Xanomeline pamorate, crystal form thereof, preparation method and use

Abstract

The present invention relates to the field of medicinal chemistry, and particularly relates to xanomeline pamolate, which has the structure shown in Formula I. The malate salt of the compound of Formula I has excellent effects in at least one aspect such as physical stability, solubility, hygroscopicity, biological activity, safety, bioavailability, toxicity and side effects.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a pamolate salt of xanomeline, its crystal form and a preparation method thereof, and also includes the application of the pamolate salt of xanomeline and its crystal form in the preparation of drugs for preventing or treating central nervous system disorder diseases. Background Art

[0002] Neurotransmitters are chemical messengers secreted by neurons to facilitate the flow of information and communicate with other cells (such as muscles or nerve-like cells) in the central and peripheral nervous systems. Acetylcholine is one of the key neurotransmitters in the brain, and it has two different receptor classes: muscarinic receptors (M receptors, G protein-coupled receptors) and nicotinic receptors (N receptors, ion channel receptors).

[0003] The M receptor family contains five subtypes from M1 to M5, all of which are expressed in the brain and peripheral tissues and play many key physiological roles in cognitive, behavioral, sensory, motor, and autonomic processes. Disruption of M receptor signaling leads to memory and cognitive impairments in patients with various diseases including schizophrenia and AD, and exacerbates psychosis. Conversely, preclinical and clinical data from third parties indicate that enhancement of M receptor signaling improves these symptoms. In addition, M receptors, especially M1, M2, and M4 receptors, are also considered to be related to analgesia.

[0004] Xanomeline is a partial agonist of muscarinic receptors, which can produce agonist effects on all five subtypes of muscarinic receptors and has no selectivity. It was jointly developed and marketed by Eli Lilly and Company and Novo Nordisk A / S, and is mainly used for the treatment of Alzheimer's disease clinically. The chemical name of xanomeline is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine, and its chemical structural formula is as follows:

[0005]

[0006] Patent document CN94192681.8 discloses that xanomeline can be converted into oxalate, but oxalate has potential side effects on the renal function of patients, so it is not suitable in pharmacy, especially when treating the elderly. It further discloses that among the series of twelve pharmaceutically acceptable acids (the specific names of the pharmaceutically acceptable acids are not disclosed), only xanomeline tartrate has good bioavailability, good handling properties, and a reproducible crystal form.

[0007] Currently, common general knowledge generally teaches that selecting a salt with the desired combination of properties remains a difficult semi-empirical choice that requires a trade-off of the properties of the salt form, but there is still difficulty in evaluating which salt form is most suitable for screening specific candidate drugs.

[0008] The screening of drug salt forms is a difficult semi-empirical choice. The hygroscopicity of drugs can seriously affect the fluidity of drugs and even affect the stability of drugs. The solubility of drugs has a crucial impact on the preparation of pharmaceutical agents, drug dissolution, absorption, etc. However, it is difficult to improve the solubility of drugs without sacrificing the hygroscopicity of drugs to obtain candidate drug salts with appropriate drug stability, solubility, and hygroscopicity.

[0009] In addition, as an M receptor activator, Xanomeline has encouraging therapeutic effects in clinically treating schizophrenia and the psychiatric and related behavioral symptoms of AD patients, but its potential has been limited by cholinergic side effects, including salivation, nausea, dizziness, etc., which are considered to be caused by stimulating M receptors in peripheral nerve tissues. The metabolism of xanomeline in the human body is complex and unpredictable, and xanomeline lacks selectivity for muscarinic receptor subtypes, thus causing difficulties in the drug development of xanomeline.

[0010] Therefore, it is necessary to further search for crystalline salts of xanomeline and their polymorphs that have good therapeutic effects, few side effects, better pharmacokinetic properties suitable for drug formation, and suitable and reliable formulation and preparation characteristics. Summary of the Invention

[0011] The object of the present invention is to provide a xanomeline pamolate represented by formula I, which can be used to prepare a drug for preventing or treating central nervous system disorder diseases, and the xanomeline pamolate has good therapeutic effects, can maintain an effective concentration in the body for a long time, is convenient for administration, has improved drug metabolism properties, improved drug toxic and side effects, and has a high compliance of patients during administration. In addition, the xanomeline pamolate of the present invention has suitable and reliable formulation and preparation characteristics, is stable in storage, and is suitable for preparing into pharmaceutical preparations.

[0012] Another object of the present invention is to provide a crystal form of the xanomeline pamolate represented by formula I, which can have excellent thermodynamic stability and mechanical stability, good repeatability, and is suitable for large-scale commercial production.

[0013] In the first aspect, the present invention provides a xanomeline pamolate represented by formula I.

[0014]

[0015] In some embodiments of the present invention, the xanomeline pamoate shown in Formula I above, wherein x is selected from 0.5 to 2.

[0016] In some embodiments of the present invention, in the compound of Formula I above, x is 0.5, 1.0, 1.5, 2.0.

[0017] In some embodiments of the present invention, in the compound of Formula I above, x is 0.5, 1.0.

[0018] In some embodiments of the present invention, in the compound of Formula I above, x is 1.0, and the structure is as shown in Formula II.

[0019]

[0020] In some embodiments of the present invention, in the compound of Formula I above, x is 0.5, and the structure is as shown in Formula III.

[0021]

[0022] In a second aspect, the present invention provides an A crystal form of xanomeline pamoate shown in Formula II, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 25.235±0.2° and 26.358±0.2°.

[0023] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 17.094±0.2°, 22.555±0.2°, 25.235±0.2° and 26.358±0.2°.

[0024] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 13.308±0.2°, 17.094±0.2°, 22.555±0.2°, 25.235±0.2° and 26.358±0.2°.

[0025] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 13.308±0.2°, 17.094±0.2°, 20.465±0.2°, 22.555±0.2°, 25.235±0.2° and 26.358±0.2°.

[0026] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 13.308±0.2°, 15.891±0.2°, 16.108±0.2°, 17.094±0.2°, 20.465±0.2°, 22.555±0.2°, 25.235±0.2° and 26.358±0.2°.

[0027] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 13.308±0.2°, 15.891±0.2°, 16.108±0.2°, 17.094±0.2°, 19.301±0.2°, 19.637±0.2°, 20.465±0.2°, 21.587±0.2°, 22.555±0.2°, 25.235±0.2° and 26.358±0.2°.

[0028] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 13.308±0.2°, 15.891±0.2°, 16.108±0.2°, 17.094±0.2°, 17.763±0.2°, 19.301±0.2°, 19.637±0.2°, 20.465±0.2°, 21.587±0.2°, 22.555±0.2°, 25.235±0.2°, 25.727±0.2°, 26.358±0.2° and 28.782±0.2°.

[0029] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above A crystal form has characteristic diffraction peaks at the following 2θ angles: 5.838±0.2°, 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 12.107±0.2°, 13.308±0.2°, 13.704±0.2°, 15.891±0.2°, 16.108±0.2°, 17.094±0.2°, 17.763±0.2°, 19.301±0.2°, 19.637±0.2°, 20.465±0.2°, 21.587±0.2°, 22.555±0.2°, 25.235±0.2°, 25.727±0.2°, 26.358±0.2° and 28.782±0.2°.

[0030] In some embodiments of the present invention, the above A crystal form has substantially as Figure 1 shown XRPD pattern.

[0031] In some embodiments of the present invention, the above A crystal form has substantially as Figure 2 shown DSC pattern.

[0032] In some embodiments of the present invention, the differential scanning calorimetry curve of the above A crystal form has endothermic peaks at 85.11 ± 5 °C and 167.56 ± 5 °C.

[0033] In some embodiments of the present invention, the above A crystal form has substantially as Figure 3 shown TGA curve.

[0034] In a third aspect, the present invention provides a B crystal form of xanomeline paminate represented by Formula II, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.415 ± 0.2 °, 10.294 ± 0.2 °, 12.105 ± 0.2 °, 24.032 ± 0.2 °, and 27.797 ± 0.2 °.

[0035] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415 ± 0.2 °, 8.480 ± 0.2 °, 10.294 ± 0.2 °, 12.105 ± 0.2 °, 16.285 ± 0.2 °, 24.032 ± 0.2 °, and 27.797 ± 0.2 °.

[0036] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415 ± 0.2 °, 8.480 ± 0.2 °, 10.294 ± 0.2 °, 12.105 ± 0.2 °, 14.038 ± 0.2 °, 16.285 ± 0.2 °, 24.032 ± 0.2 °, and 27.797 ± 0.2 °.

[0037] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415 ± 0.2 °, 8.480 ± 0.2 °, 10.294 ± 0.2 °, 12.105 ± 0.2 °, 14.038 ± 0.2 °, 16.285 ± 0.2 °, 18.868 ± 0.2 °, 24.032 ± 0.2 °, and 27.797 ± 0.2 °.

[0038] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 14.038±0.2°, 14.748±0.2°, 16.285±0.2°, 18.868±0.2°, 24.032±0.2°, 27.797±0.2° and 29.728±0.2°.

[0039] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 14.038±0.2°, 14.748±0.2°, 16.285±0.2°, 17.862±0.2°, 18.868±0.2°, 19.538±0.2°, 21.095±0.2°, 24.032±0.2°, 27.797±0.2° and 29.728±0.2°.

[0040] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 13.685±0.2°, 14.038±0.2°, 14.748±0.2°, 16.285±0.2°, 17.862±0.2°, 18.868±0.2°, 19.538±0.2°, 20.463±0.2°, 21.095±0.2°, 24.032±0.2°, 24.743±0.2°, 27.542±0.2°, 27.797±0.2°, 29.374±0.2° and 29.728±0.2°.

[0041] In some embodiments of the present invention, the above B crystal form has substantially as Figure 4 shown XRPD pattern.

[0042] In some embodiments of the present invention, the above B crystal form has substantially as Figure 5 shown DSC pattern.

[0043] In some embodiments of the present invention, the differential scanning calorimetry curve of the above B crystal form has an endothermic peak at 129.30±5°C.

[0044] Fourthly, the present invention provides a C crystal form of xanomeline pamolate represented by Formula II, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.292±0.2°, 11.240±0.2°, 15.793±0.2°, 25.707±0.2° and 26.456±0.2°.

[0045] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.292±0.2°, 9.604±0.2°, 11.240±0.2°, 15.793±0.2°, 19.577±0.2°, 25.707±0.2° and 26.456±0.2°.

[0046] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.292±0.2°, 9.604±0.2°, 10.509±0.2°, 11.240±0.2°, 15.793±0.2°, 19.577±0.2°, 25.707±0.2°, 26.456±0.2° and 30.064±0.2°.

[0047] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.292±0.2°, 9.604±0.2°, 10.509±0.2°, 11.240±0.2°, 15.793±0.2°, 19.577±0.2°, 20.898±0.2°, 23.360±0.2°, 25.707±0.2°, 26.456±0.2° and 30.064±0.2°.

[0048] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.292±0.2°, 9.604±0.2°, 10.509±0.2°, 11.240±0.2°, 13.013±0.2°, 15.793±0.2°, 19.577±0.2°, 20.898±0.2°, 22.632±0.2°, 23.360±0.2°, 25.707±0.2°, 26.456±0.2° and 30.064±0.2°.

[0049] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above C crystal form has characteristic diffraction peaks at the following 2θ angles: 6.292±0.2°, 8.105±0.2°, 8.816±0.2°, 9.604±0.2°, 10.509±0.2°, 11.240±0.2°, 13.013±0.2°, 15.793±0.2°, 19.577±0.2°, 20.898±0.2°, 22.632±0.2°, 23.360±0.2°, 25.707±0.2°, 26.456±0.2°, and 30.064±0.2°.

[0050] In some embodiments of the present invention, the above C crystal form has Figure 6 an XRPD pattern substantially as shown.

[0051] In some embodiments of the present invention, the above C crystal form has Figure 7 a DSC pattern substantially as shown.

[0052] In some embodiments of the present invention, the differential scanning calorimetry curve of the above C crystal form has an endothermic peak at 115.09±5°C.

[0053] In a fifth aspect, the present invention provides a D crystal form of xanomeline pamorate represented by Formula III, the X-ray powder diffraction pattern of which has characteristic diffraction peaks at the following 2θ angles: 5.464±0.2°, 11.061±0.2°, 16.562±0.2°, 21.449±0.2°, and 21.101±0.2°.

[0054] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above D crystal form has characteristic diffraction peaks at the following 2θ angles: 5.464±0.2°, 10.748±0.2°, 11.061±0.2°, 16.069±0.2°, 16.562±0.2°, 21.449±0.2°, and 21.101±0.2°.

[0055] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above D crystal form has characteristic diffraction peaks at the following 2θ angles: 5.464±0.2°, 10.748±0.2°, 11.061±0.2°, 12.126±0.2°, 16.069±0.2°, 16.562±0.2°, 21.449±0.2°, and 21.101±0.2°.

[0056] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above D crystal form has characteristic diffraction peaks at the following 2θ angles: 5.464 ± 0.2°, 10.748 ± 0.2°, 11.061 ± 0.2°, 12.126 ± 0.2°, 16.069 ± 0.2°, 16.562 ± 0.2°, 19.047 ± 0.2°, 21.449 ± 0.2°, and 21.101 ± 0.2°.

[0057] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above D crystal form has characteristic diffraction peaks at the following 2θ angles: 5.464 ± 0.2°, 10.748 ± 0.2°, 11.061 ± 0.2°, 12.126 ± 0.2°, 16.069 ± 0.2°, 16.562 ± 0.2°, 19.047 ± 0.2°, 20.977 ± 0.2°, 21.449 ± 0.2°, and 21.101 ± 0.2°.

[0058] In some embodiments of the present invention, the above D crystal form has substantially as Figure 8 the XRPD pattern shown.

[0059] In some embodiments of the present invention, the above D crystal form has substantially as Figure 9 the DSC pattern shown.

[0060] In some embodiments of the present invention, the differential scanning calorimetry curve of the above D crystal form has an endothermic peak at 111.42 ± 5 °C.

[0061] In some embodiments of the present invention, the above D crystal form has substantially as Figure 10 the TGA curve shown.

[0062] The present invention provides a method for preparing xanomeline pamolate represented by formula I, which includes reacting xanomeline tartrate with disodium pamoate.

[0063] The present invention provides a method for preparing xanomeline pamolate represented by formula II, and the method includes the following steps:

[0064] (1) Dissolve xanomeline tartrate in a solvent to obtain a xanomeline tartrate solution;

[0065] (2) Dissolve disodium pamoate in water to obtain a disodium pamoate solution;

[0066] (3) Mix the xanomeline tartrate solution and the disodium pamoate solution, stir and react, and then cool to precipitate a solid;

[0067] Among them, in the preparation method of xanomeline pamolate shown in the above formula II, the molar ratio of the xanomeline tartrate to the disodium pamoate is 1:0.9 - 1.3; preferably, the molar ratio of the xanomeline tartrate to the disodium pamoate is 1:1 - 1.1, such as 1:1, 1:1.05, 1:1.1.

[0068] In some embodiments of the present invention, in the preparation method of xanomeline pamolate shown in the above formula II, in step (1), the solvent is one or more combinations selected from ethanol, methanol, DMF, DMSO, isopropanol, acetone, tetrahydrofuran, acetonitrile and water; preferably, the solvent is one or more combinations selected from methanol, ethanol, tetrahydrofuran and water.

[0069] In some embodiments of the present invention, step (2) can be carried out under heating conditions, and the heating temperature is 30 - 80°C, such as 40 - 60°C.

[0070] In some embodiments of the present invention, the cooling can be to 0 - 30°C, preferably to 0 - 10°C, such as cooling to 5°C. A filtration can be carried out first before cooling.

[0071] In some embodiments of the present invention, stirring is carried out during the cooling process, and the stirring time can be 6 - 24 hours, preferably 8 - 18 hours.

[0072] According to the present invention, after the solid is precipitated, filtration and drying are carried out; in some embodiments of the present invention, before drying, an optional step of washing with a solvent is further included, and the washing solvent is selected from one or more mixtures of ethanol, isopropanol, n-propanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran.

[0073] The present invention provides a preparation method for the A crystal form of xanomeline pamolate shown in formula II, including mixing the xanomeline pamolate shown in formula II with a solvent, stirring, and then cooling to precipitate crystals;

[0074] Among them, the solvent is ethyl acetate, toluene or a mixture thereof; preferably, the solvent is ethyl acetate.

[0075] In some embodiments of the present invention, the stirring temperature is 20 - 60°C; preferably 50 - 60°C.

[0076] In some embodiments of the present invention, the stirring time is 5 - 48 hours, preferably 8 - 24 hours.

[0077] In some embodiments of the present invention, the cooling can be to 0 - 30°C, preferably to 10 - 25°C, such as cooling to 25°C.

[0078] According to the present invention, filtration and drying are carried out after crystal precipitation; in some embodiments of the present invention, a step of optionally washing with a solvent is further included before drying, and the washing solvent is selected from one or more mixtures of ethanol, isopropanol, n-propanol, acetone, ethyl acetate, acetonitrile, and tetrahydrofuran.

[0079] The present invention provides a method for preparing the B crystal form of xanomeline pamolate represented by Formula II, which includes mixing xanomeline pamolate represented by Formula II with a solvent, stirring, and then cooling to precipitate crystals;

[0080] Among them, the solvent is selected from ethanol, n-propanol or a mixture thereof, and preferably, the solvent is ethanol.

[0081] In some embodiments of the present invention, the temperature of the stirring is 0 - 60 °C; preferably 50 - 60 °C.

[0082] In some embodiments of the present invention, the time of the stirring is 6 - 48 hours, preferably 8 - 24 hours.

[0083] In some embodiments of the present invention, the cooling can be to 0 - 30 °C, preferably to 10 - 25 °C, for example, to 25 °C.

[0084] According to the present invention, filtration and drying are carried out after crystal precipitation; in some embodiments of the present invention, a step of optionally washing with a solvent is further included before drying, and the washing solvent is selected from one or more mixtures of ethanol, isopropanol, n-propanol, acetone, ethyl acetate, acetonitrile, and tetrahydrofuran.

[0085] The present invention also provides a method for preparing xanomeline pamolate represented by Formula III, which includes the following steps:

[0086] (1) Dissolving xanomeline tartrate in a solvent to obtain a xanomeline tartrate solution;

[0087] (2) Dissolving disodium pamolate in water to obtain a disodium pamolate solution;

[0088] (3) Mixing the xanomeline tartrate solution and the disodium pamolate solution, and then cooling to precipitate a solid;

[0089] Among them, for the method for preparing xanomeline pamolate represented by Formula III above, the molar ratio of xanomeline tartrate to disodium pamolate is 1:0.1 - 0.6; preferably, the molar ratio of xanomeline tartrate to disodium pamolate is 1:0.5 - 0.6, for example, 1:0.5, 1:0.55, 1:0.6.

[0090] In some embodiments of the present invention, the method for preparing xanomeline pamoate shown in Formula III above, wherein the solvent in step (1) is one or more combinations selected from ethanol, methanol, DMF, DMSO, isopropanol, acetone, tetrahydrofuran, acetonitrile, and water; preferably, the solvent is one or more combinations selected from methanol, ethanol, tetrahydrofuran, and water.

[0091] In some embodiments of the present invention, step (2) can be carried out under heating conditions, and the heating temperature is 30 - 80 °C, for example, 40 - 60 °C.

[0092] In some embodiments of the present invention, the cooling can be to 0 - 30 °C, preferably to 0 - 10 °C, for example, to 5 °C. A filtration can be carried out first before cooling.

[0093] In some embodiments of the present invention, stirring is carried out during the cooling process, and the stirring time can be 6 - 24 hours, preferably 8 - 18 hours.

[0094] According to the present invention, after the solid is precipitated, filtration and drying are carried out; in some embodiments of the present invention, before drying, it further includes an optional step of washing with a solvent, and the washing solvent is selected from one or more mixtures of ethanol, isopropanol, n - propanol, acetone, ethyl acetate, acetonitrile, and tetrahydrofuran.

[0095] The present invention provides a method for preparing the D - crystal form of xanomeline pamoate shown in Formula III, which includes mixing the xanomeline pamoate shown in Formula III with a solvent, stirring, and then cooling to precipitate crystals;

[0096] wherein the solvent is selected from one or more mixtures of methanol, ethanol, isopropanol, n - propanol, butanol, acetone, ethyl acetate, n - heptane, and acetonitrile; preferably, the solvent is acetone.

[0097] In some embodiments of the present invention, the stirring temperature is 50 - 80 °C, for example, 60 - 70 °C.

[0098] In some embodiments of the present invention, the cooling can be to 0 - 30 °C, preferably to 0 - 10 °C, for example, to 5 °C. A filtration can be carried out first before cooling.

[0099] In some embodiments of the present invention, stirring is carried out during the cooling process, and the stirring time can be 6 - 24 hours, preferably 8 - 18 hours.

[0100] According to the present invention, filtration and drying are carried out after crystal precipitation; in some embodiments of the present invention, the step of optionally washing with a solvent is further included before drying, and the washing solvent is selected from one or more mixtures of ethanol, isopropanol, n-propanol, acetone, ethyl acetate, acetonitrile, and tetrahydrofuran.

[0101] In a fourth aspect, the present invention provides a pharmaceutical composition, which comprises xanomeline pamolate shown in Formula I, xanomeline pamolate shown in Formula II, xanomeline pamolate shown in Formula III, A crystal form of xanomeline pamolate shown in Formula II, B crystal form of xanomeline pamolate shown in Formula II, D crystal form of xanomeline pamolate shown in Formula III, and an optional pharmaceutically acceptable excipient.

[0102] In a fifth aspect, the present invention provides the use of xanomeline pamolate shown in Formula I, xanomeline pamolate shown in Formula II, xanomeline pamolate shown in Formula III, A crystal form of xanomeline pamolate shown in Formula II, B crystal form of xanomeline pamolate shown in Formula II, D crystal form of xanomeline pamolate shown in Formula III, or a pharmaceutical composition comprising xanomeline pamolate shown in Formula I, or a pharmaceutical composition comprising xanomeline pamolate shown in Formula II, or a pharmaceutical composition comprising xanomeline pamolate shown in Formula III, or a pharmaceutical composition comprising A crystal form of xanomeline pamolate shown in Formula II, or a pharmaceutical composition comprising B crystal form of xanomeline pamolate shown in Formula II, or a pharmaceutical composition comprising D crystal form of xanomeline pamolate shown in Formula III in the preparation of a drug for treating central nervous system disorder diseases.

[0103] In some embodiments of the present invention, the central nervous system disorder diseases include but are not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorder, drug addiction, pain, and neurodegeneration (such as Dow's disease or synucleinopathy).

[0104] In some embodiments of the present invention, the central nervous system disorder disease is schizophrenia.

[0105] Sixth aspect, the present invention provides a method for treating or preventing central nervous system disorders in mammals (such as humans), the method comprising administering to a mammal (such as a human) a therapeutically effective amount of xanomeline pamorate represented by formula I, xanomeline pamorate represented by formula II, xanomeline pamorate represented by formula III, A crystal form of xanomeline pamorate represented by formula II, B crystal form of xanomeline pamorate represented by formula II, D crystal form of xanomeline pamorate represented by formula III, or a pharmaceutical composition comprising xanomeline pamorate represented by formula I, or a pharmaceutical composition comprising xanomeline pamorate represented by formula II, or a pharmaceutical composition comprising xanomeline pamorate represented by formula III, or a pharmaceutical composition comprising A crystal form of xanomeline pamorate represented by formula II, or a pharmaceutical composition comprising B crystal form of xanomeline pamorate represented by formula II, or a pharmaceutical composition comprising D crystal form of xanomeline pamorate represented by formula III.

[0106] In some embodiments of the present invention, the central nervous system disorders include but are not limited to schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegeneration (such as Dow's disease or synucleinopathy).

[0107] In some embodiments of the present invention, the central nervous system disorder is schizophrenia.

[0108] Beneficial effects

[0109] 1. The present invention first provides xanomeline pamorate represented by formula I, xanomeline pamorate represented by formula II, and xanomeline pamorate represented by formula III; the xanomeline pamorate of the present invention has excellent effects in at least one aspect such as physical stability, solubility, hygroscopicity, biological activity, safety, bioavailability, and toxic and side effects.

[0110] 2. The A crystal form of xanomeline pamorate represented by formula II, the B crystal form of xanomeline pamorate represented by formula II, and the D crystal form of xanomeline pamorate represented by formula III have good stability, low hygroscopicity, small differences between batches, can maintain effective concentration in vivo for a long time, high bioavailability, and significantly improved drug toxic and side effects, and have good prospects for drug development;

[0111] 3. The preparation process of the salt form and crystal form of the present invention is simple, with small differences between batches, and is suitable for industrial production. Description of the drawings

[0112] Figure 1 XRPD pattern of A crystal form of xanomeline pamorate represented by formula II;

[0113] Figure 2 DSC pattern of A crystal form of xanomeline pamorate represented by formula II;

[0114] Figure 3 The TGA spectrum of the A crystal form of xanomeline pamolate shown in Formula II;

[0115] Figure 4 The XRPD spectrum of the B crystal form of xanomeline pamolate shown in Formula II;

[0116] Figure 5 The DSC spectrum of the B crystal form of xanomeline pamolate shown in Formula II;

[0117] Figure 6 The XRPD spectrum of the C crystal form of xanomeline pamolate shown in Formula II;

[0118] Figure 7 The DSC spectrum of the C crystal form of xanomeline pamolate shown in Formula II;

[0119] Figure 8 The XRPD spectrum of the D crystal form of xanomeline pamolate shown in Formula III;

[0120] Figure 9 The DSC spectrum of the D crystal form of xanomeline pamolate shown in Formula III;

[0121] Figure 10 The TGA spectrum of the D crystal form of xanomeline pamolate shown in Formula III;

[0122] Figure 11 The XRPD spectra of the A crystal form of xanomeline pamolate shown in Formula II at 0 day, 10 days, and 30 days under high temperature (60 °C) conditions;

[0123] Figure 12 The XRPD spectra of the A crystal form of xanomeline pamolate shown in Formula II at 0 day, 10 days, and 30 days under high humidity (RH92.5%) conditions;

[0124] Figure 13 The XRPD spectra of the A crystal form of xanomeline pamolate shown in Formula II at 0 day, 10 days, and 30 days under light conditions (4500 ± 500 Lux);

[0125] Figure 14 The XRPD spectra of the B crystal form of xanomeline pamolate shown in Formula II at 0 day, 10 days, and 30 days under high temperature (40 °C) conditions;

[0126] Figure 15 The XRPD spectra of the B crystal form of xanomeline pamolate shown in Formula II at 0 day, 10 days, and 30 days under high humidity (RH92.5%) conditions;

[0127] Figure 16XRPD patterns of B crystal form of xanomeline pamorate shown in Formula II at 0 day, 10 days and 30 days under light condition (4500±500Lux).

[0128] Figure 17 XRPD patterns of D crystal form of xanomeline pamorate shown in Formula III at 0 day, 10 days and 30 days under high temperature (60°C);

[0129] Figure 18 XRPD patterns of D crystal form of xanomeline pamorate shown in Formula III at 0 day, 10 days and 30 days under high humidity (RH92.5%);

[0130] Figure 19 XRPD patterns of D crystal form of xanomeline pamorate shown in Formula III at 0 day, 10 days and 30 days under light condition (4500±500Lux).

[0131] Figure 20 Time-concentration curves of xanomeline in rat plasma after intravenous injection of A crystal form of xanomeline pamorate shown in Formula II (prepared by the method of Example 12) and D crystal form of xanomeline pamorate shown in Formula III (prepared by the method of Example 19).

[0132] Figure 21 Time-concentration curves of xanomeline in rat plasma after oral administration of xanomeline tartrate for 7 consecutive days.

[0133] Figure 22 Time-concentration curves of xanomeline in rat plasma after single oral administration of xanomeline tartrate. Detailed implementation manners

[0134] The general formula compounds of the present invention, their preparation methods and applications will be further described in detail below with reference to specific examples. It should be understood that the following examples are only for illustrative explanation of the present invention and should not be construed as limiting the protection scope of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection of the present invention.

[0135] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.

[0136] The following abbreviations are used in the present invention: DSC represents differential scanning calorimeter; 11H-NMR represents nuclear magnetic resonance hydrogen spectrum; XRPD represents X-ray powder diffraction; eq represents molar equivalent; Polymorph A represents Polymorph A of xanomeline pamolate shown in II (sample obtained according to the method of Example 12); Polymorph B represents Polymorph B of xanomeline pamolate shown in formula II (sample obtained according to the method of Example 16); Polymorph C represents Polymorph C of xanomeline pamolate shown in formula II (sample obtained according to the method of Example 18); Polymorph D represents Polymorph D of xanomeline pamolate shown in formula III (sample obtained according to the method of Example 19).

[0137] Compounds were named manually or by ChemDraw software, and commercially available compounds were named using the supplier's catalog name.

[0138] For the experimental methods without specific conditions noted in the following examples, they were generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0139] The test methods and instruments used in the examples of the present invention to characterize salts and crystals are as follows:

[0140] Powder X-ray diffraction (also known as "X-ray powder diffraction", X-ray powder diffractometer, XRPD) method

[0141] Instrument model: Bruker D8 advance X-ray diffractometer

[0142] Test method: Approximately 10 - 20 mg of the sample was used for XRPD detection.

[0143] The detailed XRPD parameters are as follows:

[0144] X-ray tube: Cu, kα

[0145] X-ray tube voltage: 40 kV, X-ray tube current: 40 mA

[0146] Scanning range: 3 - 45 deg

[0147] Step size: 0.02 deg

[0148] Step time: 0.12 s

[0149] It should be noted that in X-ray powder diffraction spectroscopy (XRPD), the diffraction pattern obtained from a crystalline compound is often characteristic of a particular crystal, and the relative intensities of the spectral bands (especially at low angles) may vary due to preferred orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Therefore, the relative intensities of the diffraction peaks are not characteristic of the targeted crystal. When determining whether it is the same as a known crystal, more attention should be paid to the relative positions of the peaks rather than their relative intensities. In addition, for any given crystal, there may be slight errors in the positions of the peaks, which is also well-known in the field of crystallography. For example, due to changes in temperature during sample analysis, sample movement, or instrument calibration, etc., the positions of the peaks can shift, and the measurement error of the 2θ value is sometimes about ±0.2°. Therefore, this error should be taken into account when determining each crystal structure. In an XRPD pattern, the peak position is usually represented by the 2θ angle or the interplanar spacing d, and there is a simple conversion relationship between the two: d = λ / 2sinθ, where d represents the interplanar spacing (also known as the "plane spacing"), λ represents the wavelength of the incident X-ray, and θ is the diffraction angle. For the same crystal of the same compound, the peak positions of its XRPD spectrum are generally similar, and the relative intensity error may be relatively large. It should also be pointed out that in the identification of mixtures, due to factors such as a decrease in content, some diffraction lines may be missing. At this time, it is not necessary to rely on all the spectral bands observed in a high-purity sample, and even a single spectral band may be characteristic of a given crystal.

[0150] Measurement differences related to such X-ray powder diffraction analysis results are caused by a variety of factors including: (a) errors in the sample preparation (such as sample height), (b) instrument errors, (c) calibration differences, (d) operator errors (including errors in determining peak positions), and (e) properties of the substance (such as preferred orientation errors). Calibration errors and sample height errors often result in a displacement of all peaks in the same direction. When using a flat holder, small differences in sample height will result in a large displacement of the XRPD peak positions. Systematic studies have shown that a 1-mm difference in sample height can result in a peak displacement of up to 1° in 2θ. These displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacement (applying a systematic calibration factor to all peak position values) or recalibrating the instrument. As described above, by applying a systematic calibration factor to make the peak positions consistent, the measurement errors from different instruments can be corrected.

[0151] Differential scanning calorimetry (DSC) method

[0152] Instrument model: METTLER TOLEDO DSC3+ differential scanning calorimeter

[0153] Testing method: Take the sample (3 - 5 mg) and place it in an aluminum DSC pan for testing. Under the condition of N₂ at 50 mL / min, with a heating rate of 10 °C / min, heat the sample from 25 °C to 200 °C. In this invention, differential scanning calorimetry (DSC) is used to determine the melting point. DSC measures the transition temperature when the crystal absorbs or releases heat due to the change in its crystal structure or crystal melting. For the same crystal of the same compound, in consecutive analyses, the thermal transition temperature and melting point error are typically within about 5 °C, usually within about 3 °C. When we say a compound has a given DSC peak or melting point, it means this DSC peak or melting point ±5 °C. DSC provides an auxiliary method for distinguishing different crystals. Different crystal forms can be identified according to their different transition temperature characteristics. It should be noted that for mixtures, their DSC peaks or melting points may vary within a larger range. In addition, since decomposition occurs during the melting process of the substance, the melting temperature is related to the heating rate.

[0154] The thermal gravimetric analysis (Thermal Gravimetric Analyzer, TGA) method of this invention

[0155] Instrument model: TA550 thermal gravimetric analyzer

[0156] Testing method: Take the sample (5 - 10 mg) and place it in a platinum TGA pan for testing. Under the condition of N₂ at 25 mL / min, with a heating rate of 10 °C / min, heat the sample from room temperature to 300 °C.

[0157] High performance liquid chromatography (HPLC) analysis method:

[0158] The instrument used is Agilent HPLC; chromatographic column: Agilent Poroshell 120 bonus - RP 4.6×100 mm, 2.7 μm;

[0159] The determination conditions are as follows:

[0160] Injection volume: 10 μl;

[0161] Flow rate: 1.0 ml / min;

[0162] Detection wavelength: 275 nm;

[0163] Sample concentration: 1.0 mg / ml;

[0164] Diluent: 20% acetonitrile aqueous solution;

[0165] Column temperature: 40 °C;

[0166] Mobile phase A: 0.2% perchloric acid solution (adjusted to pH 2.2 with 2 mol / L sodium hydroxide solution);

[0167] Mobile phase B: Acetonitrile - methanol (1:1) solution;

[0168] The elution gradient is shown in Table 1:

[0169] Table 1 Elution gradient conditions

[0170] Time (min) ％A ％B 0 90 10 15 50 50 20 20 80 30 20 80 31 90 10 40 90 10

[0171] Currently, common general knowledge generally teaches that choosing a salt with the desired combination of properties remains a difficult semi - empirical choice that requires a trade - off of the properties of the salt form, but there is still a difficulty in evaluating which salt form is most suitable for screening a specific candidate drug.

[0172] During the experiment, the inventors found that the hygroscopicity of the drug would seriously affect the fluidity of the drug and even affect the stability of the drug. The solubility of the drug is crucial for the preparation of pharmaceutical agents, drug dissolution, absorption, etc. However, it is difficult to increase the solubility of the drug without sacrificing the hygroscopicity of the drug and obtain a candidate drug salt with appropriate drug stability, solubility and hygroscopicity.

[0173] Through extensive and in - depth research, the inventors unexpectedly found that the xanomeline pamoate of the present invention has a relatively high melting point as determined by DSC. After stability experiments, it was confirmed that the xanomeline pamoate of the present invention has relatively high stability, and the xanomeline pamoate of the present invention has relatively low hygroscopicity. In addition, the xanomeline pamoate of the present invention can maintain an effective concentration in the body for a long time, has a high bioavailability, and significantly improves the drug's toxic and side effects, showing good prospects for drug development.

[0174] On this basis, the present inventor discovered the A crystal form of xanomeline pamorate shown in Formula II, the B crystal form of xanomeline pamorate shown in Formula II, the C crystal form of xanomeline pamorate shown in Formula II, and the D crystal form of xanomeline pamorate shown in Formula III. The above A, B, and D crystal forms have advantages in at least one aspect such as physical stability, thermodynamic stability, mechanical stability, hygroscopicity, bioavailability, drug toxicity and side effects, and have good prospects for drug development; the above A, B, and D crystal forms have high bioavailability and significantly improved drug toxicity and side effects, and can maintain effective concentrations in the body for a long time after administration, having good prospects for drug development. The prepared A, B, and D crystal forms have appropriate crystal sizes and small differences between batches, and are suitable for industrial production and preparation, thus completing the present invention. The combination of high stability, low hygroscopicity, high bioavailability, and significantly improved drug toxicity and side effects of the A, B, and D crystal forms of the present invention is unexpected, which makes the crystal forms of xanomeline pamorate of the present invention have good drug-forming properties and are suitable for the preparation of injection preparations, especially subcutaneous injection preparations or intramuscular injection preparations.

[0175] In summary, the xanomeline pamorate of the present invention, the A crystal form of xanomeline pamorate shown in Formula II, the B crystal form of xanomeline pamorate shown in Formula II, and the D crystal form of xanomeline pamorate shown in Formula III have good stability, low hygroscopicity, small differences between batches, high bioavailability, and significantly improved drug toxicity and side effects, and can maintain effective concentrations in the body for a long time after administration, having good prospects for drug development. The preparations made from the xanomeline pamorate of the present invention, the A crystal form of xanomeline pamorate shown in Formula II, the B crystal form of xanomeline pamorate shown in Formula II, and the D crystal form of xanomeline pamorate shown in Formula III can maintain effective physiological concentrations of xanomeline in the body for a long time, have small toxic and side effects, and are convenient for administration, thus having advantages such as improving the compliance of patients.

[0176] Example 1. Preparation of Xanomeline and Xanomeline Tartrate

[0177]

[0178] Step 1. Preparation of 2-Hydroxy-2-(3-pyridyl)acetonitrile (Intermediate 1)

[0179] To a 100 mL single-neck reaction flask, 3-pyridinecarboxaldehyde (6.00 g, 56.02 mmol, 1.0 eq), glacial acetic acid (3.36 g, 56.02 mmol, 1.0 eq) and 6 mL of pure water were added successively, and the mixture was stirred and mixed evenly at room temperature. It was dropped into an aqueous solution of TMSCN (trimethylcyanosilane) (7.42 g, 74.42 mmol, 1.3 eq) at 2 - 8 °C, and the reaction was stirred. The reaction was confirmed to be complete by TLC plate, and the temperature was lowered to -5 °C in an ice-salt bath and stirred to precipitate crystals. It was filtered, and the filter cake was washed with ice water (5 mL * 3) to obtain a white solid (6.72 g, yield 78%).

[0180] Step 2: Preparation of 2-amino-2-(3-pyridyl)acetonitrile (Intermediate 2)

[0181] To a 50 mL two-neck reaction flask, NH4Cl (1.81 g, 33.80 mmol, 1.5 eq), water (15.00 mL, 5.0 eq) and ammonia water (4.80 mL, 25%, 1.1 eq) were added successively. After stirring and dissolving clearly at room temperature, Intermediate 1 (3.00 g, 22.53 mmol, 1.0 eq) was added, and stirring was continued for 20 hours. It was extracted with dichloromethane (15 ml * 7), the organic phases were combined, and dried with 2 g of anhydrous sodium sulfate for 5 minutes. It was filtered, and the solvent was evaporated under reduced pressure to obtain a red-brown oily substance (1.30 g, yield 43%).

[0182] Step 3: Preparation of 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (Intermediate 3)

[0183] To a 250 mL three-neck reaction flask, S2Cl2 (13.99 g, 103.62 mmol, 2.0 eq) and DMF (56.00 mL, 4.0 eq) were added successively, and the mixture was stirred and cooled in an ice-water bath. Intermediate 2 (6.90 g, 61.84 mmol, 1.0 eq) dissolved in DMF (28.00 mL, 4 eq) was dropped in at 0 - 5 °C. The reaction was stirred for 40 minutes, and 9M NaOH (60 mL) was dropped in at the same temperature, and then filtered. The aqueous phase was extracted with dichloromethane (120 mL * 3), the organic phases were combined, washed with pure water (80 ml * 3), dried with anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to obtain a brown solid (7.99 g, yield 78%).

[0184] Step 4: Preparation of 3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridine (Intermediate 4)

[0185] To a 100 mL three-necked reaction flask, 60% NaH (4.44 g, 184.41 mmol, 9.0 eq), tetrahydrofuran (9.00 mL, 2.6 eq) were added successively. At 0 - 5 °C, n-hexanol (6.27 g, 61.47 mmol, 3.0 eq) diluted with tetrahydrofuran (18.00 mL, 5.3 eq) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Intermediate 3 (3.41 g, 20.49 mmol, 1.0 eq) dissolved in tetrahydrofuran (15.00 mL, 4.5 eq) was added dropwise to the system at room temperature, and the mixture was stirred magnetically for 3 hours. The reaction solution was washed with saturated aqueous NaHCO3 (30 mL), and the aqueous phase was extracted with dichloromethane (30 mL × 3), and concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether (60 - 90) / ethyl acetate 5:1 - 3:1) to obtain an off-white solid (4.61 g, yield 78.1%).

[0186] Step 5: Preparation of 1-methyl-3-(4-hexyloxy-1,2,5-thiadiazol-3-yl)pyridinium iodide (Intermediate 5)

[0187] To a 100 mL three-necked reaction flask, Intermediate 4 (3.47 g, 13.2 mmol, 1.0 eq), acetone (50.00 mL, 2.6 eq) and methyl iodide (5.72 g, 39.5 mmol, 3.0 eq) were added successively, and the mixture was stirred at room temperature for 24 hours. Intermediate 5 precipitated from the system, and was filtered to obtain a bright yellow solid (5.18 g, yield 96.2%).

[0188] Step 6: Preparation of xanomeline

[0189] To a 250 mL three-necked reaction flask, Intermediate 5 (2.00 g, 4.9 mmol, 1.0 eq) and ethanol (24.00 mL) were added successively and stirred until clear. At -5 - 0 °C, a suspension of NaBH4 (371 mg, 9.8 mmol, 2.0 eq) in ethanol (16.00 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. The reaction was quenched with pure water (100.00 mL), and the aqueous phase was extracted with dichloromethane (100 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol 20:1) to obtain a brown solid (1.11 g, yield 77.1%, purity 99.99%). Melting point: 38.26 °C.

[0190] 11H NMR (400 MHz, Chloroform-d) δ 7.01 (m, 1H), 4.44 (t, J = 6.6 Hz, 2H), 3.34 (m, 2H), 2.49 - 2.51 (t, J = 5.7 Hz, 2H), 2.32 (m, 5H), 1.88–1.79 (m, 2H), 1.46 (m, 2H), 1.34 (m, 4H), 0.91–1.79 (m, 3H). MS m / z: 281.0 [M+H] + .

[0191] Example 2. Preparation of xanomeline tartrate

[0192] Add 3.0 g of xanomeline, 1.6 g of L-tartaric acid and 15 ml of isopropanol to a 100 ml flask. Heat the mixture until completely dissolved, filter while hot to obtain a clear solution, and then add 45 ml of ethyl acetate thereto. Slowly cool the solution to 2 - 8 °C with stirring to crystallize, filter to collect the product, wash with cold ethyl acetate, and dry in vacuo at 40 °C to obtain 4.2 g of a white solid with a yield of 91.5%. The product obtained was tested to be xanomeline tartrate. 1 1H NMR (400 MHz, CDCl3) δ 7.16 (1H, brs), 4.43 (4H, m), 4.09 (2H, brs), 3.29 (2H, brs), 2.69 (2H, brs), 1.83 (2H, m), 1.43 (2H, m), 1.40 (4H, m), 0.9 (t, J = 6.5 Hz, 3H). MS m / z: 282.1 [M+H] + .

[0193] Example 3. Preparation of xanomeline pamoate of formula II

[0194] Dissolve the xanomeline tartrate (9.0 g, 20.85 mmol) prepared according to the method of Example 2 in 50 mL of methanol to obtain a xanomeline tartrate solution; add disodium pamoate (9.0 g, 20.82 mmol) to 200 mL of water, heat and stir until completely dissolved to obtain a disodium pamoate solution. Mix the xanomeline tartrate solution and the disodium pamoate solution, stir and react until complete, cool to crystallize, filter and dry in vacuo to obtain a pale yellow powder (12.9 g, yield 92.5%). The molar ratio of xanomeline to pamoic acid was confirmed to be 1:1 by high performance liquid chromatography and nuclear magnetic resonance data analysis, that is, the product obtained has the structure shown in formula II above, and the product obtained is called xanomeline pamoate of formula II. 11H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 2H), 8.16 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.40 - 7.06 (m, 5H), 4.76 (s, 2H), 4.41 (t, J = 6.5 Hz, 2H), 4.32 - 4.10 (m, 2H), 3.50 - 3.27 (m, 2H), 2.99 (s, 3H), 2.77 - 2.61 (m, 2H), 1.83 - 1.66 (m, 2H), 1.46 - 1.13 (m, 6H), 0.85 (t, J = 6.9 Hz, 3H).

[0195] Example 4. Preparation of xanomeline pamolate of formula II

[0196] Dissolve the xanomeline tartrate (5.0 g, 11.59 mmol) prepared according to the method of Example 2 in 50 mL of ethanol to obtain a xanomeline tartrate solution; add disodium pamolate (4.5 g, 10.41 mmol) to 90 mL of water, heat and stir until completely dissolved to obtain a disodium pamolate solution. Mix the xanomeline tartrate solution and the disodium pamolate solution, stir the reaction until complete, cool to crystallize, filter and vacuum dry to obtain a pale yellow powder (6.0 g, yield 85.7%). The product obtained was tested to be xanomeline pamolate of formula II.

[0197] Example 5. Preparation of xanomeline pamolate of formula II

[0198] Dissolve the xanomeline tartrate (5.0 g, 11.59 mmol) prepared according to the method of Example 2 in 25 mL of acetone to obtain a xanomeline tartrate solution; add disodium pamolate (5.5 g, 12.72 mmol) to 110 mL of water, heat and stir until completely dissolved to obtain a disodium pamolate solution. Mix the xanomeline tartrate solution and the disodium pamolate solution, stir the reaction until complete, cool to crystallize, filter and vacuum dry to obtain a pale yellow powder (6.8 g, yield 87.6%). The product obtained was tested to be xanomeline pamolate of formula II.

[0199] Example 6. Preparation of xanomeline pamolate of formula II

[0200] Dissolve the xanomeline tartrate (5.0 g, 11.59 mmol) prepared according to the method of Example 2 in a mixed solvent of 30 mL of methanol and water (V 甲醇 : V 水In (1:1), xanomeline tartrate solution was obtained; Disodium pamidronate (6.5 g, 15.03 mmol) was added to 130 mL of water, and it was heated and stirred until completely dissolved to obtain a disodium pamidronate solution. The xanomeline tartrate solution was mixed with the disodium pamidronate solution, stirred until the reaction was complete, cooled for crystallization, filtered and dried in vacuo to obtain a light yellow powder (7.0 g, yield 90.2%). The product obtained was tested to be xanomeline pamidronate shown in Formula II.

[0201] Example 7. Preparation of xanomeline pamidronate shown in Formula II

[0202] The xanomeline tartrate (5.0 g, 11.59 mmol) prepared according to the method of Example 2 was dissolved in 25 mL of tetrahydrofuran to obtain a xanomeline tartrate solution; Disodium pamidronate (5.0 g, 11.56 mmol) was added to 100 mL of water, and it was heated and stirred until completely dissolved to obtain a disodium pamidronate solution. The xanomeline tartrate solution was mixed with the disodium pamidronate solution, stirred until the reaction was complete, cooled for crystallization, filtered and dried in vacuo to obtain a light yellow powder (6.6 g, yield 85%). The product obtained was tested to be xanomeline pamidronate shown in Formula II.

[0203] Example 8. Preparation of xanomeline pamidronate shown in Formula III

[0204] The xanomeline tartrate (5.0 g, 11.59 mmol) prepared according to the method of Example 2 was dissolved in 25 mL of methanol, and it was heated and stirred until completely dissolved to obtain a xanomeline tartrate solution; Disodium pamidronate (2.5 g, 5.78 mmol) was added to 50 mL of water, and it was heated and stirred until completely dissolved to obtain a disodium pamidronate solution. The xanomeline tartrate solution was mixed with the disodium pamidronate solution, stirred until the reaction was complete, cooled for crystallization, filtered and dried in vacuo to obtain a light yellow powder (4.8 g, yield 88.2%). Through high performance liquid chromatography and nuclear magnetic resonance data analysis, it was confirmed that the molar ratio of xanomeline to pamidronic acid was 2:1, that is, the product obtained had the structure shown in Formula III above, and the product obtained was called xanomeline pamidronate shown in Formula III. 1 HNMR(400MHz,DMSO-d6)δ8.22(s,1H),8.16(d,J=8.6Hz,1H),7.68(d,J=7.9Hz,1H),7.28-6.89(m,3H),4.69(s,1H),4.44(t,J=6.6Hz,2H),4.25-4.05(m,2H),3.38-3.23(m,2H),2.93(s,3H),2.72-2.60(m,2H),1.86-1.70(m,2H)1.50-1.19(m,6H),0.86(t,J=7.0Hz,3H).

[0205] Example 9. Preparation of xanomeline pamolate shown in Formula III

[0206] Dissolve the xanomeline tartrate (5.0 g, 11.59 mmol) prepared according to the method of Example 2 in 50 mL of ethanol, heat and stir until completely dissolved to obtain a xanomeline tartrate solution; dissolve disodium pamolate (0.5 g, 1.15 mmol) in 10 mL of water, heat and stir until completely dissolved to obtain a disodium pamolate solution. Mix the xanomeline tartrate solution and the disodium pamolate solution, stir the reaction until complete, cool and crystallize, filter and vacuum dry to obtain a pale yellow powder (0.85 g, yield 77.3%), and the product obtained by testing is xanomeline pamolate shown in Formula III.

[0207] Example 10. Preparation of xanomeline pamolate shown in Formula III

[0208] Dissolve the xanomeline tartrate (5.0 g, 11.59 mmol) prepared according to the method of Example 2 in 25 mL of acetone, heat and stir until completely dissolved to obtain a xanomeline tartrate solution; dissolve disodium pamolate (2.0 g, 4.63 mmol) in 40 mL of water, heat and stir until completely dissolved to obtain a disodium pamolate solution. Mix the xanomeline tartrate solution and the disodium pamolate solution, stir the reaction until complete, cool and crystallize, filter and vacuum dry to obtain a pale yellow powder (3.8 g, yield 86.4%), and the product obtained by testing is xanomeline pamolate shown in Formula III.

[0209] Example 11. Preparation of xanomeline pamolate shown in Formula III

[0210] Dissolve the xanomeline tartrate (5.0 g, 11.59 mmol) prepared according to the method of Example 2 in a mixed solvent of 30 mL of methanol and water (V 甲醇 :V 水 = 1:1), heat and stir until completely dissolved to obtain a xanomeline tartrate solution; dissolve disodium pamolate (3.0 g, 6.94 mmol) in 60 mL of water, heat and stir until completely dissolved to obtain a disodium pamolate solution. Mix the xanomeline tartrate solution and the disodium pamolate solution, stir the reaction until complete, cool and crystallize, filter and vacuum dry to obtain a pale yellow powder (4.7 g, yield 85.6%), and the product obtained by testing is xanomeline pamolate shown in Formula III.

[0211] Example 12. Preparation of A crystal form of xanomeline pamolate shown in Formula II

[0212] Weigh 1.0 g of xanomeline pamolate shown in Formula II prepared by the method of Example 3 and mix it with 20 ml of ethyl acetate, and stir. Heat the mixture to 50 - 60 °C, stir and slurry for 8 - 24 hours, then cool to room temperature, filter to collect the product, wash with ethyl acetate, and dry in vacuo to obtain a pale yellow solid (0.8 g, yield 80%), with a melting point of 167.56 °C. 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 2H), 8.16 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.40 - 7.06 (m, 5H), 4.76 (s, 2H) 4.41 (t, J = 6.5 Hz, 2H), 4.32 - 4.10 (m, 2H), 3.50 - 3.27 (m, 2H), 2.99 (s, 3H), 2.77 - 2.61 (m, 2H), 1.83 - 1.66 (m, 2H), 1.46 - 1.13 (m, 6H), 0.85 (t, J = 6.9 Hz, 3H).

[0213] Send the obtained pale yellow solid for inspection by XRPD, DSC and TGA. After testing, it is found that the obtained white solid exists in crystal form, and the obtained crystal form is named Form A of xanomeline pamolate shown in Formula II, abbreviated as Form A. The XRPD pattern, DSC pattern and TGA pattern of the obtained Form A are basically as shown in Figure 1 , Figure 2 and Figure 3 respectively. In the X-ray powder diffraction pattern of the obtained crystal, the peak positions and intensities of the characteristic peaks are shown in Table 2; the diffraction angle data of the XRPD pattern of the obtained crystal form are basically shown in Table 3, where the error range of the 2θ value is ±0.2°.

[0214] Table 2 Peak positions and intensities of characteristic peaks in the X-ray powder diffraction pattern of Form A

[0215] Number 2θ Angle (°) Relative Intensity (%) Number 2θ Angle (°) Relative Intensity (%) 1 5.838 14.6 11 17.763 15.8 2 6.921 34.7 12 19.301 27.9 3 8.635 52.8 13 19.637 26.9 4 9.879 100.0 14 20.465 33.3 5 12.107 12.7 15 21.587 20.2 6 13.308 27.1 16 22.555 53.9 7 13.704 14.6 17 25.235 67.3 8 15.891 19.6 18 25.727 26.7 9 16.108 26.5 19 26.358 78.8 10 17.094 40.5 20 28.782 21.1

[0216] Table 3 XRPD analysis data of Form A

[0217]

[0218]

[0219] Example 13, Preparation of Form A of Xanomeline Pamolate Shown in Formula II

[0220] Weigh 1.0 g of xanomeline pamorate prepared according to the method of Example 3, mix it with 15 ml of ethyl acetate and 5 ml of toluene, stir. Heat the mixture to 50 - 60 °C, stir and slurry for 8 - 24 hours, then cool to room temperature, filter to collect the product, wash with ethyl acetate, and dry in vacuo to obtain a pale yellow solid (0.8 g, yield 80%). The product obtained was tested to be the A crystal form of xanomeline pamorate shown in Formula II.

[0221] Example 14. Preparation of the A crystal form of xanomeline pamorate shown in Formula II

[0222] Weigh 10.0 g of xanomeline pamorate prepared according to the method of Example 3 and mix it with 200 ml of ethyl acetate, stir. Heat the mixture to 50 - 60 °C, stir and slurry for 8 - 24 hours, then cool to room temperature, filter to collect the product, wash with ethyl acetate, and dry in vacuo to obtain a pale yellow solid (0.8 g, yield 80%). The product obtained was tested to be the A crystal form of xanomeline pamorate shown in Formula II.

[0223] Example 15. Preparation of the A crystal form of xanomeline pamorate shown in Formula II

[0224] Weigh 300 mg of xanomeline pamorate prepared according to the method of Example 3 and mix it with 5 ml of toluene, stir. Heat the mixture to 50 - 60 °C, stir and slurry for 8 - 24 hours, then cool to room temperature, filter to collect the product, wash with toluene, and dry in vacuo to obtain a pale yellow solid (200 mg, yield 66.7%). The product obtained was tested to be the A crystal form of xanomeline pamorate shown in Formula II.

[0225] Example 16. Preparation of the B crystal form of xanomeline pamorate shown in Formula II

[0226] Weigh 3 g of xanomeline pamorate prepared according to the method of Example 3 and mix it with 50 ml of ethanol, stir. Heat the mixture to 50 - 60 °C, stir and slurry for 8 - 24 hours, then cool to room temperature, filter to collect the product, wash with ethanol, and dry in vacuo to obtain a pale yellow solid (2.40 g, yield 80%). The melting point is 129.3 °C. 11H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 2H), 8.16 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.1 Hz, 2H), 7.40 - 7.06 (m, 5H), 4.76 (s, 2H), 4.41 (t, J = 6.5 Hz, 2H), 4.32 - 4.10 (m, 2H), 3.50 - 3.27 (m, 2H), 2.99 (s, 3H), 2.77 - 2.61 (m, 2H), 1.83 - 1.66 (m, 2H), 1.46 - 1.13 (m, 6H), 0.85 (t, J = 6.9 Hz, 3H).

[0227] The obtained pale yellow solid was submitted for XRPD and DSC tests. It was found that the obtained pale yellow solid existed in crystal form, and the obtained crystal form was named Form B of xanomeline paminate shown in Formula II, simply referred to as Form B. The XRPD pattern and DSC pattern of the obtained Form B were basically as shown in Figure 4 and Figure 5 respectively. In the X-ray powder diffraction pattern of the obtained crystal, the peak positions and intensities of the characteristic peaks are shown in Table 4; the diffraction angle data of the XRPD pattern of the obtained crystal form are basically shown in Table 5, where the error range of the 2θ value is ±0.2°.

[0228] Table 4 Peak positions and intensities of characteristic peaks in the X-ray powder diffraction pattern of Form B

[0229]

[0230] Table 5 XRPD analysis data of Form B

[0231]

[0232] Example 17. Preparation of Form B of xanomeline paminate shown in Formula II

[0233] Weigh 300 mg of xanomeline paminate shown in Formula II prepared according to the method of Example 3 and mix it with 5 mL of n-propanol, stir. Heat the mixture to 50 - 60 °C, stir and slurry for 8 - 24 hours, then cool to room temperature, filter to collect the product, wash with n-propanol, and dry in vacuum to obtain a pale yellow solid (230 mg, yield 76.7%). The obtained product was tested to be Form B of xanomeline paminate shown in Formula II.

[0234] Example 18. Preparation of Form C of xanomeline paminate shown in Formula II

[0235] Weigh 7.0 g of xanomeline pamorate shown in Formula II prepared by the method of Example 3, add it to 50 ml of acetone, heat the mixture until completely dissolved, filter while it is hot to obtain a clear solution. Cool the solution to 0 - 10 °C with stirring for crystallization, keep stirring for 10 - 24 hours, filter to collect the product, wash it with acetone, and dry it under vacuum to obtain a pale yellow solid (4.3 g, yield 61.4%), with a melting point of 115.09 °C. 1 H NMR(400MHz,DMSO-d6)δ8.38(s,2H),8.16(d,J=8.6Hz,2H),7.79(d,J=8.1Hz,2H),7.40-7.06(m,5H),4.76(s,2H)4.41(t,J=6.5Hz,2H),4.32-4.10(m,2H),3.50-3.27(m,2H),2.99(s,3H),2.77-2.61(m,2H),1.83-1.66(m,2H),1.46-1.13(m,6H),0.85(t,J=6.9Hz,3H).

[0236] Send the obtained pale yellow solid for testing of XRPD and DSC. After testing, it is found that the obtained pale yellow solid exists in a crystalline form. The obtained crystal form is named as Form C of xanomeline pamorate shown in Formula II, simply referred to as Form C. The XRPD pattern and DSC pattern of the obtained Form C are basically as shown in Figure 6 and Figure 7 respectively. In the X-ray powder diffraction pattern of the obtained crystal, the peak positions and intensities of the characteristic peaks are shown in Table 6; the diffraction angle data of the XRPD pattern of the obtained crystal form are basically shown in Table 7, where the error range of the 2θ value is ±0.2°.

[0237] Table 6 Peak positions and intensities of the characteristic peaks of the X-ray powder diffraction pattern of Form C

[0238] Number 2θ Angle (°) Relative Intensity (%) Number 2θ Angle (°) Relative Intensity (%) 1 6.292 56.2 9 19.577 47.1 2 8.105 16.5 10 20.898 30.5 3 8.816 17.8 11 22.632 18.1 4 9.604 49.9 12 23.360 20.1 5 10.509 41.0 13 25.707 58.3 6 11.240 82.2 14 26.456 99.5 7 13.013 16.3 15 30.064 62.6 8 15.793 100.0

[0239] Table 7 XRPD analysis data of Form C

[0240]

[0241]

[0242] Example 19. Preparation of Form D of xanomeline pamorate shown in Formula III

[0243] Weigh 50 g of xanomeline pamoate of formula Ⅲ prepared according to the method of Example 8, add it to 200 ml of acetone, heat the mixture until completely dissolved, filter to obtain a clear solution, cool the clear solution to 0 - 10 °C with stirring for crystallization, keep stirring for 8 - 18 hours, filter to collect the product, wash with cold acetone, and dry in vacuo to obtain a pale yellow solid (41.3 g, yield 82.6%), with a melting point of 111.42 °C. 1 H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.16(d,J=8.6Hz,1H),7.68(d,J=7.9Hz,1H),7.28-6.89(m,3H),4.69(s,1H),4.44(t,J=6.6Hz,2H),4.25-4.05(m,2H),3.38-3.23(m,2H),2.93(s,3H),2.72-2.60(m,2H),1.86-1.70(m,2H)1.50-1.19(m,6H),0.86(t,J=7.0Hz,3H).

[0244] Send the obtained pale yellow solid for XRPD, DSC and TGA tests. After testing, it is found that the obtained pale yellow solid exists in crystal form. The obtained crystal form is named Form D of xanomeline pamoate of formula Ⅲ, abbreviated as Form D. The XRPD pattern, DSC pattern and TGA pattern of the obtained Form D are basically as shown in Figure 9 、 Figure 10 and Figure 11 respectively. In the X-ray powder diffraction pattern of the obtained crystal, the peak positions and intensities of the characteristic peaks are shown in Table 8; the diffraction angle data of the XRPD pattern of the obtained crystal form are basically shown in Table 9, where the error range of the 2θ value is ±0.2°.

[0245] Table 8 Peak positions and intensities of characteristic peaks in the X-ray powder diffraction pattern of Form D

[0246] Number 2θ Angle (°) Relative Intensity (%) Number 2θ Angle (°) Relative Intensity (%) 1 5.464 100.0 6 16.562 13.8 2 10.748 29.2 7 19.047 3.9 3 11.061 31.2 8 20.977 5.8 4 12.126 4.2 9 21.449 35.6 5 16.069 8.4 10 21.101 40.3

[0247] Table 9 XRPD analysis data of Form D

[0248]

[0249]

[0250] Test Example 1 Determination experiments on the physicochemical properties of xanomeline pamoate and each crystal form of the present invention

[0251] 1. Melting point determination experiment

[0252] The melting points of Form A of xanomeline pamolate shown in Formula II (sample obtained in Example 12), Form B of xanomeline pamolate shown in Formula II (sample obtained in Example 16), Form C of xanomeline pamolate shown in Formula II (sample obtained in Example 18), Form D of xanomeline pamolate shown in Formula III (sample obtained in Example 19), xanomeline tartrate (sample obtained in Example 2), and xanomeline (sample obtained in Example 1) prepared through the experiments of the present invention were determined by a differential scanning calorimeter (DSC). The melting points of different crystal forms are shown in Table 11.

[0253] 2. Solubility determination experiment

[0254] Six portions of 2 ml of purified water were successively added with Form A of xanomeline pamolate shown in Formula II (sample obtained in Example 12), Form B of xanomeline pamolate shown in Formula II (sample obtained in Example 16), Form C of xanomeline pamolate shown in Formula II (sample obtained in Example 18), Form D of xanomeline pamolate shown in Formula III (sample obtained in Example 19), xanomeline tartrate (sample obtained in Example 2), and xanomeline (sample obtained in Example 1) prepared through the experiments of the present invention until no more dissolution occurred, and the corresponding usage amounts m were recorded. The visual solubility S = m / 10 ml was measured. The solubility results of different salt forms and crystal forms in water are shown in Table 11. The qualitative evaluation indicators for solubility are as follows: readily soluble means that 1 g (ml) of solute can dissolve in 1 to less than 10 ml of solvent; almost insoluble or insoluble means that 1 g (ml) of solute cannot completely dissolve in 10,000 ml of solvent.

[0255] 3. Hygroscopicity investigation

[0256] Appropriate amounts of samples of Form A of xanomeline pamolate shown in Formula II (sample obtained in Example 12), Form B of xanomeline pamolate shown in Formula II (sample obtained in Example 16), Form C of xanomeline pamolate shown in Formula II (sample obtained in Example 18), Form D of xanomeline pamolate shown in Formula III (sample obtained in Example 19), xanomeline tartrate (sample obtained in Example 2), and xanomeline (sample obtained in Example 1) prepared through the experiments of the present invention were precisely weighed, and the weight was m1. The samples were evenly spread in a flat weighing bottle, and the total weight was m2. After being placed at 25 ± 1 °C and 80 ± 1% RH for 24 h, the weight was m3. The moisture absorption weight gain ΔW was calculated by the following formula: ΔW = (m3 - m2) / m1 * 100%. The moisture absorption weight gain results of different salt forms are shown in Table 11. The hygroscopicity evaluation indicators are shown in Table 10:

[0257] Table 10 Hygroscopicity evaluation indicators

[0258] Hygroscopicity Classification Moisture Absorption Weight Gain (ΔW%) Deliquescence Absorbing a sufficient amount of water to form a liquid Highly Hygroscopic ΔW% ≥ 15% Hygroscopic 2% ≤ ΔW% < 15% Slightly Hygroscopic 0.2% ≤ ΔW% < 2% No or Almost No Hygroscopicity ΔW% < 0.2%

[0259] Table 11 Physicochemical properties of each sample

[0260]

[0261] Melting point determination experimental results: The xanomeline pamoate and its crystal forms of the present invention have a high melting point, and the xanomeline pamoate and its crystal forms of the present invention have good stability.

[0262] Solubility determination experimental results: The xanomeline pamoate and its various crystal forms of the present invention have low solubility.

[0263] Hygroscopicity experimental results: The weight gain of the xanomeline pamoate and its various crystal forms of the present invention under the conditions of 25±1°C and 80±1%RH does not exceed 0.82%, indicating that the xanomeline pamoate and its various crystal forms of the present invention have low hygroscopicity.

[0264] Analysis of experimental results: Through extensive and in-depth research, the inventor unexpectedly found that the xanomeline pamoate and its various crystal forms of the present invention have a high melting point (i.e., high stability) and low hygroscopicity in DSC determination, which makes the xanomeline pamoate and its various crystal forms of the present invention suitable for the preparation of long-acting sustained-release preparations, especially the preparation of long-acting sustained-release injection preparations.

[0265] Test Example 2. Physical stability study

[0266] The A crystal form of xanomeline pamoate shown in Formula II (prepared according to the method of Example 12), the B crystal form of xanomeline pamoate shown in Formula II (prepared according to the method of Example 16), the C crystal form of xanomeline pamoate shown in Formula II (prepared according to the method of Example 18), the D crystal form of xanomeline pamoate shown in Formula III (prepared according to the method of Example 19), xanomeline tartrate (prepared according to the method of Example 2), and xanomeline (prepared according to the method of Example 1) obtained through experiments were respectively placed flat and open, and the stability test of the samples was carried out under the conditions of high temperature (60°C), high humidity (RH92.5%), and light (4500±500Lux). The contents of xanomeline and related substances in the samples were measured at different sampling times (0 days, 10 days, 30 days), as shown in Table 4 specifically.

[0267] Table 12 Stability experiment

[0268]

[0269] In the above table, the purity on the 0th day refers to the purity before the start of the stability experiment; "-" indicates that the relevant test was not carried out.

[0270] From the above experiments, it can be seen that the crystal form of the present invention has very good stability under high humidity and light conditions and has good prospects for drug formation; unexpectedly, Form A, Form B and Form D are more stable than other salt forms and crystal forms under high temperature, high humidity and light conditions, which is more convenient for the storage of APIs and drug preparations.

[0271] Test Example 3 Accelerated Stability Experiment of Various Crystal Forms of Xanomeline Pamoate

[0272] The Form A of xanomeline pamoate shown in Formula II (abbreviated as Form A, prepared according to the method of Example 12), the Form B of xanomeline pamoate shown in Formula II (abbreviated as Form B, prepared according to the method of Example 16), the Form C of xanomeline pamoate shown in Formula II (abbreviated as Form C, prepared according to the method of Example 18), and the Form D of xanomeline pamoate shown in Formula III (abbreviated as Form D, prepared according to the method of Example 19) obtained through experiments were placed flat and open to the air, and the chemical stability of the samples under high temperature (60 °C), high humidity (RH92.5%) and light conditions (4500 ± 500 Lux) was investigated. A certain amount of samples were taken at 0 day, 10 days and 30 days to detect the crystal form of the samples, so as to evaluate the stability of various crystal forms of xanomeline pamoate. The experimental results are shown in Table 13.

[0273] Table 13 Experimental Results of the Stability of Various Crystal Forms of the Present Invention

[0274]

[0275] The crystal form at 0 day in the above table refers to the crystal form before the start of the stability experiment, and "-" indicates that the relevant test was not carried out.

[0276] Through experiments and XRPD spectra, it can be seen that under high temperature (60 °C), high temperature (40 °C), high humidity (RH92.5%) and light conditions (4500 ± 500 Lux), the XRPD spectra of each crystal form at 0 day, 10 days and 30 days are basically the same for Form A, Form B and Form D, and the stability of Form A, Form B and Form D is good. For the specific spectra, see Figure 11 - Figure 19 . Test Example 4 Polymorphic Study of Xanomeline Pamoate

[0277] The Form A of xanomeline pamoate shown in Formula II (prepared according to the method of Example 12) and the Form D of xanomeline pamoate shown in Formula III (prepared according to the method of Example 19) were slurried in suspension in the solvents shown in Table 8 and stirred in the dark at 40 °C for 2 days. After centrifuging the solution to remove the precipitate and drying, it was detected by XPRD. The results are shown in Table 14:

[0278] Table 14

[0279]

[0280] Analysis of the results in the above table shows that: The crystal forms A and D of the present invention have good stability and can still remain stable under different solvent systems.

[0281] Test Example 5. Study on the toxic and side effects of different salt forms and crystal forms

[0282] Experimental materials: Male SD rats (weighing 180 - 220 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., production license number: SCXK (Beijing) 2016 - 0006), crystal form A of xanomeline pamolate shown in Formula II (abbreviated as crystal form A, prepared by the method of Example 12), crystal form D of xanomeline hemipamolate shown in Formula III (abbreviated as crystal form D, prepared by the method of Example 19), xanomeline tartrate (prepared by the method of Example 2), purified water (self - made).

[0283] Experimental method: Randomly divide 24 male SD rats into 4 groups (6 rats in each group), uniquely identify them by tail numbering. Three groups are respectively denoted as groups A, B, C, and D, and they are allowed to drink water freely during the experiment. Among them, the SD rats in group A are subcutaneously administered a suspension preparation of crystal form A at a dose of 100 mg / kg (calculated based on the amount of free xanomeline); the SD rats in group B are subcutaneously administered a suspension preparation of crystal form D at a dose of 100 mg / kg (calculated based on the amount of free xanomeline); the SD rats in group C are orally gavaged with an aqueous solution of xanomeline tartrate at a dose of 50 mg / kg (calculated based on the amount of free xanomeline) each time, administered 2 times a day for 7 consecutive days, and the interval between the two administrations is 8 hours; the SD rats in group D are orally administered an appropriate amount of purified water, 2 times a day with an interval of 8 hours for 7 consecutive days. The prescription of the suspension preparation is: drug active ingredient, 1% of CMCNa, and the balance of water. Observe the mental state of the SD rats before and after administration, and observe the salivation situation of the SD rats in each group after administration, record the number of salivating rats, and continuously observe for 7 days. If any abnormality occurs before and during administration, it needs to be recorded in time. The specific results are shown in Table 15

[0284] Table 15 Side effects induced by different salt forms

[0285]

[0286] Note: In this experiment, the first day of administration is recorded as day 0.

[0287] During the experiment, the inventors found that no salivation was observed in the SD rats of the A crystal form group, D crystal form group, and purified water group; in the xanomeline tartrate group, salivation was basically observed in all rats starting from day 3. In this group of SD rats, salivation with a duration of 5 - 20 minutes was observed within the time period of 30 - 60 minutes after each administration, indicating that the xanomeline tartrate group has higher side effects compared to the xanomeline pamoate group of the present invention. The xanomeline pamoate of the present invention has good safety and low cholinergic side effects.

[0288] Analysis of experimental results: Xanomeline is an M receptor activator, which can not only act on the central nervous system, but also stimulate M receptors in peripheral nerve tissues, resulting in cholinergic side effects such as salivation, nausea, dizziness, etc. In this experiment, the toxic and side effects of each compound were evaluated by observing the salivation of SD rats in each group. From the experimental results, it can be seen that the A crystal form and D crystal form of the present invention have low cholinergic side effects and good safety.

[0289] Test Example 6. Pharmacokinetic studies of different salt forms and crystal forms

[0290] Test objective: To determine the concentration of xanomeline in plasma after subcutaneous injection (s.c.) of xanomeline pamoate suspension or xanomeline tartrate aqueous solution in SD rats, and preliminarily evaluate its pharmacokinetic behavior; and to investigate the tolerance and pharmacokinetic properties of rats after administration of xanomeline tartrate aqueous solution twice a day (B.i.d.) for 7 consecutive days.

[0291] Experimental materials: Male SD rats (weighing 180 - 220 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., production license number: SCXK (Jing) 2016 - 0006), A crystal form of xanomeline pamoate shown in Formula II (referred to as A crystal form, prepared by the method of Example 12), D crystal form of xanomeline semi - pamoate shown in Formula III (referred to as D crystal form, prepared by the method of Example 19), xanomeline tartrate (prepared by the method of Example 2), purified water (self - made).

[0292] Experimental method: Nine male Sprague-Dawley (SD) rats were randomly divided into 3 groups (3 rats in each group), uniquely identified by tail numbering. The 3 groups were denoted as groups R, S, T, and O, and they had free access to water during the experiment. Among them, the SD rats in group R were subcutaneously administered a suspension preparation of polymorph A once at a dose of 100 mg / kg (calculated based on the amount of xanomeline free base); the SD rats in group S were subcutaneously administered a suspension preparation of polymorph D once at a dose of 100 mg / kg (calculated based on the amount of xanomeline free base); the SD rats in group T were orally gavaged with xanomeline tartrate solution at a dose of 50 mg / kg (calculated based on the amount of xanomeline free base) each time, administered 2 times a day for 7 consecutive days, with an 8-hour interval between the two administrations, and administered once on the 7th day. The prescription of the suspension preparation was: active pharmaceutical ingredient, 1% CMCNa, and the balance of water.

[0293] Before dosing at 0 h and at 1 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 192 h, and 240 h after dosing, blood samples were collected from the SD rats in groups R and S into K2EDTA anticoagulant tubes and temporarily stored on ice until centrifugation. Before dosing at 0 h on the 2nd, 5th, and 7th days and at 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after dosing on the 7th day, blood samples were collected from the SD rats in group T into K2EDTA anticoagulant tubes and temporarily stored on ice until centrifugation. Plasma was centrifuged out within 60 min after blood collection (centrifuged at 8000 rpm for 5 min at 2 - 8 °C), and after centrifugation, the plasma was transferred to a 96-well plate or a centrifuge tube and stored at ≤ -15 °C until LC-MS / MS detection. The LC-MS / MS bioanalytical method was used to detect the drug concentration in the plasma of SD rats. The non-compartmental model was used, and Mass Hunter (version B.04.01, Agilent, USA) was used to analyze the plasma concentration-time data to evaluate its pharmacokinetic (PK) characteristics in SD rats. The data are shown in Table 16.

[0294] Table 16 Pharmacokinetic parameters of different salt forms and polymorphs

[0295]

[0296] From the data in the above table, it can be seen that after the rats were administered polymorph A and polymorph D of xanomeline pamolate, T 1 / 2 (half-life) had a long time and could reach the therapeutic effective concentration for a long time; C max (peak concentration) was moderate. While achieving a good therapeutic effect, it could effectively reduce cholinergic side effects; The polymorph A and polymorph D of the present invention had good bioavailability. Moreover, the polymorph A and polymorph D of the present invention had a long half-life, which could reduce the dosing frequency and effectively improve the compliance of patients.

[0297] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. Xanomeline pamoate as shown in Formula II, wherein the xanomeline pamoate is in Form A, , and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 13.308±0.2°, 15.891±0.2°, 16.108±0.2°, 17.094±0.2°, 20.465±0.2°, 22.555±0.2°, 25.235±0.2° and 26.358±0.2°.

2. The xanomeline pamoate according to claim 1, wherein the X-ray powder diffraction pattern of the Form A has characteristic diffraction peaks at the following 2θ angles: 6.921±0.2°, 8.635±0.2°, 9.879±0.2°, 13.308±0.2°, 15.891±0.2°, 16.108±0.2°, 17.094±0.2°, 17.763±0.2°, 19.301±0.2°, 19.637±0.2°, 20.465±0.2°, 21.587±0.2°, 22.555±0.2°, 25.235±0.2°, 25.727±0.2°, 26.358±0.2° and 28.782±0.2°.

3. The xanomeline pamoate according to claim 1, wherein the Form A has an XRPD pattern substantially as shown in Figure 1.

4. The xanomeline pamoate according to claim 1, wherein the Form A has a DSC pattern substantially as shown in Figure 2.

5. The xanomeline pamoate according to claim 1, wherein the differential scanning calorimetry curve of the Form A has endothermic peaks at 85.11±5°C and 167.56±5°C.

6. The xanomeline pamoate according to claim 1, wherein the Form A has a TGA curve substantially as shown in Figure 3.

7. Xanomeline pamoate as shown in Formula II, wherein the xanomeline pamoate is in Form B, , and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.415±0.2°, 8.480±0.2°, 10.294±0.2°, 12.105±0.2°, 14.038±0.2°, 14.748±0.2°, 16.285±0.2°, 18.868±0.2°, 24.032±0.2°, 27.797±0.2° and 29.728±0.2°.

8. The xanomeline pamolate according to claim 7, wherein the X-ray powder diffraction pattern of the B crystal form has characteristic diffraction peaks at the following 2θ angles: 7.415 ± 0.2°, 8.480 ± 0.2°, 10.294 ± 0.2°, 12.105 ± 0.2°, 13.685 ± 0.2°, 14.038 ± 0.2°, 14.748 ± 0.2°, 16.285 ± 0.2°, 17.862 ± 0.2°, 18.868 ± 0.2°, 19.538 ± 0.2°, 20.463 ± 0.2°, 21.095 ± 0.2°, 24.032 ± 0.2°, 24.743 ± 0.2°, 27.542 ± 0.2°, 27.797 ± 0.2°, 29.374 ± 0.2°, and 29.728 ± 0.2°.

9. The xanomeline pamolate according to claim 7, wherein the B crystal form has an XRPD pattern substantially as shown in Figure 4.

10. The xanomeline pamolate according to claim 7, wherein the B crystal form has a DSC pattern substantially as shown in Figure 5.

11. The xanomeline pamolate according to claim 7, wherein the differential scanning calorimetry curve of the B crystal form has an endothermic peak at 129.30 ± 5 °C.

12. The xanomeline pamolate represented by Formula III, wherein the xanomeline pamolate is in the D crystal form, , and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.464 ± 0.2°, 10.748 ± 0.2°, 11.061 ± 0.2°, 12.126 ± 0.2°, 16.069 ± 0.2°, 16.562 ± 0.2°, 21.449 ± 0.2°, and 21.101 ± 0.2°.

13. The xanomeline pamolate according to claim 12, wherein the X-ray powder diffraction pattern of the D crystal form has characteristic diffraction peaks at the following 2θ angles: 5.464 ± 0.2°, 10.748 ± 0.2°, 11.061 ± 0.2°, 12.126 ± 0.2°, 16.069 ± 0.2°, 16.562 ± 0.2°, 19.047 ± 0.2°, 20.977 ± 0.2°, 21.449 ± 0.2°, and 21.101 ± 0.2°.

14. The xanomeline pamolate according to claim 12, wherein the D crystal form has an XRPD pattern substantially as shown in Figure 8.

15. The xanomeline pamolate according to claim 12, wherein the D crystal form has a DSC pattern substantially as shown in Figure 9.

16. The xanomeline pamolate according to claim 12, wherein the differential scanning calorimetry curve of the D crystal form has an endothermic peak at 111.42 ± 5 °C.

17. The xanomeline pamolate according to claim 12, wherein the D crystal form has a TGA curve substantially as shown in Figure 10.

18. A method for preparing the xanomeline pamolate of formula II according to claim 1, comprising the following steps: (1) Dissolving xanomeline tartrate in a solvent to obtain a xanomeline tartrate solution; (2) Dissolving disodium pamoate in water to obtain a disodium pamoate solution; (3) Mixing the xanomeline tartrate solution with the disodium pamoate solution, stirring and reacting, then cooling to precipitate a solid to obtain the xanomeline pamolate of formula II; (4) Mixing the xanomeline pamolate of formula II with a solvent, stirring, then cooling to precipitate crystals to obtain the A crystal form of the xanomeline pamolate of formula II; wherein, The molar ratio of the xanomeline tartrate to the disodium pamoate is 1:1 to 1.1; In step (1), the solvent is selected from one or more combinations of methanol, ethanol, tetrahydrofuran, and water; Step (2) is carried out under heating conditions, and the heating temperature is 30 to 80 °C; In steps (3) and (4), the cooling is to cool to 0 to 30 °C; stirring is carried out during the cooling process, and the stirring time is 6 to 24 hours; In step (4), the solvent is selected from ethyl acetate, toluene, or a mixture thereof, and the stirring temperature is 50 to 80 °C.

19. A method for preparing the xanomeline pamolate of formula III according to claim 12, comprising the following steps: (1) Dissolving xanomeline tartrate in a solvent to obtain a xanomeline tartrate solution; (2) Dissolving disodium pamoate in water to obtain a disodium pamoate solution; (3) Mixing the xanomeline tartrate solution with the disodium pamoate solution, then cooling to precipitate a solid to obtain the xanomeline pamolate of formula III; (4) Mixing the xanomeline pamolate of formula III with a solvent, stirring, then cooling to precipitate crystals to obtain the D crystal form of the xanomeline pamolate of formula III; wherein, The molar ratio of the xanomeline tartrate to the disodium pamoate is 1:0.5 to 0.6; In step (1), the solvent is selected from one or more combinations of methanol, ethanol, tetrahydrofuran, and water; Step (2) is carried out under heating conditions, and the heating temperature is 30 to 80 °C; In steps (3) and (4), the cooling is to cool to 0 to 30 °C; stirring is carried out during the cooling process, and the stirring time is 6 to 24 hours; In step (4), the solvent is selected from one or more mixtures of methanol, ethanol, isopropanol, n-propanol, butanol, acetone, ethyl acetate, n-heptane, and acetonitrile; the stirring temperature is 50 to 80 °C.

20. A pharmaceutical composition, wherein, The pharmaceutical composition comprises the xanomeline pamoate according to any one of claims 1 to 17 and an optional pharmaceutically acceptable excipient.

21. Use of xanomeline pamoate according to any one of claims 1 to 17, or the pharmaceutical composition according to claim 20, in the preparation of a medicament for treating central nervous system disorders; the central nervous system disorders are selected from schizophrenia and Alzheimer's disease.

Images