CN111302998A - Salts of aromatic heterocyclic derivatives and their uses - Google Patents

Abstract

The invention relates to salts of aromatic heterocyclic derivatives and application thereof. The invention also relates to a pharmaceutical composition comprising said salt and the use of said salt or a pharmaceutical composition of said salt for the preparation of a medicament for the prevention, treatment or alleviation of 5-HT₆Receptor-related diseases, in particular Alzheimer's disease.

Description

Salts of aromatic heterocyclic derivatives and their uses

technical field

The invention belongs to the technical field of medicine, relates to salts of aromatic heterocyclic derivatives and uses thereof, in particular to 3-(difluoromethyl)-1-((3-fluorophenyl)sulfonyl)-4-(piperazine) Salts of -1-yl)-1H-indole and uses thereof, further related to pharmaceutical compositions comprising said salts.

Background technique

类)引起的脱隐性脑综合症、精神分裂症以及与脊柱创伤或头部损伤有关的病症(如脑积水)。预计所述5-HT₆选择性配体还可用于治疗某些胃肠类疾病如功能性肠病。(参见例如Roth,B.L.，等，J.Pharmacol.Exp.Ther.,1994,268,1403-14120；Sibley,D.R.，等，Mol,Pharmacol.,1993,43,320-327；Sleight,A.J.，等，Neurotransmission,1995,11,1-5和Sleight,A.J.，等，Serotonin ID Research Alert,1997,2(3),115-118)。A variety of central nervous system diseases such as anxiety, depression, etc. are all related to the disturbance of the neurotransmitter serotonin (5-HT) or serotonin. As the main regulatory neurotransmitter in the brain, the neurotransmitter serotonin (5-HT) functions through a process known as 5-HT ₁ , 5-HT ₂ , 5-HT ₃ , 5-HT ₄ , 5 -Mediated by a large number of receptor families of HT5, ₅ -HT6 and ₅ - _HT7 . Based on high levels of ₅ -HT6 receptor mRNA in the brain, it has been suggested that the ₅ -HT6 receptor may play a role in the pathology and treatment of central nervous system disorders. Specifically, ₅ -HT6 selective ligands have been identified as potentially therapeutic for certain CNS (central nervous system) disorders, such as Parkinson's disease, Huntington's disease, anxiety disorders, depression, manic depression, psychosis , epilepsy, obsessive-compulsive disorder, migraine, Alzheimer's disease (enhanced cognitive memory), sleep disturbances, eating disorders (eg, anorexia and bulimia), panic attacks, ADHD (attention deficit hyperactivity disorder), attention deficit hyperactivity disorder Dysfunction disorders, drugs of abuse (such as cocaine, ethanol, nicotine, and benzodiazepines)

Class ), schizophrenia, and conditions associated with spinal trauma or head injury (eg, hydrocephalus). It is expected that the ₅ -HT6 selective ligands may also be useful in the treatment of certain gastrointestinal diseases such as functional bowel disease. (See eg, Roth, BL, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403-14120; Sibley, DR, et al., MoI, Pharmacol., 1993, 43, 320-327; Sleight, AJ, et al., Neurotransmission , 1995, 11, 1-5 and Sleight, AJ, et al., Serotonin ID Research Alert, 1997, 2(3), 115-118).

The study found that known 5-HT ₆ receptor-selective antagonists significantly increased glutamate and aspartate levels in the frontal cortex without increasing norepinephrine, dopamine, or 5-HT levels. Level. This selective elevation of specific neurochemicals noted during memory and cognition strongly suggests a role for ₅ -HT6 ligands in cognition (Dawson, LA; Nguyen, HQ; Li, P. , British Journal of Pharmacology, 2000, 130(1), 23-26). Studies with known selective ₅ -HT6 receptor antagonists on memory and learning in animals have had some positive effects (Rogers, DC; Hatcher, PD; Hagan, JJ, Society of Neuroscience, Abstracts, 2000, 26 , 680). A related potential therapeutic use of ₅ -HT6 ligands is the treatment of attention deficit disorder in children and adults. Because ₅ -HT6 receptor antagonists appear to increase the activity of the nigrostriatal dopamine pathway, and because ADHD is associated with abnormalities in the caudate nucleus (Ernst, M; Zametkin, AJ; Matochik, JH; Jons, PA ; Cohen, RM, Journal of Neuroscience, 1998, 18(5), 5901-5907), therefore, ₅ -HT6 receptor antagonists can treat attention deficit disorder. ₅ -HT6 receptor antagonists have also been identified as potentially useful compounds for the treatment of obesity. See eg, Bentley et al, Br. J. Pharmac. 1999, Suppl 126; Bentley et al, J. Psychopharmacol. 1997, Suppl A64:255; Wooley et al, Neuropharmacology 2001, 41:210-129 and WO02098878.

International application WO 2016004882A1 discloses the compound 3-(difluoromethyl)-1-((3-fluorophenyl)sulfonyl)-4-(piperazin-1-yl)-1H-indole (formula (I) compound shown), which has ₅ -HT6 receptor antagonistic activity. However, there is no research on the salt of this compound or its crystal form in the prior art.

Different salts and solid forms of pharmaceutical active ingredients may have different properties. Different salts and solid forms may differ significantly in appearance, solubility, melting point, dissolution, bioavailability, etc., and also have different effects on drug stability, bioavailability, and efficacy. Therefore, in drug development, the issue of salt and/or solid forms of drugs should be fully considered.

When the inventor was studying the compound, it was found that the compound had poor water solubility and poor druggability. Therefore, in order to find a solid form with better druggability, through a large number of experimental studies, it was found that after the compound shown in formula (I) was salified, the product The purity of the preparation is obviously improved, and the physical properties and various properties are more conducive to the development of preparations.

SUMMARY OF THE INVENTION

The prior art WO 2016004882A1 discloses the compound represented by the formula (I) as a pale yellow solid, but does not specifically disclose its specific solid form or its salt. Through a large number of experimental studies, the inventor found that the salt of the compound shown in formula (I) has good stability, good water solubility, good pharmacokinetic properties in vivo, and high preparation purity of the product, that is, the present invention The physical properties and various properties of the salts are more favorable for formulation development and thus have better druggability.

Specifically, the present invention relates to a salt of a compound represented by formula (I), and the preparation of said salt or a pharmaceutical composition comprising said salt for preventing, treating or alleviating diseases related to 5-HT ₆ receptors, Especially in the use of Alzheimer's drugs. The salt of the present invention may have a stable crystal structure, and the salt may also be in the form of a solvate, such as a hydrate.

On the one hand, the present invention provides a kind of salt of the compound shown in formula (I),

In some embodiments, the salts described herein are organic or inorganic acid salts.

In some embodiments, the inorganic acid salts of the present invention include, but are not limited to, hydrochloride, hydrobromide, phosphate, nitrate or sulfate; the organic acid salt is acetate, oxalate, rich Maleate, maleate, tartrate, citrate, succinate, camphorsulfonate, malonate, benzoate, salicylate, besylate, mesylate or p-toluenesulfonate.

In some embodiments, the salt of the present invention is a p-toluenesulfonate, characterized in that the p-toluenesulfonate is a p-toluenesulfonate crystal form A, and the p-toluenesulfonate crystal form A has The X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 6.00°±0.2°, 13.43°±0.2°, 16.22°±0.2°, 17.04°±0.2°, 17.25°±0.2°, 20.09°±0.2°, 20.77°±0.2°, 25.01°±0.2°.

In some embodiments, the salt of the present invention is an oxalate salt, characterized in that the oxalate salt is oxalate crystal form A, and the X-ray powder diffraction pattern of the oxalate crystal form A is in the following 2θ Diffraction peaks at the corners: 7.69°±0.2°, 9.55°±0.2°, 12.66°±0.2°, 12.96°±0.2°, 19.17°±0.2°, 20.40°±0.2°, 22.49°±0.2°, 26.13° ±0.2°.

In some embodiments, the salt of the present invention is a succinate, characterized in that the succinate is a succinate form A, and the X-ray powder diffraction pattern of the succinate form A is in the following 2θ There are diffraction peaks at the corners: 7.65°±0.2°, 8.88°±0.2°, 13.40°±0.2°, 17.91°±0.2°, 20.92°±0.2°, 27.05°±0.2°.

In some embodiments, the salt of the present invention is a salicylate, characterized in that the salicylate is a salicylate form A, and the X-ray powder diffraction of the salicylate form A The pattern has diffraction peaks at the following 2θ angles: 8.30°±0.2°, 12.24°±0.2°, 13.20°±0.2°, 18.56°±0.2°, 19.23°±0.2°, 20.92°±0.2°, 22.86°±0.2 °,23.79°±0.2°.

In some embodiments, the salt of the present invention is a p-toluenesulfonate, characterized in that the p-toluenesulfonate is a p-toluenesulfonate crystal form A, and the p-toluenesulfonate crystal form A has The X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 6.00°±0.2°, 13.43°±0.2°, 15.90°±0.2°, 16.22°±0.2°, 17.04°±0.2°, 17.25°±0.2°, 18.14°±0.2°, 19.09°±0.2°, 20.09°±0.2°, 20.77°±0.2°, 21.76°±0.2°, 25.01°±0.2°.

In some embodiments, the salt of the present invention is an oxalate salt, characterized in that the oxalate salt is oxalate crystal form A, and the X-ray powder diffraction pattern of the oxalate crystal form A is in the following 2θ Diffraction peaks at the corners: 6.37°±0.2°, 7.69°±0.2°, 12.66°±0.2°, 12.96°±0.2°, 15.83°±0.2°, 16.01°±0.2°, 19.17°±0.2°, 22.49° ±0.2°, 23.06°±0.2°, 26.13°±0.2°, 28.47°±0.2°.

In some embodiments, the salt of the present invention is a succinate, characterized in that the succinate is a succinate form A, and the X-ray powder diffraction pattern of the succinate form A is in the following 2θ Diffraction peaks at the corners: 7.65°±0.2°, 8.88°±0.2°, 11.88°±0.2°, 13.40°±0.2°, 17.91°±0.2°, 20.17°±0.2°, 20.92°±0.2°, 23.27° ±0.2°, 24.48°±0.2°, 25.78°±0.2°, 27.05°±0.2°.

In some embodiments, the salt of the present invention is a salicylate, characterized in that the salicylate is a salicylate form A, and the X-ray powder diffraction of the salicylate form A The pattern has diffraction peaks at the following 2θ angles: 8.30°±0.2°, 9.61°±0.2°, 9.92°±0.2°, 12.24°±0.2°, 13.20°±0.2°, 17.71°±0.2°, 18.56°±0.2 °, 19.23°±0.2°, 20.92°±0.2°, 21.78°±0.2°, 22.86°±0.2°, 23.79°±0.2°, 24.69°±0.2°.

In some embodiments, the salt of the present invention is a p-toluenesulfonate, characterized in that the p-toluenesulfonate is a p-toluenesulfonate crystal form A, and the p-toluenesulfonate crystal form A has The X-ray powder diffraction pattern has diffraction peaks at the following 2θ angles: 6.00°±0.2°, 6.64°±0.2°, 10.80°±0.2°, 11.99°±0.2°, 13.43°±0.2°, 14.71°±0.2°, 14.98°±0.2°, 15.90°±0.2°, 16.22°±0.2°, 17.04°±0.2°, 17.25°±0.2°, 17.93°±0.2°, 18.14°±0.2°, 19.09°±0.2°, 19.28° ±0.2°, 20.09°±0.2°, 20.77°±0.2°, 21.13°±0.2°, 21.52°±0.2°, 21.76°±0.2°, 22.03°±0.2°, 22.83°±0.2°, 23.39°±0.2 °, 23.95°±0.2°, 25.01°±0.2°, 25.89°±0.2°, 29.95°±0.2°.

In some embodiments, the salt of the present invention is an oxalate salt, characterized in that the oxalate salt is oxalate crystal form A, and the X-ray powder diffraction pattern of the oxalate crystal form A is in the following 2θ Diffraction peaks at the corners: 6.37°±0.2°, 7.69°±0.2°, 9.55°±0.2°, 12.66°±0.2°, 12.96°±0.2°, 13.47°±0.2°, 14.88°±0.2°, 15.83° ±0.2°, 16.01°±0.2°, 17.07°±0.2°, 17.96°±0.2°, 19.17°±0.2°, 20.40°±0.2°, 20.84°±0.2°, 21.28°±0.2°, 21.74°±0.2 °, 22.49°±0.2°, 23.06°±0.2°, 24.45°±0.2°, 25.00°±0.2°, 25.52°±0.2°, 26.13°±0.2°, 28.47°±0.2°, 29.04°±0.2°, 31.77°±0.2°, 32.03°±0.2°, 33.30°±0.2°.

In some embodiments, the salt of the present invention is a succinate, characterized in that the succinate is a succinate form A, and the X-ray powder diffraction pattern of the succinate form A is in the following 2θ Diffraction peaks at angles: 7.65°±0.2°, 8.88°±0.2°, 11.88°±0.2°, 13.40°±0.2°, 15.40°±0.2°, 16.39°±0.2°, 17.91°±0.2°, 18.53° ±0.2°, 20.17°±0.2°, 20.92°±0.2°, 22.20°±0.2°, 23.27°±0.2°, 23.57°±0.2°, 24.48°±0.2°, 25.78°±0.2°, 27.05°±0.2 °,29.49°±0.2°,30.15°±0.2°,31.40°±0.2°,33.09°±0.2°,34.21°±0.2°,36.37°±0.2°,37.18°±0.2°,37.81°±0.2°, 38.69°±0.2°.

In some embodiments, the salt of the present invention is a salicylate, characterized in that the salicylate is a salicylate form A, and the X-ray powder diffraction of the salicylate form A The pattern has diffraction peaks at the following 2θ angles: 8.30°±0.2°, 9.61°±0.2°, 9.92°±0.2°, 12.24°±0.2°, 13.20°±0.2°, 15.60°±0.2°, 16.21°±0.2 °,16.45°±0.2°,17.52°±0.2°,17.71°±0.2°,18.56°±0.2°,19.23°±0.2°,20.92°±0.2°,21.78°±0.2°,22.24°±0.2°, 22.86°±0.2°, 23.79°±0.2°, 24.45°±0.2°, 24.69°±0.2°, 25.83°±0.2°, 26.60°±0.2°, 28.19°±0.2°, 29.10°±0.2°, 30.18° ±0.2°, 30.68°±0.2°, 31.80°±0.2°, 37.32°±0.2°.

In some embodiments, the salt of the present invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is a p-toluenesulfonate salt form A, and the p-toluenesulfonate salt form A has An X-ray powder diffraction pattern substantially as shown in FIG. 1 .

In some embodiments, the salt of the present invention is an oxalate salt, characterized in that the oxalate salt is an oxalate salt form A, and the oxalate salt form A has substantially as shown in FIG. 2 . X-ray powder diffraction pattern.

In some embodiments, the salt of the present invention is a succinate salt, characterized in that the succinate salt is a succinate salt form A, and the succinate salt form A has substantially as shown in FIG. 3 . X-ray powder diffraction pattern.

In some embodiments, the salt of the present invention is a salicylate, characterized in that the salicylate is a salicylate form A, and the salicylate form A has substantially as shown in Fig. 4 shows the X-ray powder diffraction pattern.

In some embodiments, the salt of the present invention is a p-toluenesulfonate, characterized in that the p-toluenesulfonate is a p-toluenesulfonate crystal form A, and the p-toluenesulfonate crystal form A has The differential scanning calorigram contains an endothermic peak at 203.19°C ± 3°C.

In some embodiments, the salt of the present invention is an oxalate salt, wherein the oxalate salt is oxalate crystal form A, and the differential scanning calorimetry of the oxalate crystal form A comprises Endothermic peak at 212.51°C ± 3°C.

In some embodiments, the salt of the present invention is a succinate salt, wherein the succinate salt is a succinate form A, and the differential scanning calorimetry of the succinate form A comprises Endothermic peak at 179.31°C ± 3°C.

In some embodiments, the salt of the present invention is a salicylate, characterized in that the salicylate is a salicylate crystal form A, and the differential scanning quantity of the salicylate crystal form A The heatmap contains an endothermic peak at 221.92°C ± 3°C.

In some embodiments, the salt of the present invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is a p-toluenesulfonate salt form A, and the p-toluenesulfonate salt form A has Basically the differential scanning calorimetry map shown in Figure 5.

In some embodiments, the salt of the present invention is an oxalate salt, wherein the oxalate salt is an oxalate salt form A, and the oxalate salt form A has substantially as shown in FIG. 6 . Differential Scanning Calorimetry.

In some embodiments, the salt of the present invention is a succinate salt, characterized in that the succinate salt is a succinate salt form A, and the succinate salt form A has substantially as shown in FIG. 7 . Differential Scanning Calorimetry.

In some embodiments, the salt of the present invention is a salicylate, characterized in that the salicylate is a salicylate form A, and the salicylate form A has substantially as shown in Fig. Differential scanning calorimetry map shown in 8.

In another aspect, the present invention relates to a pharmaceutical composition comprising any one of the salts of the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.

In one aspect, the present invention relates to the use of the salt or the pharmaceutical composition in the preparation of a medicament for preventing, treating or alleviating a disease related to the ₅ -HT6 receptor.

In some such embodiments, the ₅ -HT6 receptor-related disease of the invention is a central nervous system disorder, a gastrointestinal disorder, or obesity.

In some such embodiments, the central nervous system disorder described herein is attention deficit hyperactivity disorder, anxiety, stress-related disorders, schizophrenia, obsessive-compulsive disorder, manic-depressive disorder, neurological disorder, Memory impairment, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's disease.

In another aspect, the present invention relates to the use of the salt or the pharmaceutical composition in the preparation of a medicament for antagonizing the 5-HT ₆ receptor.

On the other hand, the present invention also relates to a method for preparing a salt of the compound represented by formula (I) or a crystalline form thereof.

The solvent used in the preparation method of the salt or its crystal form of the present invention is not particularly limited, and any solvent that can dissolve the starting material to a certain extent and does not affect its properties is included in the present invention. In addition, many similar modifications in the art, equivalent replacements, or equivalents to the solvents, solvent combinations, and different ratios of solvent combinations described in the present invention are all deemed to be within the scope of the present invention. The present invention provides the preferred solvent used in each reaction step.

The preparation experiments of the salts of the present invention or their crystalline forms will be described in detail in the Examples section. At the same time, the present invention provides pharmacological property testing experiments (such as pharmacokinetics experiments), solubility experiments, stability experiments and hygroscopicity experiments of the salt or its crystalline form. Experiments have proved that the salt of the present invention has good stability and water solubility. Therefore, the salt of the present invention has better biological activity, higher stability, and is more suitable for pharmaceutical use.

Definitions and General Terms

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or identical to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices and materials are described herein.

"Crystalline" or "crystalline form" refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Inclusion compounds, co-crystals, salts, solvates of salts, hydrates of salts. Crystalline forms of materials can be obtained by a number of methods known in the art. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces, e.g., in nanopores or capillaries, crystallization on surfaces or templates, e.g., on polymers, Crystallization, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding in the presence of additives such as co-crystallizing anti-molecules, among others.

"Amorphous" or "amorphous form" refers to a substance formed when its particles (molecules, atoms, ions) are arranged aperiodically in three-dimensional space, characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural features suggest that it is inextricably linked with crystalline matter. Amorphous forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.

"Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol , ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, Methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

"Antisolvent" refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent. The antisolvent may comprise a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.

"Solvate" means a compound having a solvent on the surface, in the crystal lattice, or both on the surface and in the crystal lattice, the solvent may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, Dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylmethane Amide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, Toluene, xylene and mixtures thereof, etc. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the lattice or both on the surface and in the lattice is water. Hydrates may or may not have solvents other than water on the surface of the substance, in the lattice, or both on the surface and in the lattice.

Crystal forms can be identified by various techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance Resonance method, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscope (SEM), quantitative analysis, solubility and dissolution rate, etc.

X-ray powder diffraction (XRPD) can detect the change of crystal form, crystallinity, crystal structure and other information, and is a common method to identify crystal form. In some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention. At the same time, there may be experimental errors in the measurement of the 2θ of the XRPD spectrum, and the measurement of the 2θ of the XRPD spectrum may be slightly different between different instruments and different samples, so the value of the 2θ cannot be regarded as absolute. According to the condition of the instrument used in this experiment, there is an error tolerance of ±0.2° for the diffraction peaks.

Differential Scanning Calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly α-Al ₂ O ₃ ) as a function of temperature by continuously heating or cooling under program control. The endothermic peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms described herein are characterized by DSC patterns having characteristic peak positions substantially as shown in the DSC patterns provided in the accompanying drawings of the present invention. At the same time, the DSC spectrum may have experimental errors, and the peak positions and peaks of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. Depending on the condition of the instrument used in this test, there is a tolerance of ±3°C for the endothermic peak.

Thermogravimetric analysis (TGA) is a technique for measuring the change of the mass of a substance with temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains water of crystallization or crystallization solvent. Case. The mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments and between different samples. Depending on the condition of the instrumentation used for this test, there is a ±0.1% error tolerance for mass variation.

In the context of the present invention, the 2Θ values in an X-ray powder diffraction pattern are all in degrees (°).

The term "substantially as shown" means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least a 90%, or at least 95%, or at least 99% of the peaks are shown in their graph.

When referring to a spectrum or/and data appearing in a graph, a "peak" refers to a feature that would be recognized by those skilled in the art that would not be attributed to background noise.

The present invention relates to the crystalline form of the salt of (3-(difluoromethyl)-1-((3-fluorophenyl)sulfonyl)-4-(piperazin-1-yl)-1H-indole, Exists in substantially pure crystalline form.

"Substantially pure" means that a crystalline form is substantially free of one or more other crystalline forms, ie, the crystalline form is at least 80% pure, or at least 85% pure, or at least 90% pure, or at least 93% pure, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, said The percentage of other crystal forms in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

"Substantially free" means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.

The "relative intensity" (or "relative peak height") in the XRPD pattern refers to when the intensity of the first strong peak among all diffraction peaks in the X-ray powder diffraction pattern is 100%, the intensity of other peaks is the same as the intensity of the first strong peak ratio.

In the context of the present invention, when or whether the words "about" or "about" are used, it means within 10%, suitably within 5%, especially within 1% of the given value or range . Alternatively, to those of ordinary skill in the art, the terms "about" or "about" mean within an acceptable standard error of the mean. Whenever a number with a value of N is disclosed, any number with N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8% or N+ Numbers within the /-10% value are explicitly disclosed, where "+/-" means plus or minus.

In the present invention, "room temperature" refers to a temperature from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to 20°C, 22.5°C, 25°C, 27.5°C, and the like.

Pharmaceutical Compositions, Formulations, Administration and Uses of the Salts of the Invention

The characteristics of the pharmaceutical composition of the present invention include the salt of the compound represented by formula (I) and a pharmaceutically acceptable carrier, adjuvant or excipient. The amount of the salt of the compound in the pharmaceutical composition of the present invention is effective to detectably treat or reduce central nervous system dysfunction in a patient. The pharmaceutical compositions of the present invention may also optionally contain other therapeutic and/or prophylactic ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al. , Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

The skilled artisan possesses the knowledge and skills in the art to enable them to select appropriate amounts of suitable pharmaceutically acceptable excipients for use in the present invention. In addition, there are numerous resources available to the skilled artisan describing pharmaceutically acceptable excipients and for use in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

Disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, MarcelDekker, New York The various carriers used to formulate pharmaceutically acceptable compositions, and well-known techniques for their preparation, the contents of each of these documents are incorporated herein by reference. Except for any commonly used carriers that are incompatible with the compounds of the present invention, such as by producing any undesired biological effects, or interacting in a deleterious manner with any other ingredient of the pharmaceutically acceptable composition, concerns for their use are within the scope of the present invention. scope of invention.

The pharmaceutical compositions of the present invention are prepared using techniques and methods known to those skilled in the art. A description of some commonly used methods in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

In another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, The process involves mixing the various ingredients. Pharmaceutical compositions comprising salts of compounds of the present invention can be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The salts of the compounds of the present invention, or crystalline forms thereof, are generally formulated into dosage forms suitable for administration to patients by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, Solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes , sprays, foams and gels.

The pharmaceutical compositions provided by the present invention can be provided in soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two segments, one tucked into the other, thus completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention can be encapsulated in capsules. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in US Patents U.S. Pat. Nos. 4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain active ingredient dissolution.

In one embodiment, the method of treatment of the present invention comprises administering to a patient in need thereof a safe and effective amount of a salt of a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof. Embodiments of the present invention include treating the diseases referred to in the present invention by administering to a patient in need thereof a safe and effective amount of a salt of a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof .

In one embodiment, a salt of a compound of the present invention, or a crystalline form thereof, or a pharmaceutical composition comprising a salt of a compound of the present invention, or a crystalline form thereof, may be administered by any suitable route of administration, including systemic and topical administration . Systemic administration includes oral, parenteral, transdermal, and rectal administration. Typical parenteral administration refers to administration by injection or infusion, including intravenous, intramuscular and subcutaneous injection or infusion. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhalation and intranasal administration. In one embodiment, a salt of a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof may be administered orally. In another embodiment, a salt of a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof may be administered by inhalation. In yet another embodiment, a salt of the compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of the compound of the present invention or a crystalline form thereof may be administered intranasally.

In one embodiment, a salt of a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof may be administered at one time, or, according to the dosing regimen, over a specified period of time, at different times administered several times at a time interval. For example, it is administered once, twice, three times or four times a day. In one embodiment, the administration is once a day. In yet another embodiment, the administration is twice daily. Administration may be performed until the desired therapeutic effect is achieved or maintained indefinitely. A suitable dosing regimen for a salt of a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof depends on the pharmacokinetic properties of the salt or crystalline form of the compound, such as absorption, Distribution and half-life, these can be determined by the skilled person. In addition, a suitable dosing regimen of a salt of a compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the present invention or a crystalline form thereof, including the duration for which the regimen is carried out, depends on the disease being treated, being treated The severity of the disease, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of the concurrent therapy, the desired treatment effect, etc. are factors within the knowledge and experience of the technician. Such skilled artisans will also appreciate that adjustments to appropriate dosing regimens may be required as individual patient responses to dosing regimens or as individual patient needs change over time.

A salt of a compound of the present invention, or a crystalline form thereof, may be administered simultaneously with, before or after one or more other therapeutic agents. The salts of the compounds of the present invention or their crystalline forms can be administered separately with other therapeutic agents through the same or different routes of administration, or in the same pharmaceutical composition.

The salts of the compounds of the present invention or their crystalline forms can be used in combination with drugs for the treatment of Alzheimer's disease, drugs for the treatment of neurological disorders, etc., that is, to form the drug combination of the present invention, such as: donepezil, nalmefene, peridone, vitamin E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, RVT-101, naluzaton, idalopirdine, tacrine, rivastigmine, galan Tamine, memantine, mitazapine, venlafaxine, desyumin, nortriptyline, zolpidem, zopiclone, nicergoline, piracetam, selegiline, pentococoa Bases and their salts and compositions and the like, or salts of the compounds of the present invention or crystalline forms thereof may be administered concurrently with physical means such as light therapy or electrical stimulation.

For an individual of about 50-70 kg, the pharmaceutical compositions and pharmaceutical combinations of the present invention may contain about 1-1000 mg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or A unit dosage form of about 1-50 mg of active ingredient. A therapeutically effective amount of a salt of a compound or a crystalline form thereof, a pharmaceutical composition or a combination thereof will depend on the species, body weight, age and individual condition of the individual, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.

The dosage characteristics cited above have been demonstrated in in vitro and in vivo tests using advantageous mammals (eg, mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof.

In one embodiment, a therapeutically effective dose of a salt of a compound of the present invention or a crystalline form thereof is in an amount of about 0.1 mg to about 2,000 mg per day of the compound. Pharmaceutical compositions thereof should provide a dose of about 0.1 mg to about 2,000 mg of the compound. In a specific embodiment, pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the primary active ingredient or per dosage unit form combination of the main components. In a particular embodiment, a pharmaceutical dosage unit form is prepared to provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the primary active ingredient.

The salts of the compounds provided by the present invention or their crystal forms and pharmaceutical compositions can be used to prepare medicines for preventing, treating or alleviating Alzheimer's disease in mammals, including humans, and can also be used to prepare medicines for preventing, treating or reducing Alzheimer's disease. Medicines for alleviating ₅ -HT6 receptor-related diseases in mammals, including humans, can also be used to prepare medicines for antagonizing ₅ -HT6 receptors.

Specifically, the amount of the compound in the pharmaceutical composition of the present invention is effective to detectably selectively antagonize the 5-HT ₆ receptor, and the salt of the compound of the present invention or a crystalline form thereof can be used as a therapeutic agent with 5-HT ₆ receptor. body-related diseases such as Alzheimer's drugs.

The salt of the compound of the present invention or a crystalline form thereof can be applied, but in no way limited to, the use of an effective amount of the salt of the compound of the present invention or a crystalline form or a pharmaceutical composition administered to a patient to prevent, treat or alleviate the interaction with 5-HT ₆ receptor-related diseases. The disease related to the 5-HT ₆ receptor is a disorder of the central nervous system, a disorder of the gastrointestinal tract or obesity; wherein, the disorder of the central nervous system is attention deficit hyperactivity disorder, anxiety, related to mental stress disease, schizophrenia, obsessive-compulsive disorder, manic-depressive disorder, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's disease, etc. .

An "effective amount" or "effective dose" of a salt of a compound of the present invention, or a crystalline form or a pharmaceutically acceptable composition thereof, refers to an amount effective to treat or lessen the severity of one or more of the disorders referred to herein. According to the methods of the present invention, a salt of a compound of the present invention, or a crystalline form or a pharmaceutically acceptable composition thereof, may be administered in any amount and by any route of administration effective for treating or reducing the severity of a disease. The exact amount necessary will vary from patient to patient, depending on race, age, the general condition of the patient, the severity of the infection, particular factors, the mode of administration, and the like. A salt of a compound of the present invention, or a crystalline form or a pharmaceutically acceptable composition thereof, may be administered in combination with one or more other therapeutic agents, as discussed herein.

In addition to being beneficial to human therapy, the salts of the compounds of the present invention or their crystalline forms and pharmaceutical compositions can also be used in veterinary treatment of mammals in pets, introduced breed animals and farm animals. Examples of other animals include horses, dogs and cats.

Description of drawings

Fig. 1 is an X-ray powder diffraction (XRPD) pattern of the p-toluenesulfonate salt form A of the compound represented by formula (I).

Figure 2 is an X-ray powder diffraction (XRPD) pattern of the oxalate crystal form A of the compound represented by formula (I).

Figure 3 is an X-ray powder diffraction (XRPD) pattern of the succinate salt form A of the compound represented by formula (I).

Figure 4 is an X-ray powder diffraction (XRPD) pattern of the salicylate crystal form A of the compound represented by formula (I).

Figure 5 is a differential scanning calorimetry (DSC) chart of the p-toluenesulfonate salt form A of the compound represented by formula (I).

Figure 6 is a differential scanning calorimetry (DSC) chart of the oxalate salt form A of the compound represented by formula (I).

Figure 7 is a differential scanning calorimetry (DSC) chart of the succinate salt form A of the compound represented by formula (I).

Figure 8 is a differential scanning calorimetry (DSC) chart of the salicylate crystal form A of the compound represented by formula (I).

Detailed ways

The present invention is further described below by way of examples, and therefore the present invention is not limited to the scope of the described examples.

The X-ray powder diffraction analysis method used in the present invention is: Empyrean diffractometer, using Cu-Kα radiation (45KV, 40mA) to obtain the X-ray powder diffraction pattern. Powdered samples were prepared as thin layers on a single crystal silicon sample holder, placed on a rotating sample stage, and analyzed in 0.0167° steps over a range of 3°-60°. Data was collected using Data Collector software, processed by HighScore Plus software, and read by Data Viewer software.

The differential scanning calorimetry (DSC) analysis method used in the present invention is: using a TA Q2000 module with a thermal analysis controller to perform differential scanning calorimetry. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5 mg of sample was accurately weighed into a special aluminum crucible with a lid, and the sample was analyzed from room temperature to about 300°C using a 10°C/min line heating device. During use, the DSC cell was purged with dry nitrogen.

The solubility of the present invention is measured by an Agilent 1200 high performance liquid chromatograph DAD/VWD detector, and the chromatographic column model is Agilent XDB-C18 (4.6×50 mm, 5 μm). Detection wavelength is 266nm, flow rate is 1.0mL/min, column temperature is 35℃, mobile phase A: acetonitrile/0.01M ammonium acetate=10/90 (V/V) Analysis method: acetonitrile/mobile phase A=70/30 ( V/V), run time: 10 minutes.

The hygroscopicity of the present invention is measured by a DVS INT-Std dynamic moisture and gas adsorption analyzer from Surface Measurement Systems, UK. Humidity test range: 0%-95%, airflow: 200mL/min, temperature: 25°C, test point: per liter Take a test point at 5% humidity.

Specific implementation method

Compound represented by formula (I): 3-(difluoromethyl)-1-((3-fluorophenyl)sulfonyl)-4-(piperazin-1-yl)-1H-indole, specific synthesis method Reference is made to Example 5 in International Application WO 2016004882A1.

Example

Embodiment 1 p-toluenesulfonate crystal form A of the present invention

1. Preparation of p-toluenesulfonate Form A

The compound represented by formula (I) (50 mg) was added to EA (2 mL), then p-toluenesulfonic acid (42 mg) was added, and the reaction was carried out at room temperature overnight. The reaction was stopped, suction filtered, and dried to obtain an off-white solid powder, which was the crystal form A of p-toluenesulfonate.

2. Identification of p-toluenesulfonate Form A

(1) Identification by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by angle 2θ: 6.00°, 6.64°, 10.80°, 11.99°, 13.43°, 14.71°, 14.98 °,15.90°,16.22°,17.04°,17.25°,17.93°,18.14°,19.09°,19.28°,20.09°,20.77°,21.13°,21.52°,21.76°,22.03°,22.83°,23.39°, 23.95°, 25.01°, 25.89°, 29.95°, there is an error tolerance of ±0.2°.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 203.19°C is included, and there is an error tolerance of ±3°C.

Example 2 Oxalate crystal form A of the present invention

1. Preparation of oxalate crystal form A

The compound represented by formula (I) (50 mg) was added to EA (5 mL), then oxalic acid (25 mg) was added, and the reaction was carried out at room temperature overnight. The reaction was stopped, suction filtered, and dried to obtain an off-white solid powder, which was the oxalate crystal form A.

2. Identification of oxalate crystal form A

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by angle 2θ: 6.37°, 7.69°, 9.55°, 12.66°, 12.96°, 13.47°, 14.88 °,15.83°,16.01°,17.07°,17.96°,19.17°,20.40°,20.84°,21.28°,21.74°,22.49°,23.06°,24.45°,25.00°,25.52°,26.13°,28.47°, 29.04°, 31.77°, 32.03°, 33.30°, with an error tolerance of ±0.2°.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 212.51°C is included, and there is an error tolerance of ±3°C.

Example 3 Succinate crystal form A of the present invention

1. Preparation of Succinate Form A

The compound represented by formula (I) (50 mg) was added to EA (5 mL), and then succinic acid (33 mg) was added, and the reaction was carried out at room temperature overnight. The reaction was stopped, suction filtration, and drying to obtain an off-white solid powder, which was succinate crystal form A.

2. Identification of Succinate Form A

(1) Identification by Empyrean X-ray Powder Diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by angle 2θ: 7.65°, 8.88, 11.88°, 13.40°, 15.40°, 16.39°, 17.91° ,18.53°,20.17°,20.92°,22.20°,23.27°,23.57°,24.48°,25.78°,27.05°,29.49°,30.15°,31.40°,33.09°,34.21°,36.37°,37.18°,37.81 °, 38.69°, with an error tolerance of ±0.2°.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 179.31°C is included, and there is an error tolerance of ±3°C.

Embodiment 4 Salicylate crystal form A of the present invention

1. Preparation of Salicylate Form A

The compound represented by formula (I) (50 mg) was added to IPA (2 mL), then salicylic acid (32 mg) was added, and the reaction was carried out at room temperature overnight. The reaction was stopped, suction filtered, and dried to obtain an off-white solid powder, which was the salicylate crystal form A.

2. Identification of Salicylate Form A

(1) Identification by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-Kα radiation, with the following characteristic peaks represented by angles 2θ: 8.30°, 9.61°, 9.92°, 12.24°, 13.20°, 15.60°, 16.21 °,16.45°,17.52°,17.71°,18.56°,19.23°,20.92°,21.78°,22.24°,22.86°,23.79°,24.45°,24.69°,25.83°,26.60°,28.19°,29.10°, 30.18°, 30.68°, 31.80°, 37.32°, there is an error tolerance of ±0.2°.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scanning speed is 10°C/min, the endothermic peak at 221.92°C is included, and there is an error tolerance of ±3°C.

Example 5 Pharmacokinetic experiment of the salt of the present invention

The test samples were filled into capsules for oral administration.

Three 8-12kg male beagle dogs were taken orally administered capsules containing the test sample at a dose of 5mg/kg, and blood was collected at time points 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h. A standard curve with a suitable range was established according to the sample concentration. Using AB SCIEX API4000 LC-MS/MS, the concentration of the test sample in the plasma sample was determined in the MRM mode, and the quantitative analysis was carried out. According to the drug concentration-time curve, the non-compartmental model method of WinNonLin 6.3 software was used to calculate the pharmacokinetic parameters. Experiments show that the salt of the present invention has higher exposure in beagle dogs and better pharmacokinetic properties.

Example 6 Stability test of the salt of the present invention

Take an appropriate amount of the test sample under light (4500±500lx, ultraviolet light ≥0.7w/m ² ), high humidity (25℃, 75%±5%RH, 90%±5%RH), high temperature (40℃±5%RH) 2 ℃, 60 ℃ ± 2 ℃, uncontrolled humidity) conditions, carry out the influence factor experiment, take samples on the 5th, 10th, 15th, and 30th days respectively, carry out XRPD detection, and investigate the stability of the samples.

Experiments have proved that under the conditions of high temperature (40°C or 60°C), high humidity (25°C, RH 75% ± 5% or RH 90% ± 5%), and light conditions, the salt of the present invention under various stakeout conditions Good stability, suitable for pharmaceutical use.

Example 7 The hygroscopicity experiment of the salt of the present invention

An appropriate amount of the test sample was taken, and its hygroscopicity was tested by a dynamic moisture adsorption instrument. Experiments show that the salt of the present invention is not easily affected by high humidity and deliquescence.

Example 8 Solubility test of the salt of the present invention

Take the test sample and put it in water at 37°C to prepare a supersaturated turbid solution, shake it for 24 hours, filter it, take the filtrate, and detect the solubility of the target sample in water by HPLC. The experimental results show that the salt of the present invention has high solubility in water, so it has good druggability and is suitable for formulation development.

The above content is only a basic description under the concept of the present invention, and any equivalent transformation made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (10)

1. A salt of a compound of formula (I),

wherein the salt is an organic acid salt or an inorganic acid salt.

2. The salt of claim 1, wherein the inorganic acid salt is a hydrochloride, hydrobromide, phosphate, nitrate, or sulfate; the organic acid salt is acetate, oxalate, fumarate, maleate, tartrate, citrate, succinate, camphorsulfonate, malonate, benzoate, salicylate, benzenesulfonate, methanesulfonate or p-toluenesulfonate.

3. The salt of claim 2, wherein the p-toluenesulfonate salt is form A p-toluenesulfonate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 6.00 degrees +/-0.2 degrees, 13.43 degrees +/-0.2 degrees, 16.22 degrees +/-0.2 degrees, 17.04 degrees +/-0.2 degrees, 17.25 degrees +/-0.2 degrees, 20.09 degrees +/-0.2 degrees, 20.77 degrees +/-0.2 degrees and 25.01 degrees +/-0.2 degrees; or

The oxalate is oxalate crystal form A, and an X-ray powder diffraction pattern of the oxalate crystal form A has diffraction peaks at the following 2 theta angles: 7.69 ° ± 0.2 °,9.55 ° ± 0.2 °,12.66 ° ± 0.2 °,12.96 ° ± 0.2 °,19.17 ° ± 0.2 °,20.40 ° ± 0.2 °,22.49 ° ± 0.2 °,26.13 ° ± 0.2 °; or

The succinate salt is succinate salt crystal form A, and an X-ray powder diffraction pattern of the succinate salt crystal form A has diffraction peaks at the following 2 theta angles: 7.65 ° ± 0.2 °,8.88 ° ± 0.2 °,13.40 ° ± 0.2 °,17.91 ° ± 0.2 °,20.92 ° ± 0.2 °,27.05 ° ± 0.2 °; or

The salicylate is salicylate crystal form A, and an X-ray powder diffraction pattern of the salicylate crystal form A has diffraction peaks at the following 2 theta angles: 8.30 ° ± 0.2 °,12.24 ° ± 0.2 °,13.20 ° ± 0.2 °,18.56 ° ± 0.2 °,19.23 ° ± 0.2 °,20.92 ° ± 0.2 °,22.86 ° ± 0.2 °,23.79 ° ± 0.2 °.

4. The salt of claim 2, wherein the p-toluenesulfonate salt is form A p-toluenesulfonate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 6.00 degrees +/-0.2 degrees, 13.43 degrees +/-0.2 degrees, 15.90 degrees +/-0.2 degrees, 16.22 degrees +/-0.2 degrees, 17.04 degrees +/-0.2 degrees, 17.25 degrees +/-0.2 degrees, 18.14 degrees +/-0.2 degrees, 19.09 degrees +/-0.2 degrees, 20.09 degrees +/-0.2 degrees, 20.77 degrees +/-0.2 degrees, 21.76 degrees +/-0.2 degrees and 25.01 degrees +/-0.2 degrees; or

The oxalate is oxalate crystal form A, and an X-ray powder diffraction pattern of the oxalate crystal form A has diffraction peaks at the following 2 theta angles: 6.37 ° ± 0.2 °,7.69 ° ± 0.2 °,12.66 ° ± 0.2 °,12.96 ° ± 0.2 °,15.83 ° ± 0.2 °,16.01 ° ± 0.2 °,19.17 ° ± 0.2 °,22.49 ° ± 0.2 °,23.06 ° ± 0.2 °,26.13 ° ± 0.2 °,28.47 ° ± 0.2 °; or

The succinate salt is succinate salt crystal form A, and an X-ray powder diffraction pattern of the succinate salt crystal form A has diffraction peaks at the following 2 theta angles: 7.65 ° ± 0.2 °,8.88 ° ± 0.2 °,11.88 ° ± 0.2 °,13.40 ° ± 0.2 °,17.91 ° ± 0.2 °,20.17 ° ± 0.2 °,20.92 ° ± 0.2 °,23.27 ° ± 0.2 °,24.48 ° ± 0.2 °,25.78 ° ± 0.2 °,27.05 ° ± 0.2 °; or

The salicylate is salicylate crystal form A, and an X-ray powder diffraction pattern of the salicylate crystal form A has diffraction peaks at the following 2 theta angles: 8.30 ° ± 0.2 °,9.61 ° ± 0.2 °,9.92 ° ± 0.2 °,12.24 ° ± 0.2 °,13.20 ° ± 0.2 °,17.71 ° ± 0.2 °,18.56 ° ± 0.2 °,19.23 ° ± 0.2 °,20.92 ° ± 0.2 °,21.78 ° ± 0.2 °,22.86 ° ± 0.2 °,23.79 ° ± 0.2 °,24.69 ° ± 0.2 °.

5. The salt of claim 2, wherein the p-toluenesulfonate salt is form A p-toluenesulfonate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 6.00 ° ± 0.2 °,6.64 ° ± 0.2 °,10.80 ° ± 0.2 °,11.99 ° ± 0.2 °,13.43 ° ± 0.2 °,14.71 ° ± 0.2 °,14.98 ° ± 0.2 °,15.90 ° ± 0.2 °,16.22 ° ± 0.2 °,17.04 ° ± 0.2 °,17.25 ° ± 0.2 °,17.93 ° ± 0.2 °,18.14 ° ± 0.2 °,19.09 ° ± 0.2 °,19.28 ° ± 0.2 °,20.09 ° ± 0.2 °,20.77 ° ± 0.2 °,21.13 ° ± 0.2 ° ± 0.52 ° ± 0.2 °,21.76 ° ± 0.2 °,22.03 ° ± 0.2 °,22.83 ° ± 0.23.23 ° ± 0.2 ° ± 0.23 ° ± 0.2 °, 21.95 ° ± 0.25 ° ± 0.2 °,25 ° ± 0.2.29 ° ± 0.2 ° ± 0; or

The oxalate is oxalate crystal form A, and an X-ray powder diffraction pattern of the oxalate crystal form A has diffraction peaks at the following 2 theta angles: 6.37 ° ± 0.2 °,7.69 ° ± 0.2 °,9.55 ° ± 0.2 °,12.66 ° ± 0.2 °,12.96 ° ± 0.2 °,13.47 ° ± 0.2 °,14.88 ° ± 0.2 °,15.83 ° ± 0.2 °,16.01 ° ± 0.2 °,17.07 ° ± 0.2 °,17.96 ° ± 0.2 °,19.17 ° ± 0.2 °,20.40 ° ± 0.2 °,20.84 ° ± 0.2 °,21.28 ° ± 0.2 °,21.74 ° ± 0.2 °,22.49 ° ± 0.2 °,23.06 ° ± 0.2 °,24.45 ° ± 0.2 °,25.00 ° ± 0.2 °,25.52 ° ± 0.2 °,26.13 ° ± 0.2 °,28.47 ° ± 0.2.29.04 ° ± 0.2 ° 360.2 ° ± 0.31 ° ± 2.32 ° ± 52 ° ± 2.3.3 ° ± 52 ° ± 2 ° 3.2 °; or

The succinate salt is succinate salt crystal form A, and an X-ray powder diffraction pattern of the succinate salt crystal form A has diffraction peaks at the following 2 theta angles: 7.65 ° ± 0.2 °,8.88 ° ± 0.2 °,11.88 ° ± 0.2 °,13.40 ° ± 0.2 °,15.40 ° ± 0.2 °,16.39 ° ± 0.2 °,17.91 ° ± 0.2 °,18.53 ° ± 0.2 °,20.17 ° ± 0.2 °,20.92 ° ± 0.2 °,22.20 ° ± 0.2 °,23.27 ° ± 0.2 °,23.57 ° ± 0.2 °,24.48 ° ± 0.2 °,25.78 ° ± 0.2 °,27.05 ° ± 0.2 °,29.49 ° ± 0.2 °,30.15 ° ± 0.2 °,31.40 ° ± 0.2 °,33.09 ° ± 0.2 °,34.21 ° ± 0.2 °,36.37 ° ± 0.2 °,37.18 ° ± 0.2 °,37.81 ° ± 0.2 ° ± 38.69 ° ± 0.2 °; or

The salicylate is salicylate crystal form A, and an X-ray powder diffraction pattern of the salicylate crystal form A has diffraction peaks at the following 2 theta angles: 8.30 ° ± 0.2 °,9.61 ° ± 0.2 °,9.92 ° ± 0.2 °,12.24 ° ± 0.2 °,13.20 ° ± 0.2 °,15.60 ° ± 0.2 °,16.21 ° ± 0.2 °,16.45 ° ± 0.2 °,17.52 ° ± 0.2 °,17.71 ° ± 0.2 °,18.56 ° ± 0.2 °,19.23 ° ± 0.2 °,20.92 ° ± 0.2 °,21.78 ° ± 0.2 °,22.24 ° ± 0.2 °,22.86 ° ± 0.2 °,23.79 ° ± 0.2 °,24.45 ° ± 0.24 ° ± 0.69 ° ± 0.2 °,25.83 ° ± 0.2 °,26.60 ° ± 0.2 °,28.19 ° ± 0.2 °,29.10 ° ± 0.2.18 ° ± 0.2 °, 24.68 ° ± 0.68 ° ± 0.2 °, 3580 ° ± 0.31 ° ± 0.2 °.

6. The salt of any one of claims 2-5, wherein the p-toluenesulfonate salt is form A p-toluenesulfonate salt having an X-ray powder diffraction pattern substantially as shown in FIG. 1; or

The oxalate salt is oxalate form a having an X-ray powder diffraction pattern substantially as shown in figure 2; or

The succinate salt is succinate salt form a having an X-ray powder diffraction pattern substantially as shown in figure 3; or

The salicylate is salicylate form a having an X-ray powder diffraction pattern substantially as shown in figure 4.

7. The salt of any of claims 2-5, wherein the p-toluenesulfonate salt is form A p-toluenesulfonate salt, and wherein a differential scanning calorimetry trace of form A p-toluenesulfonate comprises an endothermic peak at 203.19 ℃ ± 3 ℃; or

The oxalate is oxalate form A, and a differential scanning calorimetry chart of the oxalate form A comprises an endothermic peak at 212.51 ℃ +/-3 ℃; or

The succinate salt is succinate salt form A, and a differential scanning calorimetry trace of succinate salt form A comprises an endothermic peak at 179.31 ℃ ± 3 ℃; or

The salicylate is salicylate form a, and a differential scanning calorimetry trace of salicylate form a comprises an endothermic peak at 221.92 ℃ ± 3 ℃.

8. The salt of claim 7, wherein the p-toluenesulfonate is form A p-toluenesulfonate having a differential scanning calorimetry pattern substantially as shown in FIG. 5; or

The oxalate salt is oxalate form a having a differential scanning calorimetry trace substantially as shown in figure 6; or

The succinate salt is succinate form a having a differential scanning calorimetry pattern substantially as shown in figure 7; or

The salicylate is salicylate form a having a differential scanning calorimetry pattern substantially as shown in figure 8.

9. A pharmaceutical composition comprising a salt of any one of claims 1-8, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

10. Use of a salt according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the prevention, treatment or alleviation of 5-HT₆A receptor-associated disease;

wherein, the said and 5-HT₆The receptor-related disease is a central nervous system disorder, a gastrointestinal disorder, or obesity;

wherein the central nervous system disorder is attention deficit hyperactivity disorder, anxiety, a stress-related disorder, schizophrenia, obsessive compulsive disorder, manic depression, a neurological disorder, a memory disorder, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's chorea.

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