

[0270] 1 H-NMR (500 MHz, Chloroform-d): δ 12.93 (s, 1H), 7.25-7.22 (m, 1H), 4.49-4.42 (m, 3H), 3.91-3.74 (m, 1H), 3.56-3.53 (m, 1H), 3.26-3.16 (m, 1H), 3.06-2.98 (m, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.58-2.53 (m, 1H), 1.83-1.78 (m, 2H), 1.46-1.39 (m, 2H), 1.36-1.31 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H).

[0271] Intermediate Preparation Example 2: Preparation of Zanamivir Soluble Salt (L-tartaric acid salt)

[0272] Zanamivir (12.00 g, 42.6 mmol) and L-tartaric acid powder (6.40 g, 42.6 mmol, 1 eq) were weighed into isopropanol (80 mL), dissolved at 40 °C, and then ethyl acetate (120 mL) was added. The solution was cooled to 4 °C and stirred for 6 h, filtered, and washed with cold ethyl acetate to give zanamivir L-tartaric acid salt solids (77% yield). The zanamivir to L-tartaric acid molar ratio was 1:1 as tested by H-NMR. 1 H-NMR (500 MHz, Chloroform-d): δ 12.93 (s, 1H), 7.25-7.22 (m, 1H), 4.49-4.42 (m, 3H), 3.91-3.74 (m, 1H), 3.56-3.53 (m, 1H), 3.26-3.16 (m, 1H), 3.06-2.98 (m, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.58-2.53 (m, 1H), 1.83-1.78 (m, 2H), 1.46-1.39 (m, 2H), 1.36-1.31 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H).

[0273] 1 H-NMR (500 MHz, Chloroform-d): δ 12.93 (s, 1H), 7.25-7.22 (m, 1H), 4.49-4.42 (m, 3H), 3.91-3.74 (m, 1H), 3.56-3.53 (m, 1H), 3.26-3.16 (m, 1H), 3.06-2.98 (m, 1H), 2.94 (d, J = 4.8 Hz, 3H), 2.58-2.53 (m, 1H), 1.83-1.78 (m, 2H), 1.46-1.39 (m, 2H), 1.36-1.31 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H).

[0274] Example 1: Preparation of Zanamivir Palmoate Crude Based on Hydrochloride Salt

[0275] Zanomeline hydrochloride (0.794 g, 2.5 mmol) prepared by the method in Intermediate Preparation Example 1 was added to methanol (14 mL) to form a zanomeline hydrochloride solution by stirring at room temperature; pamonic acid disodium monohydrate (1.126 g, 2.5 mmol, 1 eq) was added to water (55 mL) to form a pamonic acid disodium solution by stirring at room temperature; the pamonic acid disodium solution was added dropwise to the zanomeline hydrochloride solution, and stirred at room temperature for 12 h, and a precipitate was separated out, which was filtered, the filter cake was washed with water, and the filter cake was dried at 30 °C under vacuum for 12 h to obtain a light yellow zanomeline pamonic acid salt crude product (yield 90%). The product was analyzed by HPLC and 1 The molar ratio of zanomeline to pamonic acid was 1:1 by H-NMR determination, i.e. the product obtained was a compound having the structure as shown in Formula I.

[0276] 1 H-NMR (500 MHz, DMSO-d6): δ 8.33 (s, 2H), 8.16 (d, J = 8.6 Hz, 2H), 7.76 (dd, J = 8.2, 1.3 Hz, 2H), 7.25 (ddd, J = 8.5, 6.7, 1.4 Hz, 2H), 7.16-7.13 (m, 1H), 7.11 (ddd, J = 7.9, 6.8, 1.0 Hz, 2H), 4.74 (s, 2H), 4.44 (t, J = 6.6 Hz, 2H), 4.19 (s, 2H), 3.30 (d, J = 7.4 Hz, 2H), 2.95 (s, 3H), 2.74-2.58 (m, 2H), 1.78 (p, J = 6.7 Hz, 2H), 1.48-1.34 (m, 2H), 1.29 (dq, J = 6.6, 3.4 Hz, 4H), 0.91-0.83 (m, 3H).

[0277] Example 2: Preparation of zanomeline pamonic acid salt crude product based on L-tartrate salt

[0278] Zanomeline L-tartrate salt (111 g, 0.26 mol) prepared by the method in Intermediate Preparation Example 2 was added to methanol (1440 mL) to form a zanomeline L-tartrate salt solution by stirring at room temperature; pamonic acid disodium (111.6 g, 0.26 mol, 1 eq) was added to water (4709 mL) to form a pamonic acid disodium solution by stirring at room temperature; the pamonic acid disodium solution was added dropwise to the zanomeline L-tartrate salt solution, and stirred at room temperature for 17 h, and a precipitate was separated out, which was filtered, the filter cake was washed with water, and the filter cake was dried at 30 °C under vacuum for 17 h to obtain a light yellow zanomeline pamonic acid salt crude product (158.13 g). The product was analyzed by HPLC and 1H-NMR determination showed that the molar ratio of zanomeline to pamoic acid was 1:1, i.e. the obtained product was a compound having the structure as shown in Formula I.

[0279] 1 H-NMR (500 MHz, DMSO-d6): δ 8.35 (s, 2H), 8.17 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.25 (ddd, J = 8.5, 6.7, 1.4 Hz, 2H), 7.15 (d, J = 5.5 Hz, 1H), 7.12 (d, J = 7.4 Hz, 2H), 4.76 (s, 2H), 4.41 (t, J = 6.6 Hz, 2H), 4.21 (s, 2H), 3.37 (m, 2H), 2.98 (s, 3H), 2.68 (q, J = 5.2, 4.7 Hz, 2H), 1.76 (p, J = 6.8 Hz, 2H), 1.38 (p, J = 7.2 Hz, 2H), 1.28 (hept, J = 3.2 Hz, 4H), 0.85 (s, 3H).

[0280] Example 3: Preparation of zanomeline pamoate salt with crystal form B3 (Method 1)

[0281] The crude zanomeline pamoate salt prepared by the method in Example 2 was placed in a mixed solution of ACN and DCM (1:1, v / v), and the ratio of the crude zanomeline pamoate salt to the solvent was 1 g:10 mL. The mixture was stirred at room temperature for 48 h, and the solid was collected by filtration and dried under vacuum to obtain a light yellow zanomeline pamoate salt product (yield 80%, HPLC purity 98.1%).

[0282] The obtained product was tested by XRPD, DSC and TGA, and it was found that the light yellow solid existed in a crystal form, and thus the crystal form was named as zanomeline pamoate salt crystal form B3 (abbreviated as crystal form B3). The XRPD, DSC and TGA patterns of crystal form B3 are shown in Figures 1, 2 and 3, respectively, and the peak positions and intensities of the characteristic diffraction peaks in the XRPD pattern are shown in Table 1, wherein the error range of the 2θ angle value is ±0.2°.

[0283] Table 1. Peak positions and intensities of characteristic diffraction peaks in the XRPD pattern of crystal form B3

[0284] Example 4: Preparation of zanomeline pamoate salt with crystal form B3 (Method 2)

[0285] The crude zanomeline pamoate prepared by the method of Example 1 was placed in EA at a ratio of 1 g: 10 mL solvent, stirred at room temperature for 24 h, and the solid was collected by filtration and dried under vacuum to produce a light yellow zanomeline pamoate product (yield 75%). The product was tested by XRPD, DSC, and TGA and was confirmed to be zanomeline pamoate having Form B3.

[0286] Example 5: Preparation of zanomeline pamoate having Form B3 (Method 3)

[0287] The crude zanomeline pamoate prepared by the method of Example 1 was placed in acetone at a ratio of 1 g: 10 mL solvent, stirred at room temperature for 24 h, and the solid was collected by filtration and dried under vacuum to produce a light yellow zanomeline pamoate product (yield 80%). The product was tested by XRPD, DSC, and TGA and was confirmed to be zanomeline pamoate having Form B3.

[0288] Example 6: Preparation of zanomeline pamoate having Form B3 (Method 4)

[0289] The crude zanomeline pamoate prepared by the method of Example 1 was placed in methanol at a ratio of 1 g: 10 mL solvent, stirred at room temperature for 24 h, and the solid was collected by filtration and dried under vacuum to produce a light yellow zanomeline pamoate product (yield 73%). The product was tested by XRPD, DSC, and TGA and was confirmed to be zanomeline pamoate having Form B3.

[0290] Example 7: Preparation of zanomeline pamoate having Form B3 (Method 5)

[0291] The crude zanomeline pamoate prepared by the method of Example 2 was placed in a mixture of THF and EA (3: 1, v / v) at a ratio of 1 g: 10 mL solvent and stirred at room temperature for 5 min. The zanomeline pamoate having Form B3 prepared by the method of Example 3 was added as seed crystals and stirred at room temperature for 48 h. The solid was collected by filtration and dried under vacuum to produce a light yellow zanomeline pamoate product (yield 77%). The product was tested by XRPD, DSC, and TGA and was confirmed to be zanomeline pamoate having Form B3.

[0292] Example 8: Preparation of zanomeline pamoate having Form B3 (Method 6)

[0293] The crude zanomeline pamoate prepared by the method of Example 2 was placed in THF at a ratio of 1 g: 10 mL, and stirred for 5 minutes at room temperature. Zanomeline pamoate Form B3 prepared by the method of Example 3 was added as seed crystals, and stirred for 17 hours at 50 °C. The mixture was allowed to cool to room temperature, and the solid was collected by filtration and dried under vacuum to yield a yellowish zanomeline pamoate product (70% yield). The product was tested by XRPD, DSC, and TGA, and was confirmed to be zanomeline pamoate Form B3.

[0294] Example 9: Preparation of zanomeline pamoate Form B3 (Method 7)

[0295] The crude zanomeline pamoate prepared by the method of Example 2 was placed in acetone-water (1:1, v / v) at a ratio of 1 g: 10 mL, and stirred for 5 minutes at room temperature. Zanomeline pamoate Form B3 prepared by the method of Example 3 was added as seed crystals, and stirred for 12 hours at room temperature. The solid was collected by filtration and dried under vacuum to yield a yellowish zanomeline pamoate product (81% yield). The product was tested by XRPD, DSC, and TGA, and was confirmed to be zanomeline pamoate Form B3.

[0296] Example 10: Preparation of zanomeline pamoate Form B3 (Method 8)

[0297] The crude zanomeline pamoate prepared by the method of Example 2 was placed in acetone-ethyl ether (1:1, v / v) at a ratio of 1 g: 10 mL, and stirred for 5 minutes at room temperature. Zanomeline pamoate Form B3 prepared by the method of Example 3 was added as seed crystals, and stirred for 12 hours at room temperature. The solid was collected by filtration and dried under vacuum to yield a yellowish zanomeline pamoate product (79% yield). The product was tested by XRPD, DSC, and TGA, and was confirmed to be zanomeline pamoate Form B3.

[0298] Example 11: Preparation of zanomeline pamoate Form B3 (Method 9)

[0299] The crude zanomeline pamoate prepared according to the method of Example 2 was placed in acetone-ethyl acetate (3:1, v / v) at a ratio of 1 g of crude zanomeline pamoate to 10 mL of solvent and stirred at room temperature for 5 minutes. Seed crystals of zanomeline pamoate having Form B3, prepared according to the method of Example 3, were added and the mixture was stirred at room temperature for 12 hours. The solids were collected by filtration and dried under vacuum to produce a yellowish zanomeline pamoate product (84% yield). The product was tested by XRPD, DSC and TGA and was confirmed to be zanomeline pamoate having Form B3.

[0300] Example 12: Preparation of zanomeline pamoate having Form B3 (Method 10)

[0301] The crude zanomeline pamoate prepared according to the method of Example 2 was placed in acetone-ethyl acetate (2:1, v / v) at a ratio of 1 g of crude zanomeline pamoate to 10 mL of solvent and stirred at room temperature for 5 minutes. Seed crystals of zanomeline pamoate having Form B3, prepared according to the method of Example 3, were added and the mixture was stirred at room temperature for 12 hours. The solids were collected by filtration and dried under vacuum to produce a yellowish zanomeline pamoate product (86% yield). The product was tested by XRPD, DSC and TGA and was confirmed to be zanomeline pamoate having Form B3.

[0302] Example 13: Preparation of zanomeline pamoate having Form B3 (Method 11)

[0303] The crude zanomeline pamoate prepared according to the method of Example 2 was placed in acetone-ethyl acetate (1:1, v / v) at a ratio of 1 g of crude zanomeline pamoate to 10 mL of solvent and stirred at room temperature for 5 minutes. Seed crystals of zanomeline pamoate having Form B3, prepared according to the method of Example 3, were added and the mixture was stirred at room temperature for 12 hours. The solids were collected by filtration and dried under vacuum to produce a yellowish zanomeline pamoate product (81% yield). The product was tested by XRPD, DSC and TGA and was confirmed to be zanomeline pamoate having Form B3.

[0304] Example 14: Preparation of zanomeline pamoate having Form B3 (Method 12)

[0305] The crude zanomeline pamoate prepared in Example 2 was suspended in acetone-ethyl acetate (1 :2, v / v) at a ratio of 1 g: 10 mL solvent, and stirred for 5 min at room temperature. Zanomeline pamoate with Form B3 prepared in Example 3 was added as seed crystals, and stirred for 12 h at room temperature. The solid was collected by filtration and dried under vacuum to give a yellowish zanomeline pamoate product (yield 78%). The product was tested by XRPD, DSC and TGA, and confirmed to be zanomeline pamoate with Form B3 as well.

[0306] Example 15: Preparation of zanomeline pamoate with Form B3 (Method 13)

[0307] The crude zanomeline pamoate prepared in Example 2 was suspended in acetone-ethyl acetate (1 :3, v / v) at a ratio of 1 g: 10 mL solvent, and stirred for 5 min at room temperature. Zanomeline pamoate with Form B3 prepared in Example 3 was added as seed crystals, and stirred for 12 h at room temperature. The solid was collected by filtration and dried under vacuum to give a yellowish zanomeline pamoate product (yield 74%). The product was tested by XRPD, DSC and TGA, and confirmed to be zanomeline pamoate with Form B3 as well.

[0308] Example 16: Preparation of zanomeline pamoate with Form B3 single crystal

[0309] Zanomeline pamoate with Form B3 prepared in Example 3 (20 mg) was added to a mixed solvent of ACN and H2O (6 ml, 1 : 1, v / v) and sonicated for 5 min. The filtrate was filtered through a 0.22 μιη microporous filter and the filtrate was left to stand in a 10 ml glass vial to evaporate the solvent. Blocky single crystals were obtained after 2 days. The single crystal was tested by XRPD and the XRPD pattern was fitted, and confirmed to be zanomeline pamoate with Form B3 as well. The crystal structure parameters of Form B3 are shown in Table 2, and the crystal is monoclinic without solvate.

[0310] Table 2. Crystal structure parameters of Form B3

[0311] The connection mode of zanomeline and pamoic acid molecules in Form B3 is shown in Figure 1 1A, and the molecules are built together by π-π stacking of the benzene ring in pamoic acid (PA) and the thiadiazole ring in zanomeline (XAN), and weak intermolecular hydrogen bonding. In addition, the fitted XRPD pattern of single crystal B3 is shown in Figure 1 1B, which is consistent with the XRPD pattern of Form B3, with only slight differences at medium to high diffraction angles, which can be caused by the difference in testing temperature.

[0312] Example 17: Preparation of zanomeline pamoate salt with Form E (Method 1)

[0313] The crude zanomeline pamoate salt prepared by the method in Example 2 was suspended in a mixed solution of ACN and DCM (2:1, v / v) at a ratio of 1 g:10 mL, and stirred at 50 °C for 12 h. After cooling to room temperature, the solid was collected by filtration and dried under vacuum to obtain a yellowish zanomeline pamoate salt product (yield 70%, HPLC purity 98.3%).

[0314] 1 H-NMR (500 MHz, DMSO-d6): δ 8.34 (s, 2H), 8.18 (d, J = 8.6 Hz, 2H), 7.77 (dd, J = 8.2, 1.3 Hz, 2H), 7.26 (ddd, J = 8.4, 6.7, 1.4 Hz, 2H), 7.19-7.15 (m, 1H), 7.13 (ddd, J = 7.9, 6.7, 1.0 Hz, 2H), 4.76 (s, 2H), 4.46 (t, J = 6.6 Hz, 2H), 4.20 (s, 2H), 3.36 (m, 2H), 2.97 (s, 3H), 2.68 (d, J = 5.9 Hz, 2H), 1.80 (p, J = 6.7 Hz, 2H), 1.42 (s, 2H), 1.32 (pd, J = 7.3, 6.5, 3.2 Hz, 4H), 0.96-0.82 (m, 3H).

[0315] The obtained product was found to exist in a crystalline form after XRPD, DSC and TGA tests, and thus the corresponding crystal form was named as zanomeline pamoate salt Form E (abbreviated as Form E). The XRPD, DSC and TGA patterns of Form E are substantially shown in FIG. 5, FIG. 6 and FIG. 7, respectively, and the peak position and intensity of the characteristic diffraction peaks in the XRPD pattern are shown in Table 3, wherein the error range of the 2θ angle value is ±0.2°.

[0316] Table 3. Peak position and intensity of characteristic diffraction peaks in the XRPD pattern of Form E

[0317] Example 18: Preparation of zanomeline pamoate salt with Form E (Method 2)

[0318] The crude zanomeline pamoate prepared in Example 2 was suspended in a mixed solution of ACN and DCM (1 : 1, v / v) at a ratio of 1 g: 10 mL solvent, and stirred at room temperature for 17 h. The solid was collected by filtration and dried under vacuum to give a yellowish zanomeline pamoate product (yield 68%). The product was tested by XRPD, DSC and TGA, and was confirmed to be zanomeline pamoate with Form E.

[0319] Further research was carried out on the methods in Examples 17 and 18 to investigate whether there was a certain conversion relationship between Form E and Form B3. It was subsequently found that the two forms could indeed be obtained in the same recrystallization system, i.e. a mixed solution of ACN and DCM (2: 1 v / v or 1 : 1 v / v), first appearing as metastable Form E, and then under certain conditions (e.g. continuing to beat for a long time) stable Form B3. In addition, it was found that the introduction of Form B3 as a seed could reduce the nucleation energy, thereby allowing Form B3 to form rapidly.

[0320] Example 19: Stability test of zanomeline pamoate with Form B3 / Form E

[0321] Zanomeline pamoate with Form B3 (prepared according to the method in Example 3) and zanomeline pamoate with Form E (prepared according to the method in Example 11) were respectively left to stand open and flat, and subjected to a stability test under high temperature (40, 60°C), high humidity (92.5% RH), light (4500 ± 500 Lux) conditions, and the zanomeline pamoate form and related substance content at different sampling times (0, 10, 30 days) were determined, with the results shown in Tables 4 and 5, respectively. The XRPD changes of Form B3 are shown in Figure 12, and the XRPD changes of Form E are shown in Figure 13.

[0322] Table 4. Form stability data for Form B3 and Form E

[0323] Table 5. Chemical stability data for Form B3 and Form E

[0324] From the above experiments, it can be seen that the XRPD patterns of Form B3 and Form E of the present disclosure are essentially the same under high temperature, high humidity and light conditions, and there is no significant change in the purity of zanomeline, indicating that Form B3 and Form E have very good stability and good prospects for drug development.

[0325] Example 20: Intrinsic dissolution rate (IDR) test of zanomeline pamoate salt with crystal form B3 / crystal form E

[0326] Zanomeline pamoate salt with crystal form B3 (prepared according to the method in Example 3), zanomeline pamoate salt with crystal form E (prepared according to the method in Example 8) were subjected to intrinsic dissolution rate test.

[0327] The test conditions were as follows: die diameter: 4 mm; sample amount: 50 mg; tabletting process: 234 MPa 1 min; dissolution medium: 0.3 mg / mL SDS-containing aqueous PBS solution (pH = 7.4); volume: 500 ml; temperature: 37 °C; rotation speed: 50 rpm. The sampling time points were set at 15, 30, 45, 60, 75 and 90 min, and each sampling volume was 4 ml, which was filtered through a 0.22 μm microporous filter and subjected to HPLC injection analysis.

[0328] The IDR test results are shown in Table 6, the IDR test results of crystal form B3 are shown in Figure 14, and the IDR test results of crystal form E are shown in Figure 15.

[0329] Table 6. Intrinsic dissolution rate data of crystal form B3 and crystal form E

[0330] Intrinsic dissolution rate can dynamically reflect the dissolution behavior of a drug in a dissolution medium, and is one of the important parameters of the physicochemical properties of a drug, and belongs to the inherent characteristics of a drug. Zanomeline pamoate salt with crystal form E and crystal form B3 has very low intrinsic dissolution rate, and has obvious clinical application value in the release of controlled-release drugs and the adjustment of pharmacokinetic parameters. Compared with crystal form E, crystal form B3 has a lower IDR value, and theoretically, the slow-release effect of zanomeline will be more obvious, and therefore, the pharmacokinetic study thereof was performed.

[0331] According to the verification of the present disclosure, zanomeline pamoate salt (particularly crystal form B3) can bring about a relatively ideal slow-release effect, and can improve the tolerance of patients to medication. In addition, the inventors found that the development of parenteral administration formulations (such as injection suspension formulations) suitable for zanomeline pamoate salt can solve the obvious gastrointestinal side effects caused by oral zanomeline tartrate, and at the same time, can avoid the serious first-pass effect, so as to achieve the clinical effect of reducing the blood drug difference of patients.

[0332] Example 21: Pharmacokinetic study of zanomeline pamoate salt with crystal form B3

[0333] Compared with oral administration of nalmefene tartrate, the nalmefene pamoate crystal forms A and D in CN114853750A have certain safety and drug release effect in subcutaneous injection test, but the release time is maintained for a short time, in which the half-life of the crystal form A is only 30 h, and the burst release is obvious; the crystal form D is completely released after one week, and the blood concentration of nalmefene falls on the 0 axis.

[0334] Considering that the absorption speed of drugs through the intramuscular injection route is generally faster than that through the subcutaneous injection route, the certain degree of release effect exhibited in the subcutaneous injection test is likely to be unable to be exhibited in the intramuscular injection test (Zuidema J., et al., Release and absorption rates of intramuscularly and subcutaneously injected pharmaceuticals (II) [J], International Journal of Pharmaceutics, 1994, 105 (3): 189-207). In addition, the administration modes of the crystal forms A and D are both subcutaneous injection, and the volume of subcutaneous injection is obviously smaller than that of conventional intramuscular injection, which compresses the space for increasing the drug dose and limits the development design for prolonging the release time.

[0335] In this embodiment, the pharmacokinetics of nalmefene active substance through the intramuscular injection administration route is studied to evaluate the release effect of the nalmefene pamoate suspension with crystal form B3. The oil solution preparation of free base is generally easy to prepare and can be used as a conventional control preparation for intramuscular injection administration, and the oil solution has a certain release effect in application. In this embodiment, the oil solution of nalmefene free base is selected as a control to evaluate the in vivo release effect of the nalmefene pamoate suspension preparation with crystal form B3.

[0336] Experimental materials:

[0337] Male SD rats (body weight 200-300 g), nalmefene pamoate with crystal form B3 (prepared according to the method in embodiment 3), nalmefene (purity 99.33%, self-prepared according to the method in CN114853750A and identified by H-NMR for structure), purified water. 1 H-NMR for structure), purified water.

[0338] Experimental method:

[0339] Twelve rats were randomly divided into two groups (ear numbers, respectively recorded as group A and group B), 6 rats in each group, 3 rats in each cage for feeding, and free feeding.

[0340] The rat thigh lateral muscle injection site was depilated, and group A was administered with a single intramuscular injection (i.m.) of nalmefene sesame oil solution (formulation as shown in Table 7) at a dose of 100 mg / kg (based on the weight of nalmefene free base) using a 1 mL syringe, and the administration volume was 0.5 ml / kg; group B was administered with a single intramuscular injection of nalmefene pamoate salt suspension with crystal form B3 (formulation as shown in Table 7) at a dose of 100 mg / kg (based on the weight of nalmefene free base) using a 1 mL syringe, and the administration volume was 0.5 ml / kg.

[0341] Table 7. Formulation of the preparation

[0342] Groups A and B were taken blood (500 μl) from the orbit into a 2 mL centrifuge tube wetted with sodium heparin at different time points (group A: 1, 2, 4, 6, 10, 24, 48, 72, 96, 120, 144, and 168 h; group B: 1, 2, 4, 6, 10, 24, 48, 72, 96, 120, 144, 168, 192, and 216 h), and after centrifugation, the upper plasma was taken and stored in a -80℃ refrigerator until LC-MS detection.

[0343] The blood concentration-time data were analyzed using non-compartment model and Winnonlin (version 8.1.0) to evaluate the pharmacokinetic (PK) characteristics of the two preparations in rats, and the relevant data are shown in Table 8, and the blood concentration-time curves are shown in Figures 16 and 17.

[0344] Table 8. Pharmacokinetic parameters of different preparations

[0345] Note:

[0346] [1]. Crystal form A is the A crystal form of nalmefene pamoate salt represented by formula II in CN114853750A; in the PK study, SD rats were administered with a single subcutaneous injection (s.c.) of the A crystal form suspension preparation at a dose of 100 mg / kg (based on the weight of nalmefene free base); the PK data are derived from Table 16 in the specification of CN114853750A;

[0347] [2]. Crystal form D is the D crystal form of nalmefene pamoate salt represented by formula III in CN114853750A; in the PK study, SD rats were administered with a single subcutaneous injection (s.c.) of the D crystal form suspension preparation at a dose of 100 mg / kg (based on the weight of nalmefene free base); the PK data are derived from Table 16 in the specification of CN114853750A.

[0348] In this embodiment, the sesame oil solution of nemonapride is used as a control group for intramuscular injection. Although the oil preparation has certain drug release characteristics, the drug half-life is 35.2 hours, but this slow release rate does not achieve the ideal long-acting slow release effect, and the release of nemonapride is still relatively fast, T max is 1 hour, and C max is as high as 302.9 ng / mL. Compared with the oil preparation control group, nemonapride in the crystal form B3 suspension achieves good slow release effect, C max is only 37.9 ng / mL, which is significantly lower than the oil preparation and the crystal form A suspension in CN114853750A. Moreover, more unexpectedly, in the PK test for 9 days, the crystal form B3 suspension group does not obtain T 1 / 2 value, and the blood drug concentration still maintains in the steady state interval of 10-20 ng / mL, which is significantly better than the oil preparation, the crystal form A suspension and the crystal form D suspension in CN114853750A.

[0349] In summary, compared with the slow release effect of the crystal form A and the crystal form D suspensions in CN114853750A by subcutaneous injection, the crystal form B3 suspension by intramuscular injection has more obvious slow release effect in vivo. The good slow release effect will be beneficial to the application of the crystal form B3 to more long-acting slow release administration, reduce the administration frequency of schizophrenic patients, and increase the compliance of patients.

[0350] Example 22: In-vivo stability study of nemonapride pamoate with crystal form B3

[0351] This embodiment is carried out after the SD rats are intramuscularly injected with the drug for 216 hours in Example 15. After the rats are sacrificed, the muscles at the injection site are taken out, the drug remaining at the injection site is taken out, and Raman scanning is performed. As shown in FIG. 18, the Raman spectrum of the drug remaining in vivo is the same as that of the crystal form B3 control (prepared by the method in Example 3).

[0352] Generally, the change of crystal form will directly reflect the change of Raman spectrum. In this embodiment, the crystal form does not change after the crystal form B3 is released in vivo for 216 hours, which indicates that the crystal form B3 has good in-vivo stability.

[0353] Example 23: Toxic side effect study of nemonapride pamoate with crystal form B3

[0354] Experimental materials:

[0355] Male SD rats (body weight 200-300 g), nemonapride pamoate with crystal form B3 (prepared according to the method in Example 3), nemonapride, purified water.

[0356] Experimental method:

[0357] Twelve rats were randomly divided into two groups (ear numbers, denoted as group A and group B), 6 rats in each group, 3 rats in each cage for feeding, and free feeding.

[0358] The rats were injected with 1 mL of the drug at a dose of 100 mg / kg (based on the weight of the free base of zanoterol) in the form of zanoterol sesame oil solution (formulation as shown in Table 7) for single intramuscular injection (i.m.) with a volume of 0.5 ml / kg. Group B was injected with 1 mL of the drug at a dose of 100 mg / kg (based on the weight of the free base of zanoterol) in the form of zanoterol sesame oil solution (formulation as shown in Table 7) for single intramuscular injection (i.m.) with a volume of 0.5 ml / kg.

[0359] The rats were observed for their mental state before and after administration, and the salivation of the rats in each group was observed after administration. The number of salivating rats was recorded, and the observation was continued for 9 days. If any abnormality occurred before and during administration, it should be recorded in time. The specific results are shown in Table 9.

[0360] Table 9. Side effects induced by different formulations

[0361] Example 5 of CN114853750A was administered to 6 SD rats by gavage with zanoterol tartrate aqueous solution at a dose of 50 mg / kg (based on the weight of the free base of zanoterol) twice a day for 7 consecutive days, with an interval of 8 hours between the two administrations, and the salivation of the rats after administration was observed and recorded. The results showed that on the day of administration, 1 rat was observed to have salivation for 5-20 minutes during the 30-60 minute period after administration, 2 rats were observed to have salivation 1 day after administration, 5 rats were observed to have salivation 2 days after administration, and 6 rats were observed to have salivation 4 days after administration, until the end of the experiment, indicating that oral administration of zanoterol has relatively obvious toxic and side effects.

[0362] In this embodiment, 1 rat in group A had salivation and 2 rats had eye wetness as side effects after intramuscular injection of zanoterol sesame oil solution on day 0 of administration. Among them, 1 rat began to have salivation 1 hour after administration, and the symptoms disappeared 2 hours later. In addition, 2 rats had eye wetness symptoms 1-4 hours after administration, and then recovered to normal. These side effects are related to the stimulation of peripheral muscarinic receptors by zanoterol. Group B did not find any side effects after intramuscular injection of zanoterol tartrate suspension with crystal form B3, indicating that the administration of crystal form B3 by injection can reduce the toxic and side effects caused by the stimulation of peripheral muscarinic receptors, and has good safety.

[0363] Example 24: Preparation of deuterated zanomeline pamoate salt having crystalline Form d-B3

[0364] 1) Preparation of deuterated zanomeline hydrochloride salt

[0365] A 4M solution of hydrochloric acid in 1,4-dioxane (1.78 mL, containing 7.1 mmol of HC1, 1 eq) was added dropwise to a solution of 2 g of deuterated zanomeline (7.1 mmol) in DCM (20 mL) and stirred at 25 °C for 12 h. The reaction solution was added dropwise to THF and stirred, crystallized, filtered, and dried to obtain white to off-white deuterated zanomeline hydrochloride salt solid (yield 29%).

[0366] 1 H-NMR (500 MHz, Chloroform-d): δ 12.84 (s, 1H), 7.26-7.22 (m, 1H), 4.49-4.42 (m, 3H), 3.80-3.75 (m, 1H), 3.54-3.53 (m, 1H), 3.21-3.16 (m, 1H), 3.10-3.00 (m, 1H), 2.57-2.53 (m, 1H), 1.85-1.78 (m, 2H), 1.44-1.30 (m, 6H), 0.88 (t, J = 7.2 Hz, 3H).

[0367] 2) Preparation of crude deuterated zanomeline pamoate salt

[0368] Deuterated zanomeline hydrochloride salt (0.796 g, 2.5 mmol) was added to methanol (14 mL) and stirred at room temperature to form a solution of deuterated zanomeline hydrochloride salt; pamoic acid disodium salt monohydrate (1.081 g, 2.5 mmol, 1 eq) was added to water (55 mL) and stirred at room temperature to form a solution of pamoic acid disodium salt; the solution of pamoic acid disodium salt was added dropwise to the solution of deuterated zanomeline hydrochloride salt and stirred at room temperature for 12 h, a precipitate was separated out, the filter cake was washed with water, and the filter cake was dried at 30 °C under vacuum for 12 h to obtain a light yellow crude deuterated zanomeline pamoate salt (yield 93%). The molar ratio of deuterated zanomeline to pamoic acid was determined to be 1 : 1 by HPLC and H-NMR, i.e., the obtained product was a compound having a structure as shown in Formula II. 1 H-NMR (500 MHz, Chloroform-d): δ 12.84 (s, 1H), 7.26-7.22 (m, 1H), 4.49-4.42 (m, 3H), 3.80-3.75 (m, 1H), 3.54-3.53 (m, 1H), 3.21-3.16 (m, 1H), 3.10-3.00 (m, 1H), 2.57-2.53 (m, 1H), 1.85-1.78 (m, 2H), 1.44-1.30 (m, 6H), 0.88 (t, J = 7.2 Hz, 3H).

[0369] 1H-NMR (500 MHz, DMSO-d6): δ 8.23 (s, 2H), 8.17 (d, J = 8.6 Hz, 2H), 7.68 (dd, J = 8.2, 1.3 Hz, 2H), 7.18 (ddd, J = 8.5, 6.7, 1.4 Hz, 2H), 7.16-7.13 (m, 1H), 7.05 (ddd, J = 7.9, 6.8, 1.0 Hz, 2H), 4.71 (s, 2H), 4.46 (t, J = 6.5 Hz, 2H), 4.11 (s, 2H), 3.28 (d, J = 7.3 Hz, 2H), 2.66 (m, 2H), 1.80 (p, J = 6.6 Hz, 2H), 1.42 (m, 2H), 1.32 (dq, J = 6.6, 3.4 Hz, 4H), 0.91-0.83 (m, 3H).

[0370] 3) Preparation of deuterated zanolimum pamate salt having crystalline form d-B3

[0371] The crude deuterated zanolimum pamate salt was placed in acetone, wherein the ratio of the crude deuterated zanolimum pamate salt to the solvent was 1 g: 10 mL, stirred at room temperature for 24 h, the solid was collected by filtration, and dried under vacuum to obtain a light yellow deuterated zanolimum pamate salt product (yield 76%).

[0372] After the obtained product was tested by XRPD, DSC and TGA, it was found that the light yellow solid existed in a crystalline form, and therefore the corresponding crystalline form was named as deuterated zanolimum pamate salt crystalline form d-B3 (abbreviated as crystalline form d-B3), and the XRPD, DSC and TGA patterns thereof were substantially as shown in FIGS. 8, 9 and 10, respectively.

[0373] It should be noted that although the embodiments of the present disclosure are introduced and described above, those skilled in the art can understand that the present disclosure should not be limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present disclosure shall be included in the protection scope of the present disclosure.

Claims

1. A pamoate of nomomeline as shown in Formula I, The pamoate of nomomelin has crystal form B3, and crystal form B3 satisfies at least one of conditions i)-iii): i) The X-ray powder diffraction pattern of the crystal form B3 has characteristic diffraction peaks at the following 2θ angles: 14.06±0.2°, 17.48±0.2°, 20.86±0.2° and 22.42±0.2°; ii) The differential scanning calorimetry (DSC) spectrum of crystal form B3 shows an endothermic peak at 211.0 ± 5 °C; and, iii) The Raman spectrum of crystal form B3 has a characteristic peak at the following shift: 1685±0.5cm -1 1652±0.5cm -1 1577±0.5cm -1 1448±0.5cm -1 1400±0.5cm -1 1371±0.5cm -1 1355±0.5cm -1 1310±0.5cm -1 1270±0.5cm -1 1027±0.5cm -1 858±0.5cm -1 790±0.5cm -1 736±0.5cm -1 688±0.5cm -1 646±0.5cm -1 550±0.5cm -1 457±0.5cm -1 436±0.5cm -1 425±0.5cm -1 336±0.5cm -1 240±0.5cm -1 166±0.5cm -1 146±0.5cm -1 and 100±0.5cm -1 .

2. The pamoate citrate according to claim 1, characterized in that, The X-ray powder diffraction pattern of the crystal form B3 also has a characteristic diffraction peak at at least one of the following 2θ angles: 7.80±0.2°, 7.96±0.2°, 10.38±0.2°, 21.04±0.2°, 24.12±0.2°, 28.56±0.2° and 28.96±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal form B3 also has a characteristic diffraction peak at at least one of the following 2θ angles: 12.88±0.2°, 13.74±0.2°, 17.78±0.2°, 20.56±0.2°, 23.32±0.2°, 23.64±0.2°, 26.36±0.2°, and 29.98±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form B3 also has a characteristic diffraction peak at at least one of the following 2θ angles: 8.70±0.2°, 15.62±0.2°, 16.10±0.2°, 24.84±0.2° and 27.34±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form B3 also has a characteristic diffraction peak at at least one of the following 2θ angles: 11.00±0.2°, 17.06±0.2°, 18.88±0.2°, 22.02±0.2°, 25.30±0.2°, and 26.00±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form B3 is basically as shown in Figure 1.

3. The pamoate citrate according to claim 1 or 2, characterized in that, The differential scanning calorimetry (DSC) spectrum of crystal form B3 is basically shown in Figure 2.

4. The pamoate chamole according to any one of claims 1 to 3, characterized in that, The Raman spectrum of crystal form B3 is shown in Figure 4.

5. The pamoate chamole according to any one of claims 1 to 4, characterized in that, The crystal form B3 also satisfies condition iv): iv) The thermogravimetric analysis spectrum of the crystal form B3 is basically shown in Figure 3.

6. A pamoate of nomomeline as shown in Formula I, The pamoate of nomomelin has crystal form E, and crystal form E satisfies at least one of conditions i')-ii'): The X-ray powder diffraction pattern of crystal form E described in i') exhibits characteristic diffraction peaks at the following 2θ angles: 7.94±0.2°, 10.34±0.2°, 25.48±0.2°, and 26.44±0.2°; and The differential scanning calorimetry spectrum of crystal form E shows an endothermic peak at 149.1 ± 5 °C.

7. The pamoate chamoxetine according to claim 6, characterized in that, The X-ray powder diffraction pattern of the crystal form E also has a characteristic diffraction peak at at least one of the following 2θ angles: 6.28±0.2°, 8.70±0.2°, and 22.40±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal form E also has a characteristic diffraction peak at at least one of the following 2θ angles: 11.44±0.2°, 12.96±0.2°, 15.92±0.2° and 16.68±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form E also has a characteristic diffraction peak at at least one of the following 2θ angles: 14.54±0.2°, 18.92±0.2°, 20.38±0.2°, 20.78±0.2° and 21.78±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form E also has a characteristic diffraction peak at at least one of the following 2θ angles: 15.46±0.2°, 17.38±0.2°, 20.04±0.2° and 21.20±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form E is basically as shown in Figure 5.

8. The pamoate citrate according to claim 6 or 7, characterized in that, The differential scanning calorimetry (DSC) spectrum of crystal form E is basically shown in Figure 6.

9. The pamoate of nomerin according to any one of claims 6 to 8, characterized in that, The crystal form E also satisfies condition iii'): The thermogravimetric analysis spectrum of crystal form E described in iii') is basically shown in Figure 7.

10. A method for preparing pamoate according to any one of claims 1 to 5, comprising the following steps: 1) Preparation of crude pramosiderin pamoate; and 2) Recrystallization of the crude pamoate of the pamoate.

11. The preparation method according to claim 10, characterized in that, The preparation of the crude pramosiderin pamoate comprises the following steps: 1-1) Dissolve the water-soluble salt of zenomeline in solvent A to obtain a water-soluble salt solution of zenomeline; 1-2) Dissolve the peramic acid salt in solvent B to obtain a peramic acid salt solution; and 1-3) Mix the zanomeline water-soluble salt solution with the pamoate solution, optionally stirring, to precipitate a solid.

12. The preparation method according to claim 11, characterized in that, The water-soluble salts of zenomeline described in step 1-1) and / or the pamoate salts described in step 1-2) can each exist independently as solvates, preferably hydrates, more preferably monohydrates.

13. The preparation method according to claim 11 or 12, characterized in that, The molar ratio of the water-soluble salt of phenomeline described in step 1-1) to the pamoate salt described in step 1-2) is 1:0.9-1:1.3, preferably 1:

1.

14. The preparation method according to any one of claims 11 to 13, characterized in that, In step 1-1), the water-soluble salt of zenomeline is a salt obtained by reacting zenomeline with a pharmaceutically acceptable water-soluble acid; Preferably, the pharmaceutically acceptable water-soluble acid is hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, nitric acid, tartaric acid, oxalic acid, citric acid, maleic acid, lactic acid, malic acid, fumaric acid, gluconic acid, glutamic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, mandelic acid, methanesulfonic acid, mucoic acid, pantothenic acid, saccharinic acid, or succinic acid, preferably hydrochloric acid or tartaric acid.

15. The preparation method according to any one of claims 11 to 14, characterized in that, In step 1-1), solvent A is one or a combination of two or more of methanol, isopropanol, N,N-dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,3-dioxane and water, preferably one or a combination of two or more of methanol, tetrahydrofuran and water, more preferably methanol, water or a combination thereof.

16. The preparation method according to any one of claims 11 to 15, characterized in that, In step 1-1), the ratio of the amount of the water-soluble salt of phenomenal to the amount of solvent A is 1g:10-20ml, preferably 1g:12-18ml.

17. The preparation method according to any one of claims 11 to 16, characterized in that, In steps 1-2), the peramate salt is a salt obtained by reacting peramic acid with a pharmaceutically acceptable water-soluble base; Preferably, the pharmaceutically acceptable water-soluble base is sodium hydroxide, potassium hydroxide, lithium hydroxide, or ammonia, with sodium hydroxide being the most preferred. or, In steps 1-2), the pamoate is a disodium pamoate, a dipotassium pamoate, a dilithium pamoate, or a diammonium pamoate, preferably a disodium pamoate.

18. The preparation method according to any one of claims 11 to 17, characterized in that, In steps 1-2), solvent B is one or a combination of two or more of methanol, isopropanol, tetrahydrofuran and water, preferably water.

19. The preparation method according to any one of claims 11 to 18, characterized in that, In steps 1-2), the ratio of the amount of peramic acid salt to solvent B is 1g:20-70ml, preferably 1g:40-60ml.

20. The preparation method according to any one of claims 11 to 19, characterized in that, In steps 1-3), The mixing time is 6-24 hours, preferably 12-24 hours; And / or, The mixing temperature is room temperature.

21. The preparation method according to any one of claims 10 to 20, characterized in that, The recrystallization of the crude tamsulosin pamoate comprises the following steps: 2-1) The crude pamoate of zenomeline is suspended in solvent C and optionally stirred to precipitate crystals.

22. The preparation method according to claim 21, characterized in that, In step 2-1), the solvent C is one or a combination of two or more of methanol, acetone, ethyl acetate, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, or water. Preferably, the solvent C is one of the following solvents: A mixture of tetrahydrofuran and ethyl acetate, wherein the volume ratio of tetrahydrofuran to ethyl acetate is 1:1 to 3:1, preferably 3:1; Tetrahydrofuran; A mixture of acetonitrile and dichloromethane, wherein the volume ratio of acetonitrile to dichloromethane is 1:1 to 3:1, preferably 1:1; A mixture of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 1:1 to 3:1, preferably 1:1; Methanol; acetone; A mixture of acetone and water, wherein the volume ratio of acetone to water is 5:1 to 1:2, preferably 1:1; A mixture of acetone and diethyl ether, wherein the volume ratio of acetone to water is 5:1 to 1:2, preferably 1:1; Ethyl acetate; A mixture of acetone and ethyl acetate, wherein the volume ratio of acetone to ethyl acetate is 5:1 to 1:5, preferably 3:1 to 1:3, and more preferably 3:

1.

23. The preparation method according to claim 21 or 22, characterized in that, In step 2-1), the ratio of the crude pamoate to solvent C is 1g:5-20ml, preferably 1g:10mL.

24. The preparation method according to any one of claims 21 to 23, characterized in that, In step 2-1), The suspension time is 6-72 hours, preferably 8-48 hours; And / or, The temperature of the suspension is 10-60℃, preferably 20-60℃, and more preferably room temperature.

25. A method for preparing pamoate according to any one of claims 6 to 9, comprising the following steps: 1') Preparation of crude pramosiderin pamoate; and 2') Recrystallization of the crude pamoate of 2') 26. The preparation method according to claim 25, characterized in that, The preparation of the crude tamsulosin pamoate is the same as that of the crude tamsulosin pamoate described in claim 11.

27. The preparation method according to claim 25 or 26, characterized in that, The recrystallization of the crude tamsulosin pamoate comprises the following steps: 2'-1) The crude pamoate of zenomeline is suspended in solvent D and optionally stirred to precipitate crystals.

28. The preparation method according to claim 27, characterized in that, In step 2'-1), the solvent D is one or a combination of two or more of methanol, acetone, ethyl acetate, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether or water, preferably acetonitrile, dichloromethane or a combination thereof, more preferably a combination of acetonitrile and dichloromethane; Preferably, the solvent D is a mixture of acetonitrile and dichloromethane, wherein the volume ratio of acetonitrile to dichloromethane is 1:1-3:1, preferably 2:

1.

29. The preparation method according to claim 27 or 28, characterized in that, In step 2'-1), the ratio of the crude pamoate to solvent D is 1g:5-20mL, preferably 1g:10mL.

30. The preparation method according to any one of claims 27 to 29, characterized in that, In step 2'-1), The suspension time is 1-48 hours, preferably 6-24 hours; And / or, The temperature of the suspension is 10-70℃, preferably 20-60℃, more preferably 40-60℃ or room temperature.

31. A deuterated pamoate of nomeropenem as shown in Formula II, The deuterated pamoate has a crystal form d-B3, and the crystal form d-B3 satisfies at least one of conditions i”)-ii”): The X-ray powder diffraction pattern of the crystal form d-B3 described in i”) exhibits characteristic diffraction peaks at the following 2θ angles: 14.06±0.2°, 17.48±0.2°, 20.86±0.2°, and 22.42±0.2°; and The differential scanning calorimetry spectrum of the crystal form d-B3 described in ii”) shows an endothermic peak at 206.6±5℃.

32. The deuterated pamoate according to claim 31, characterized in that, The X-ray powder diffraction pattern of the crystal form d-B3 also has a characteristic diffraction peak at at least one of the following 2θ angles: 7.80±0.2°, 7.96±0.2°, 10.38±0.2°, 21.04±0.2°, 24.12±0.2°, 28.56±0.2° and 28.96±0.2°; Preferably, the X-ray powder diffraction pattern of the crystal form d-B3 also has a characteristic diffraction peak at at least one of the following 2θ angles: 12.88±0.2°, 13.74±0.2°, 17.78±0.2°, 20.56±0.2°, 23.32±0.2°, 23.64±0.2°, 26.36±0.2°, and 29.98±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form d-B3 also has a characteristic diffraction peak at at least one of the following 2θ angles: 8.70±0.2°, 15.62±0.2°, 16.10±0.2°, 24.84±0.2° and 27.34±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form d-B3 also has a characteristic diffraction peak at at least one of the following 2θ angles: 11.00±0.2°, 17.06±0.2°, 18.88±0.2°, 22.02±0.2°, 25.30±0.2°, and 26.00±0.2°; More preferably, the X-ray powder diffraction pattern of the crystal form d-B3 is basically as shown in Figure 8.

33. The deuterated pamoate according to claim 31 or 32, characterized in that, The differential scanning calorimetry (DSC) spectrum of the crystal form d-B3 is basically shown in Figure 9.

34. The deuterated pamoate according to any one of claims 31 to 33, characterized in that, The crystal form d-B3 also satisfies condition iii): The thermogravimetric analysis spectrum of the crystal form d-B3 described in iii” is basically shown in Figure 10.

35. A method for preparing deuterated pamoate according to any one of claims 31 to 34, comprising the following steps: 1”) Preparation of crude deuterated pamoate; and 2”) recrystallization of the crude deuterated pamoate.

36. A pharmaceutical composition comprising one or more of the following active pharmaceutical ingredients: A) Parmolate salt according to any one of claims 1 to 5; B) pamoate according to any one of claims 6 to 9; and C) Deuterated pamoate according to any one of claims 31 to 34; Preferably, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients; More preferably, the pharmaceutically acceptable excipients include diluents (or fillers), lubricants, binders, disintegrants, stabilizers, surfactants, flavoring agents, odorants, solvents, cosolvents, pH adjusters, and osmotic pressure adjusters.

37. A pharmaceutical preparation comprising one or more of the following components: A) Parmolate salt according to any one of claims 1 to 5; B) Parmolate salt according to any one of claims 6 to 9; C) Deuterated pamoate according to any one of claims 31 to 34; and D) The pharmaceutical composition according to claim 36; Preferably, the pharmaceutical formulation is made from janomyl pamoate according to any one of claims 1 to 5, janomyl pamoate according to any one of claims 6 to 9, deuterated janomyl pamoate according to any one of claims 31 to 34, or the pharmaceutical composition according to claim 36; And / or, Preferably, the pharmaceutical preparation includes tablets, capsules, granules, lozenges, suppositories, ointments, creams, injections, suspensions, mixtures, tinctures, liniments, lotions, inhalers, and aerosols. It is more preferably a pharmaceutical preparation suitable for injection, more preferably a pharmaceutical preparation suitable for intramuscular or subcutaneous injection, and even more preferably a pharmaceutical preparation suitable for intramuscular injection. And / or, The drug formulation can be administered orally, by injection, by local administration, and by inhalation, with injection being preferred, intramuscular injection or subcutaneous injection being more preferred, and intramuscular injection being even more preferred. And / or, Based on the weight of the free base in the zanomelin pamoate according to any one of claims 1 to 5, the zanomelin pamoate according to any one of claims 6 to 9, or the deuterated zanomelin pamoate according to any one of claims 31 to 34, the dosage of the pharmaceutical preparation is from about 1 mg to about 3000 mg, or from about 1 mg to about 2000 mg, or from about 1 mg to about 1000 mg, or from about 1 mg to about 300 mg, or from about 1 mg to about 200 mg, or from about 1 mg to about 100 mg, or from about 1 mg to about 30 mg, or from about 1 mg to about 20 mg, or from about 1 mg to about 10 mg; And / or, The drug preparation is administered at a frequency of 4 times / day, or 3 times / day, or 2 times / day, or 1 time / day, or 1 time / two days, or 2 times / week, or 1 time / week, or 1 time / two weeks, or 1 time / month, or 1 time / two months, or 1 time / three months.

38. Use of janomyl pamoate according to any one of claims 1 to 5, janomyl pamoate according to any one of claims 6 to 9, deuterated janomyl pamoate according to any one of claims 31 to 34, the pharmaceutical composition according to claim 36, or the pharmaceutical preparation according to claim 37 in the preparation of a medicament for the prevention and / or treatment of disorders of the central nervous system; Preferably, the central nervous system disorders include schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegenerative diseases (e.g., Dow disease or synucleinosis); More preferably, the central nervous system disorder is schizophrenia or Alzheimer's disease.

39. The zanomilin pamoate according to any one of claims 1 to 5, the zanomilin pamoate according to any one of claims 6 to 9, the deuterated zanomilin pamoate according to any one of claims 31 to 34, the pharmaceutical composition according to claim 36, or the pharmaceutical preparation according to claim 37, for the prevention and / or treatment of central nervous system disorders; Preferably, the central nervous system disorders include schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegenerative diseases (e.g., Dow disease or synucleinosis); More preferably, the central nervous system disorder is schizophrenia or Alzheimer's disease.

40. A method for preventing and / or treating central nervous system disorders, comprising administering to an individual in need (preferably by injection, more preferably by intramuscular or subcutaneous injection, and further preferably by intramuscular injection) zonomorin pamoate according to any one of claims 1 to 5, zonomorin pamoate according to any one of claims 6 to 9, deuterated zonomorin pamoate according to any one of claims 31 to 34, ... The pharmaceutical composition according to claim 36 or the pharmaceutical formulation according to claim 37; Preferably, the central nervous system disorders include schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegenerative diseases (e.g., Dow disease or synucleinosis); More preferably, the central nervous system disorder is schizophrenia or Alzheimer's disease.

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