CN111362859B

CN111362859B - Salts of heteroaromatic derivatives and use thereof

Info

Publication number: CN111362859B
Application number: CN202010181634.7A
Authority: CN
Inventors: 金传飞; 钟文和; 叶辉青
Original assignee: Dongguan Dongyangguang New Drug R & D Co ltd; Sunshine Lake Pharma Co Ltd
Current assignee: Dongguan Dongyangguang New Drug R & D Co ltd; Guangdong HEC Pharmaceutical
Priority date: 2020-03-16
Filing date: 2020-03-16
Publication date: 2021-05-11
Anticipated expiration: 2040-03-16
Also published as: CN111362859A

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 heteroaromatic derivatives and use thereof

Technical Field

The invention belongs to the technical field of medicines, relates to salts of aromatic heterocyclic derivatives and application thereof, and particularly relates to salts of 3- (difluoromethyl) -1- ((3-fluorophenyl) sulfonyl) -4- (piperazine-1-yl) -1H-indole, crystal forms of the salts and application thereof, and further relates to a pharmaceutical composition containing the salts or the crystal forms of the salts.

Background

Various central nervous system disorders such as anxiety, depression, and the like are associated with the disorder of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotoninThe disorder is related. The neurotransmitter 5-hydroxytryptamine (5-HT) functions as the primary regulatory neurotransmitter in the brain by being termed 5-HT₁，5-HT₂，5-HT₃，5-HT₄，5-HT₅，5-HT₆And 5-HT₇Are mediated by a large family of receptors. Based on high levels of 5-HT in the brain₆Receptor mRNA, 5-HT has been proposed₆Receptors may play a role in the pathology and treatment of central nervous system disorders. In particular, 5-HT has been determined₆Selective ligands have potential therapeutic utility in certain CNS (central nervous system) disorders, e.g. Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive-compulsive disorders, migraine, Alzheimer's disease (cognitive memory enhancement), sleep disorders, eating disorders (e.g. anorexia and bulimia), panic attacks, ADHD (attention deficit hyperactivity disorder), attention deficit disorder, drug abuse (e.g. cocaine, ethanol, nicotine and benzodiazepines)

Class) and conditions associated with spinal trauma or head injury (e.g., hydrocephalus). The 5-HT is expected₆Selective ligands may also be useful in the treatment of certain gastrointestinal disorders such as functional bowel disorders. (see, e.g., Roth, B.L., et al, J.Pharmacol. exp. Ther.,1994,268, 1403-14120; Sibley, D.R., et al, Mol, Pharmacol.,1993,43, 320-327; Sleight, A.J., et al, Neurotranssmision, 1995,11,1-5 and Sleight, A.J., et al, Serotonin ID Research Alert,1997,2(3), 115-118).

It was found that known 5-HT₆Receptor selective antagonists are capable of significantly increasing glutamate and aspartate levels in the frontal cortex without increasing norepinephrine, dopamine, or 5-HT levels. This selective increase in specific neurochemicals noted during memory and cognition strongly suggests 5-HT₆Role of ligands in cognition (Dawson, L.A.; Nguyen, H.Q.; Li, P., British Journal of Pharmacology,2000,130(1), 23-26). With known selectivity for 5-HT₆ReceptorsAntagonists have some positive effects on studies of memory and learning in animals (Rogers, D.C.; Hatcher, P.D.; Hagan, J.J., Society of Neuroscience, Abstract, 2000, 26, 680). 5-HT₆A related potential therapeutic use of ligands is in the treatment of attention deficit disorders in children and adults. Because of 5-HT₆Receptor 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, A.J.; Matochik, J.H.; Journal, P.A.; Cohen, R.M., Journal of Neuroscience, 1998, 18(5), 5901-₆Receptor antagonists may be useful in the treatment of attention deficit disorders. 5-HT has also been determined₆Receptor antagonists are potentially useful compounds for the treatment of obesity. See, e.g., Bentley et al, br.j.pharmac.1999, supplement 126; bentley et al, j.psychopharmacol.1997, supplement a 64: 255; wooley et al, Neuropharmacology 2001, 41: 210-129 and WO 02098878.

International application WO 2016004882A1 discloses the compound 3- (difluoromethyl) -1- ((3-fluorophenyl) sulfonyl) -4- (piperazin-1-yl) -1H-indole (compound of formula (I)) having 5-HT₆Receptor antagonistic activity. However, no research on the salt of the compound or its crystal form has been made in the prior art.

Different salts and solid forms of a pharmaceutically active ingredient may have different properties. Different salts and solid forms may have significant differences in appearance, solubility, melting point, dissolution rate, bioavailability, etc., and may also have different effects on the stability, bioavailability, therapeutic effect, etc. of the drug. Therefore, in drug development, the problem of salt form and/or solid form of the drug should be fully considered.

The inventor discovers that the compound has poor water solubility and drug forming property when researching the compound, so that after the compound shown in the formula (I) forms salts, the physicochemical properties of different salts are greatly changed, and the properties of some salts are not better than those of the compound in a free state through a large amount of experimental research in order to search for a solid form with better drug forming property; the inventor finds that the physical properties and various properties of the acetate of the compound shown in the formula (I) prepared by the method can be obviously improved, and the preparation is more beneficial to development of preparations.

Disclosure of Invention

The invention provides a salt of a compound shown as a formula (I), and researches on the preparation of the salt, the solid form of the salt, the physical and chemical properties and the pharmacological properties of the salt are carried out, so that the salt formed by the compound and different acids is found to have large difference in physical and chemical properties; various physicochemical properties of acetate are better than those of other salts, for example, the pharmacokinetic properties of the acetate crystal form A obtained after the compound shown in the formula (I) and acetic acid are salified are better than those of the corresponding citrate crystal form B and sulfate crystal form A. Therefore, the acetate crystal form A has better property and better pharmacokinetic property, thereby having better pharmaceutical property.

In particular, the invention relates to a salt of a compound shown as a formula (I), and a crystal form of the salt or a pharmaceutical composition containing the salt or the crystal form of the salt, which are used for preparing a medicine for preventing, treating or relieving 5-HT₆Receptor-related diseases, in particular Alzheimer's disease. The salt of the invention is acetate. Further, the salt of the invention is acetate form a. The crystalline forms of the present invention may also be in the form of solvates, for example hydrates.

In one aspect, the invention provides a salt of a compound of formula (I),

in some embodiments, the salts described herein are salts of organic or inorganic acids.

In other embodiments, the inorganic acid salts described herein include, but are not limited to, hydrochloride, hydrobromide, phosphate, nitrate, or sulfate salts, and the like; the organic acid salt includes, but is not limited to, acetate, oxalate, fumarate, maleate, tartrate, citrate, succinate, camphorsulfonate, malonate, benzoate, salicylate, benzenesulfonate, methanesulfonate, or p-toluenesulfonate, and the like.

In some embodiments, the salt of the compound of formula (I) of the present invention is an acetate salt.

In some embodiments, the salt of the invention is an acetate salt, wherein the acetate salt is form a of acetate salt, and wherein the form a of acetate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.50 ° ± 0.2 °,12.82 ° ± 0.2 °,17.83 ° ± 0.2 °,18.93 ° ± 0.2 °,20.14 ° ± 0.2 °,22.19 ° ± 0.2 °,22.66 ° ± 0.2 °,24.34 ° ± 0.2 °.

In some embodiments, the salt of the invention is an acetate salt, wherein the acetate salt is form a of acetate salt, and wherein the form a of acetate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.50 ° ± 0.2 °,10.16 ° ± 0.2 °,12.82 ° ± 0.2 °,14.49 ° ± 0.2 °,17.83 ° ± 0.2 °,18.93 ° ± 0.2 °,19.34 ° ± 0.2 °,20.14 ° ± 0.2 °,21.77 ° ± 0.2 °,22.19 ° ± 0.2 °,22.66 ° ± 0.2 °,24.34 ° ± 0.2 °.

In some embodiments, the salt of the invention is an acetate salt, wherein the acetate salt is form a of acetate salt, and wherein the form a of acetate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.50 ° ± 0.2 °,10.16 ° ± 0.2 °,12.82 ° ± 0.2 °,13.40 ° ± 0.2 °,14.49 ° ± 0.2 °,16.01 ° ± 0.2 °,16.59 ° ± 0.2 °,16.94 ° ± 0.2 °,17.83 ° ± 0.2 °,18.93 ° ± 0.2 °,19.34 ° ± 0.2 °,19.95 ° ± 0.2 °,20.14 ° ± 0.2 °,20.45 ° ± 0.2 °,21.25 ° ± 0.2 °,21.77 ° ± 0.2 °,22.19 ° ± 0.2 °,22.66 ° ± 0.2 °,24.34 ° ± 0.2 °,26.20 ° ± 0.2 °,27.01 ° ± 0.2 °,27.84 ° ± 0.2 °,33.00 ° ± 0.2 °.

In some embodiments, the salt of the invention is an acetate salt, wherein the acetate salt is form a of acetate salt having an X-ray powder diffraction pattern substantially as shown in figure 1.

In some embodiments, the salt of the invention is acetate, wherein the acetate is form a of acetate, and wherein a differential scanning calorimetry trace of form a of acetate comprises an endothermic peak at 162.89 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is an acetate salt, wherein the acetate salt is acetate form a having a differential scanning calorimetry pattern substantially as shown in fig. 16.

In some embodiments, the salt of the invention is an acetate salt, wherein the acetate salt is form B acetate, wherein the form B acetate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.81 ° ± 0.2 °,13.16 ° ± 0.2 °,21.59 ° ± 0.2 °,22.47 ° ± 0.2 °,23.01 ° ± 0.2 °.

In some embodiments, the salt of the invention is an acetate salt, wherein the acetate salt is form B acetate, wherein the form B acetate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.81 ° ± 0.2 °,13.16 ° ± 0.2 °,19.25 ° ± 0.2 °,20.47 ° ± 0.2 °,21.59 ° ± 0.2 °,22.47 ° ± 0.2 °,23.01 ° ± 0.2 °,24.68 ° ± 0.2 °,31.89 ° ± 0.2 °,36.95 ° ± 0.2 °.

In some embodiments, the salt of the invention is an acetate salt, wherein the acetate salt is form B acetate salt having an X-ray powder diffraction pattern substantially as shown in figure 2.

In some embodiments, the salt of the invention is acetate, wherein the acetate is form B acetate, and wherein a differential scanning calorimetry trace of form B acetate comprises an endothermic peak at 159.86 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is acetate, wherein the acetate is acetate form B having a differential scanning calorimetry pattern substantially as shown in fig. 17.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is citrate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.54 ° ± 0.2 °,15.17 ° ± 0.2 °,15.78 ° ± 0.2 °,20.26 ° ± 0.2 °,22.31 ° ± 0.2 °,29.89 ° ± 0.2 °.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is citrate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.54 ° ± 0.2 °,10.72 ° ± 0.2 °,15.78 ° ± 0.2 °,17.26 ° ± 0.2 °,19.68 ° ± 0.2 °,20.26 ° ± 0.2 °,22.04 ° ± 0.2 °,22.31 ° ± 0.2 °,22.87 ° ± 0.2 °,24.65 ° ± 0.2 °,29.89 ° ± 0.2 °.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is citrate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.54 ° ± 0.2 °,10.72 ° ± 0.2 °,12.86 ° ± 0.2 °,15.17 ° ± 0.2 °,15.78 ° ± 0.2 °,17.26 ° ± 0.2 °,17.77 ° ± 0.2 °,18.40 ° ± 0.2 °,18.80 ° ± 0.2 °,19.68 ° ± 0.2 °,20.26 ° ± 0.2 °,21.56 ° ± 0.2 °,22.04 ° ± 0.2 °,22.31 ° ± 0.2 °,22.87 ° ± 0.2 °,23.54 ° ± 0.2 °,24.13 ° ± 0.2 °,24.65 ° ± 0.2 °,25.00 ° ± 0.2 °,25.26 ° ± 0.2 °,26.05 ° ± 0.2 °,27.44 ° ± 0.2 °,28.41 ° ± 0.2 °, 24.89 ° ± 0.2 °, 362 ° ± 0.2 °.

In some embodiments, the salt of the present invention is a citrate salt, wherein the citrate salt is form a citrate salt having an X-ray powder diffraction pattern substantially as shown in figure 3.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is citrate form a, and wherein a differential scanning calorimetry trace of the citrate form a comprises an endothermic peak at 181.64 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is citrate form a having a differential scanning calorimetry pattern substantially as shown in figure 18.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is form B citrate, which has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.66 degrees +/-0.2 degrees, 6.84 degrees +/-0.2 degrees, 7.72 degrees +/-0.2 degrees, 9.54 degrees +/-0.2 degrees, 11.31 degrees +/-0.2 degrees, 22.99 degrees +/-0.2 degrees and 23.92 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is form B citrate, which has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.66 ° ± 0.2 °,6.84 ° ± 0.2 °,7.72 ° ± 0.2 °,9.54 ° ± 0.2 °,11.31 ° ± 0.2 °,13.69 ° ± 0.2 °,16.22 ° ± 0.2 °,22.99 ° ± 0.2 °,23.92 ° ± 0.2 °,30.05 ° ± 0.2 °,32.61 ° ± 0.2 °,34.43 ° ± 0.2 °.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is form B citrate, which has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.66 degrees +/-0.2 degrees, 6.84 degrees +/-0.2 degrees, 7.72 degrees +/-0.2 degrees, 9.54 degrees +/-0.2 degrees, 11.31 degrees +/-0.2 degrees, 13.69 degrees +/-0.2 degrees, 16.22 degrees +/-0.2 degrees, 17.00 degrees +/-0.2 degrees, 19.17 degrees +/-0.2 degrees, 20.56 degrees +/-0.2 degrees, 22.99 degrees +/-0.2 degrees, 23.92 degrees +/-0.2 degrees, 25.86 degrees +/-0.2 degrees, 28.21 degrees +/-0.2 degrees, 30.05 degrees +/-0.2 degrees, 32.61 degrees +/-0.2 degrees, 34.43 degrees +/-0.2 degrees, 36.48 degrees +/-0.2 degrees and 37.63 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is form B citrate salt having an X-ray powder diffraction pattern substantially as shown in figure 4.

In some embodiments, the salt of the invention is citrate, wherein the citrate is citrate form B, and wherein a differential scanning calorimetry trace of the citrate form B comprises an endothermic peak at 132.49 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is citrate form B having a differential scanning calorimetry pattern substantially as shown in figure 19.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is form C citrate salt, wherein the form C citrate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.72 ° ± 0.2 °,10.92 ° ± 0.2 °,15.35 ° ± 0.2 °,15.97 ° ± 0.2 °,19.87 ° ± 0.2 °,20.72 ° ± 0.2 °,22.50 ° ± 0.2 °.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is form C citrate salt, wherein the form C citrate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.72 ° ± 0.2 °,10.92 ° ± 0.2 °,13.05 ° ± 0.2 °,14.75 ° ± 0.2 °,15.97 ° ± 0.2 °,17.20 ° ± 0.2 °,17.47 ° ± 0.2 °,17.95 ° ± 0.2 °,19.87 ° ± 0.2 °,20.72 ° ± 0.2 °,22.50 ° ± 0.2 °.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is form C citrate salt, wherein the form C citrate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 7.72 ° ± 0.2 °,10.92 ° ± 0.2 °,12.35 ° ± 0.2 °,13.05 ° ± 0.2 °,14.75 ° ± 0.2 °,15.35 ° ± 0.2 °,15.97 ° ± 0.2 °,17.20 ° ± 0.2 °,17.47 ° ± 0.2 °,17.95 ° ± 0.2 °,18.60 ° ± 0.2 °,18.95 ° ± 0.2 °,19.87 ° ± 0.2 °,20.72 ° ± 0.2 °,21.72 ° ± 0.2 °,22.20 ° ± 0.2 °,22.50 ° ± 0.2 °,23.06 ° ± 0.2 °,23.58 ° ± 0.2 °,24.34 ° ± 0.2 °,24.81 ° ± 0.2 °,25.45 ° ± 0.2 °, 26.23.26.2 ° ± 0.54 ° ± 0.2 °, 360.2 ° ± 0.2 °.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is form C citrate salt having an X-ray powder diffraction pattern substantially as shown in figure 5.

In some embodiments, the salt of the invention is citrate, characterized in that the citrate is citrate form C, and the differential scanning calorimetry trace of citrate form C comprises endothermic peaks at 107.30 ℃ ± 3 ℃ and 180.22 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a citrate salt, wherein the citrate salt is citrate form C having a differential scanning calorimetry pattern substantially as shown in figure 20.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is sulfate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 9.76 ° ± 0.2 °,14.55 ° ± 0.2 °,15.65 ° ± 0.2 °,16.35 ° ± 0.2 °,17.95 ° ± 0.2 °,18.93 ° ± 0.2 °,19.37 ° ± 0.2 °,19.64 ° ± 0.2 °,20.22 ° ± 0.2 °,20.98 ° ± 0.2 °,21.38 ° ± 0.2 °,21.81 ° ± 0.2 °,22.18 ° ± 0.2 °,23.22 ° ± 0.2 °,23.60 ° ± 0.2 °,24.09 ° ± 0.2 °,25.24 ° ± 0.2 °,26.25 ° ± 0.2 °,27.62 ° ± 0.2 °,29.66 ° ± 0.2 °,29.96 ° ± 0.2 °,34.52 ° ± 0.2 °.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form a sulfate salt having an X-ray powder diffraction pattern substantially as shown in figure 6.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form B of sulfate salt, and wherein the form B of sulfate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 9.83 ° ± 0.2 °,15.18 ° ± 0.2 °,15.85 ° ± 0.2 °,16.49 ° ± 0.2 °,18.47 ° ± 0.2 °,19.54 ° ± 0.2 °,20.94 ° ± 0.2 °,21.55 ° ± 0.2 °,21.95 ° ± 0.2 °,22.34 ° ± 0.2 °,23.21 ° ± 0.2 °,24.21 ° ± 0.2 °,26.38 ° ± 0.2 °,26.58 ° ± 0.2 °,29.97 ° ± 0.2 °,34.98 ° ± 0.2 °.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form B sulfate salt, wherein the form B sulfate salt has an X-ray powder diffraction pattern substantially as shown in figure 7.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is sulfate form C, and wherein the sulfate salt form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.81 ° ± 0.2 °,15.58 ° ± 0.2 °,16.33 ° ± 0.2 °,17.25 ° ± 0.2 °,18.30 ° ± 0.2 °,19.28 ° ± 0.2 °,19.79 ° ± 0.2 °,20.02 ° ± 0.2 °,20.62 ° ± 0.2 °,20.80 ° ± 0.2 °,22.25 ° ± 0.2 °,22.88 ° ± 0.2 °,23.48 ° ± 0.2 °,24.07 ° ± 0.2 °,25.29 ° ± 0.2 °,26.83 ° ± 0.2 °,28.63 ° ± 0.2 °,29.80 ° ± 0.2 °,32.54 ° ± 0.2 °.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form C of the sulfate salt, wherein the form C of the sulfate salt has an X-ray powder diffraction pattern substantially as shown in figure 8.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form D of a sulfate salt, and wherein the form D of the sulfate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 9.44 ° ± 0.2 °,10.64 ° ± 0.2 °,14.33 ° ± 0.2 °,15.20 ° ± 0.2 °,15.54 ° ± 0.2 °,15.82 ° ± 0.2 °,18.18 ° ± 0.2 °,18.89 ° ± 0.2 °,19.23 ° ± 0.2 °,19.74 ° ± 0.2 °,20.22 ° ± 0.2 °,21.20 ° ± 0.2 °,21.54 ° ± 0.2 °,21.87 ° ± 0.2 °,22.21 ° ± 0.2 °,22.74 ° ± 0.2 °,23.27 ° ± 0.2 °,24.80 ° ± 0.2 °,26.50 ° ± 0.2 °,27.16 ° ± 0.2 °,28.54 ° ± 0.2 °,31.37 ° ± 0.2 °,33.90 ° ± 0.2 °.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form D of the sulfate salt, wherein the form D of the sulfate salt has an X-ray powder diffraction pattern substantially as shown in figure 9.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form E of sulfate salt, and wherein the form E of sulfate salt has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 9.84 ° ± 0.2 °,10.51 ° ± 0.2 °,11.15 ° ± 0.2 °,14.99 ° ± 0.2 °,16.40 ° ± 0.2 °,18.54 ° ± 0.2 °,19.21 ° ± 0.2 °,20.49 ° ± 0.2 °,21.48 ° ± 0.2 °,21.91 ° ± 0.2 °,22.44 ° ± 0.2 °,23.62 ° ± 0.2 °,24.12 ° ± 0.2 °,24.40 ° ± 0.2 °,26.44 ° ± 0.2 °,27.64 ° ± 0.2 °,30.07 ° ± 0.2 °.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form E of sulfate salt, wherein form E of sulfate salt has an X-ray powder diffraction pattern substantially as shown in figure 10.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form a, and the tartrate form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,13.51 ° ± 0.2 °,19.37 ° ± 0.2 °,19.88 ° ± 0.2 °,21.47 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form a, and the tartrate form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,9.16 ° ± 0.2 °,10.17 ° ± 0.2 °,13.51 ° ± 0.2 °,13.79 ° ± 0.2 °,18.32 ° ± 0.2 °,19.37 ° ± 0.2 °,19.88 ° ± 0.2 °,21.47 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form a, and the tartrate form a has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.12 ° ± 0.2 °,9.16 ° ± 0.2 °,10.17 ° ± 0.2 °,12.20 ° ± 0.2 °,13.51 ° ± 0.2 °,13.79 ° ± 0.2 °,14.21 ° ± 0.2 °,15.45 ° ± 0.2 °,16.27 ° ± 0.2 °,18.32 ° ± 0.2 °,19.37 ° ± 0.2 °,19.88 ° ± 0.2 °,20.38 ° ± 0.2 °,20.84 ° ± 0.2 °,21.47 ° ± 0.2 °,22.14 ° ± 0.2 °,24.16 ° ± 0.2 °,24.54 ° ± 0.2 °,25.37 ° ± 0.2 °,26.30 ° ± 0.2 °,27.86 ° ± 0.2 °,29.63 ° ± 0.2 °,30.73 ° ± 0.2.2 ° ± 0.2 °, 25.56 ° ± 0.2 °,26.30 ° ± 0.2 °,27.32 ° ± 0.33 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form a, the tartrate form a having an X-ray powder diffraction pattern substantially as shown in figure 11.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form a, and wherein a differential scanning calorimetry trace of the tartrate form a comprises an endothermic peak at 196.97 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form a, the tartrate form a having a differential scanning calorimetry pattern substantially as shown in figure 21.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form B, and the X-ray powder diffraction pattern of the tartrate form B has diffraction peaks at the following 2 Θ angles: 3.42 degrees +/-0.2 degrees, 6.74 degrees +/-0.2 degrees, 10.09 degrees +/-0.2 degrees, 17.09 degrees +/-0.2 degrees, 18.30 degrees +/-0.2 degrees, 20.23 degrees +/-0.2 degrees, 23.44 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form B, and the X-ray powder diffraction pattern of the tartrate form B has diffraction peaks at the following 2 Θ angles: 3.42 degrees +/-0.2 degrees, 6.74 degrees +/-0.2 degrees, 10.09 degrees +/-0.2 degrees, 12.78 degrees +/-0.2 degrees, 13.46 degrees +/-0.2 degrees, 17.09 degrees +/-0.2 degrees, 18.30 degrees +/-0.2 degrees, 20.23 degrees +/-0.2 degrees, 20.90 degrees +/-0.2 degrees and 23.44 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form B, and the X-ray powder diffraction pattern of the tartrate form B has diffraction peaks at the following 2 Θ angles: 3.42 ° ± 0.2 °,6.74 ° ± 0.2 °,7.76 ° ± 0.2 °,8.87 ° ± 0.2 °,10.09 ° ± 0.2 °,11.67 ° ± 0.2 °,12.78 ° ± 0.2 °,13.46 ° ± 0.2 °,14.06 ° ± 0.2 °,15.47 ° ± 0.2 °,17.09 ° ± 0.2 °,17.37 ° ± 0.2 °,17.87 ° ± 0.2 °,18.30 ° ± 0.2 °,19.01 ° ± 0.2 °,19.50 ° ± 0.2 °,19.82 ° ± 0.2 °,20.23 ° ± 0.2 °,20.90 ° ± 0.2 °,21.99 ° ± 0.2 °,22.32 ° ± 0.2 °,22.86 ° ± 0.2 °,23.44 ° ± 0.2.23 ° ± 0.2 ± 0.24.24 ° ± 0.2 °,21.99 ° ± 0.2.2.2 °,22.32 ° ± 0.2 ° ± 2 °, 22.28 ° ± 2.2.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form B, the tartrate form B having an X-ray powder diffraction pattern substantially as shown in figure 12.

In some embodiments, the salt of the invention is a tartrate salt, characterized in that the tartrate salt is tartrate form B, a differential scanning calorimetry trace of which comprises endothermic peaks at 84.06 ℃ ± 3 ℃ and 194.68 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form B, the tartrate form B having a differential scanning calorimetry pattern substantially as shown in figure 22.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form C, and the tartrate form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.16 ° ± 0.2 °,16.64 ° ± 0.2 °,19.20 ° ± 0.2 °,20.58 ° ± 0.2 °,20.83 ° ± 0.2 °,21.01 ° ± 0.2 °,21.85 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form C, and the tartrate form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.16 ° ± 0.2 °,9.27 ° ± 0.2 °,13.22 ° ± 0.2 °,16.64 ° ± 0.2 °,18.69 ° ± 0.2 °,19.20 ° ± 0.2 °,20.58 ° ± 0.2 °,20.83 ° ± 0.2 °,21.01 ° ± 0.2 °,21.85 ° ± 0.2 °,25.93 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form C, and the tartrate form C has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.16 ° ± 0.2 °,9.27 ° ± 0.2 °,13.22 ° ± 0.2 °,13.97 ° ± 0.2 °,15.10 ° ± 0.2 °,15.80 ° ± 0.2 °,16.64 ° ± 0.2 °,18.69 ° ± 0.2 °,19.20 ° ± 0.2 °,19.65 ° ± 0.2 °,20.58 ° ± 0.2 °,20.83 ° ± 0.2 °,21.01 ° ± 0.2 °,21.85 ° ± 0.2 °,22.29 ° ± 0.2 °,23.09 ° ± 0.2 °,23.80 ° ± 0.2 °,25.05 ° ± 0.2 °,25.93 ° ± 0.2 °,27.72 ° ± 0.2 °,28.81 ° ± 0.2 °,30.67 ° ± 0.2 °,31.13 ° ± 0.2.63 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form C, the tartrate form C having an X-ray powder diffraction pattern substantially as shown in figure 13.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form C, and wherein a differential scanning calorimetry trace of the tartrate form C comprises an endothermic peak at 192.69 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form C, the tartrate form C having a differential scanning calorimetry pattern substantially as shown in figure 23.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form D, and the tartrate form D has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.15 degrees +/-0.2 degrees, 7.75 degrees +/-0.2 degrees, 13.45 degrees +/-0.2 degrees, 19.28 degrees +/-0.2 degrees, 24.13 degrees +/-0.2 degrees and 29.04 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form D, and the tartrate form D has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.15 degrees +/-0.2 degrees, 7.75 degrees +/-0.2 degrees, 9.61 degrees +/-0.2 degrees, 11.36 degrees +/-0.2 degrees, 13.45 degrees +/-0.2 degrees, 19.28 degrees +/-0.2 degrees, 21.01 degrees +/-0.2 degrees, 24.13 degrees +/-0.2 degrees and 29.04 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form D, and the tartrate form D has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.15 ° ± 0.2 °,7.75 ° ± 0.2 °,9.61 ° ± 0.2 °,11.36 ° ± 0.2 °,13.45 ° ± 0.2 °,14.47 ° ± 0.2 °,15.56 ° ± 0.2 °,16.96 ° ± 0.2 °,18.32 ° ± 0.2 °,18.71 ° ± 0.2 °,19.28 ° ± 0.2 °,20.18 ° ± 0.2 °,21.01 ° ± 0.2 °,21.53 ° ± 0.2 °,22.26 ° ± 0.2 °,23.67 ° ± 0.2 °,24.13 ° ± 0.2 °,25.35 ° ± 0.2 °,26.78 ° ± 0.2 °,28.19 ° ± 0.2 °,29.04 ° ± 0.2 °,30.59 ° ± 0.2 °,31.90 ° ± 0.2.95 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is in tartrate form D, the tartrate form D having an X-ray powder diffraction pattern substantially as shown in figure 14.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form D, and wherein a differential scanning calorimetry trace of the tartrate form D comprises an endothermic peak at 196.10 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form D, the tartrate form D having a differential scanning calorimetry pattern substantially as shown in figure 24.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form E, and the tartrate form E has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.53 degrees +/-0.2 degrees, 9.85 degrees +/-0.2 degrees, 11.14 degrees +/-0.2 degrees, 17.43 degrees +/-0.2 degrees, 20.70 degrees +/-0.2 degrees, 22.11 degrees +/-0.2 degrees, 23.17 degrees +/-0.2 degrees and 23.81 degrees +/-0.2 degrees.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form E, and the tartrate form E has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 4.69 ° ± 0.2 °,6.53 ° ± 0.2 °,9.85 ° ± 0.2 °,11.14 ° ± 0.2 °,12.96 ° ± 0.2 °,17.43 ° ± 0.2 °,20.70 ° ± 0.2 °,22.11 ° ± 0.2 °,23.17 ° ± 0.2 °,23.81 ° ± 0.2 °,24.01 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form E, and the tartrate form E has an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 4.69 ° ± 0.2 °,6.53 ° ± 0.2 °,8.12 ° ± 0.2 °,9.85 ° ± 0.2 °,11.14 ° ± 0.2 °,12.96 ° ± 0.2 °,14.32 ° ± 0.2 °,15.24 ° ± 0.2 °,16.76 ° ± 0.2 °,17.43 ° ± 0.2 °,18.93 ° ± 0.2 °,19.40 ° ± 0.2 °,20.70 ° ± 0.2 °,21.61 ° ± 0.2 °,22.11 ° ± 0.2 °,23.17 ° ± 0.2 °,23.81 ° ± 0.2 °,24.01 ° ± 0.2 °,24.69 ° ± 0.2 °,25.04 ° ± 0.2 °,25.31 ° ± 0.2 °,26.24 ° ± 0.2 °,26.83 ° ± 0.2 °, 850.2 ° ± 0.2 °,35 ± 0.33 ° ± 0.2 °.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form E, the tartrate form E having an X-ray powder diffraction pattern substantially as shown in figure 15.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form E, and a differential scanning calorimetry trace of the tartrate form E comprises an endothermic peak at 195.27 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a tartrate salt, wherein the tartrate salt is tartrate form E, the tartrate form E having a differential scanning calorimetry pattern substantially as shown in figure 25.

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

In one aspect, the invention relates to the use of said salt or said pharmaceutical composition for the preparation of a medicament for the prevention, treatment or alleviation of 5-HT₆A receptor associated disease.

In some such embodiments, the invention relates to 5-HT₆The receptor-associated disease is a central nervous system disorder, a gastrointestinal disorder, or obesity.

In some such embodiments, the central nervous system disorder of the present invention is attention deficit hyperactivity disorder, anxiety, a stress-related disorder, schizophrenia, obsessive compulsive disorder, manic depression, a neurological disorder, a memory disorder, an attention deficit disorder, parkinson's disease, amyotrophic lateral sclerosis, alzheimer's disease, or huntington's chorea.

In another aspect, the invention relates to the use of said salt or said pharmaceutical composition for the preparation of a medicament for antagonizing 5-HT₆A receptor.

In another aspect, the invention also relates to a preparation method of the salt of the compound shown in the formula (I) or the crystal form thereof.

The solvent used in the method for preparing the salt or the crystalline form thereof according to the present invention is not particularly limited, and any solvent that can dissolve the starting materials to an extent that does not affect the properties thereof is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. The invention provides a preferable solvent used in each reaction step.

The experiments for the preparation of the salts or crystalline forms of the invention are described in detail in the examples section. Meanwhile, the invention provides pharmacological property test experiments (such as pharmacokinetic experiments), solubility experiments, stability experiments, hygroscopicity experiments and the like of the salt or the crystal form thereof. Experiments prove that the acetate crystal form A has unexpected technical advantages:

1. the acetate crystal form A has good stability, for example, no or almost no hygroscopicity, can not change when being placed at normal temperature, is stable under the conditions of high temperature, high humidity and illumination, and has basically no change in appearance and purity; the water solubility is good.

2. Compared with other salts, such as citrate crystal form B and sulfate crystal form A, the acetate crystal form A has higher blood concentration and exposure in a beagle dog, so that the acetate crystal form A has better pharmacokinetic properties.

Therefore, the acetate crystal form A has better biological activity and higher stability, and is more suitable for pharmaceutical use.

Definitions and general terms

Unless defined otherwise, 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 equivalent 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 form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single or multicomponent crystals, and/or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of compounds. Crystalline forms of the substance 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 a defined space, e.g., in a nanopore or capillary, on a surface or template, e.g., on a polymer, in the presence of an additive such as a co-crystallizing counter molecule, desolventization, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent drop milling, among others.

"amorphous" or "amorphous form" refers to a substance formed when particles (molecules, atoms, ions) of the substance are aperiodically arranged in three-dimensional space, and is characterized by a diffuse, non-peaked, X-ray powder diffraction pattern. Amorphous is a particular physical form of solid material, with locally ordered structural features suggesting a myriad of connections to crystalline materials. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent 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 useful in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, 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.

By "anti-solvent" is meant a fluid that facilitates precipitation of the product (or product precursor) from the solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes precipitation by 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" refers to a compound having a solvent on a surface, in a crystal lattice, or on and in a crystal lattice, which may be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.

Crystalline forms can be identified by a variety of techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point methods, Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance methods, raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, Scanning Electron Microscopy (SEM), quantitative analysis, solubility, and dissolution rate, and the like.

Information such as change, crystallinity, crystal structure state and the like of the crystal form can be detected by X-ray powder diffraction (XRPD), and the method is a common means for identifying the crystal form. The peak positions of the XRPD patterns depend primarily on the structure of the crystalline form, being relatively insensitive to experimental details, while their relative peak heights depend on a number of factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, substantially as shown in the XRPD patterns provided in the figures of the present invention. Also, the 2 θ measurement of the XRPD pattern may have experimental error, and the 2 θ measurement of the XRPD pattern may be slightly different from instrument to instrument and from sample to sample, so the 2 θ value cannot be considered absolute. The diffraction peaks have a tolerance of ± 0.2 ° according to the conditions of the instrument used in the test.

Differential Scanning Calorimetry (DSC) is to measure the temperature of a sample and an inert reference substance (usually alpha-Al) by continuously heating or cooling under the control of a program₂O₃) The energy difference therebetween varies with temperature. The endothermic peak height of the DSC curve depends onSample preparation and instrument geometry are many factors, and peak position is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline form of the present invention is characterized by a DSC profile with characteristic peak positions substantially as shown in the DSC profiles provided in the figures of the present invention. Meanwhile, the DSC profile may have experimental errors, and the peak position and peak value of the DSC profile may slightly differ between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. The endothermic peak has a tolerance of + -3 deg.C depending on the instrument used in the experiment.

Thermogravimetric analysis (TGA) is a technique for measuring the change in mass of a substance with temperature under program control, and is suitable for examining the loss of a solvent in a crystal or the sublimation and decomposition of a sample, and it can be presumed that the crystal contains crystal water or a crystal solvent. The change in mass shown by the TGA profile depends on many factors such as sample preparation and instrumentation; the mass change of the TGA detection varies slightly from instrument to instrument and from sample to sample. There is a tolerance of + -0.1% for mass change depending on the condition of the instrument used in the test.

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

The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffraction pattern or DSC pattern or raman spectrum or infrared spectrum are shown in the figure.

When referring to a spectrogram or/and data appearing in a graph, "peak" refers to a feature that one skilled in the art would recognize as not being attributable to background noise.

The present invention relates to salts of said (3- (difluoromethyl) -1- ((3-fluorophenyl) sulfonyl) -4- (piperazin-1-yl) -1H-indole and/or crystalline forms thereof, which exist in substantially pure crystalline form.

By "substantially pure" is meant that a crystalline form is substantially free of one or more additional crystalline forms, i.e., the crystalline form is at least 80%, or at least 85%, or at least 90%, or at least 93%, 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% pure, or the crystalline form contains additional crystalline forms, the percentage of which in the total volume or weight of the crystalline 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%.

By "substantially free" is meant that the percentage of one or more other crystalline forms in the total volume or 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%.

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

In the context of the present invention, the word "about" or "approximately" when used or whether used, means within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, the term "about" or "approximately" means within an acceptable standard error of the mean, for one of ordinary skill in the art. Whenever a number is disclosed with a value of N, any number within the values of N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8% or N +/-10% is explicitly disclosed, wherein "+/-" means plus or minus.

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

Pharmaceutical compositions, formulations, administration and uses of the salts or crystalline forms thereof of the invention

The pharmaceutical composition of the invention is characterized by comprising salts and/or crystal forms of the compounds shown in the formula (I) and pharmaceutically acceptable carriers, auxiliary agents or excipients. The amount of the salt of the compound or crystalline form thereof 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 comprise 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, for example, in Ansel h.c.et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, philidelphia; 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 person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select 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).

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are 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. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

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

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

The salts of the compounds of the present invention or crystalline forms thereof are generally formulated in a dosage form suitable for administration to a patient by a 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, e.g., 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 composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted 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. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent 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 dissolution of the active ingredient.

In one embodiment, the treatment methods of the present invention comprise 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. Various embodiments of the present invention encompass the treatment of the diseases mentioned herein 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, the salt of the compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising the salt of the compound of the present invention or a crystalline form thereof may be administered by any suitable route of administration, including systemic administration 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 and intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, a salt of a compound of the invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof may be administered orally. In another embodiment, a salt of a compound of the invention or a crystalline form thereof or a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof may be administered by inhalation. In yet another embodiment, the salt of the compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising the salt of the compound of the present invention or a crystalline form thereof may be administered intranasally.

In one embodiment, the salt of the compound of the present invention or a crystalline form thereof or a pharmaceutical composition comprising the salt of the compound of the present invention or a crystalline form thereof may be administered once or several times at different time intervals within a specified time period according to a dosing regimen. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for a salt of a compound of the invention or a crystalline form thereof, or a pharmaceutical composition comprising a salt of a compound of the invention or a crystalline form thereof, depend on the pharmacokinetic properties of the salt of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, suitable dosing regimens of the salts of the compounds of the invention or crystalline forms thereof, or pharmaceutical compositions comprising the salts of the compounds of the invention or crystalline forms thereof, including the duration of the regimen, will depend upon the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The salts of the compounds of the present invention or crystalline forms thereof may be administered concurrently with, before or after one or more other therapeutic agents. The salts of the compounds of the present invention or their crystalline forms may be administered separately from the other therapeutic agents by the same or different routes of administration, or in the form of the same pharmaceutical compositions.

The salts of the compounds of the present invention or their crystalline forms may be used in combination with, i.e. form a pharmaceutical combination according to the present invention, e.g.: donepezil, nalmefene, risperidone, vitamins E, SAM-760, AVN-211, AVN-101, RP-5063, tozadenant, PRX-3140, PRX-8066, RVT-101, naluzaton, idalopidine, tacrine, rivastigmine, galantamine, memantine, mirtazapine, venlafaxine, despramine, nortriptyline, zolpidem, zopiclone, nicergoline, piracetazone, selegiline, pentoxifylline, and salts and combinations thereof, etc., or a salt of a compound of the invention or a crystalline form thereof may be administered in combination with a physical method such as phototherapy or electrical stimulation.

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

The above cited dose profiles have been demonstrated in vitro and in vivo tests using beneficial mammals (e.g., mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof.

In one embodiment, the amount of the compound in a therapeutically effective dose of a salt of a compound of the invention is from about 0.1mg to about 2,000mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide from about 1mg to about 2,000mg, from about 10mg to about 1,000mg, from about 20mg to about 500mg, or from about 25mg to about 250mg of the principal active ingredient or a combination of principal ingredients per dosage unit form. In a particular embodiment, the pharmaceutical dosage unit form is prepared to provide about 10mg,20mg,25mg,50mg,100mg,250mg,500mg,1000mg or 2000mg of the primary active ingredient.

The salt of the compound or the crystal form and the pharmaceutical composition thereof provided by the invention can be used for preparing medicaments for preventing, treating or relieving the Alzheimer's disease of mammals including human beings, and can also be used for preparing medicaments for preventing, treating or relieving the Alzheimer's disease of the mammals including human beings and 5-HT₆Pharmaceutical compositions for the treatment of receptor-related diseases, and their use for antagonizing 5-HT₆A pharmaceutical product of a recipient.

In particular, the amount of compound in the pharmaceutical compositions of the present invention is effective to detectably and selectively antagonize 5-HT₆Receptor, salts of the compounds of the inventionOr a crystalline form thereof, can be used as a therapeutic agent for treating 5-HT₆A drug for a receptor-related disease such as alzheimer's disease.

The salts of the compounds of the present invention or their crystalline forms may be used in, but are in no way limited to, the prevention, treatment or alleviation of 5-HT by administering to a patient an effective amount of a salt of a compound of the present invention or a crystalline form or a pharmaceutical composition thereof₆A receptor associated disease. The above-mentioned 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, stress-related disorders, schizophrenia, obsessive compulsive disorder, manic depression, neurological disorders, memory disorders, attention deficit disorder, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's chorea, or the like.

An "effective amount" or "effective dose" of a salt of a compound of the invention or a crystalline form or pharmaceutically acceptable composition thereof refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The salt of the compound of the present invention or a crystalline form or pharmaceutically acceptable composition thereof may be administered in any amount and by any route effective to treat or reduce the severity of the disease in accordance with the methods of the present invention. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The salts of the compounds of the present invention or crystalline forms or pharmaceutically acceptable compositions thereof may be administered in combination with one or more other therapeutic agents, as discussed herein.

The salts of the compounds of the present invention or their crystalline forms and pharmaceutical compositions are useful in veterinary therapy for pets, animals of the introduced breed and mammals in farm animals, in addition to human therapy. Examples of other animals include horses, dogs, and cats.

Drawings

Figure 1 is an X-ray powder diffraction (XRPD) pattern of acetate form a of the compound of formula (I).

Figure 2 is an X-ray powder diffraction (XRPD) pattern of acetate form B of the compound of formula (I).

Figure 3 is an X-ray powder diffraction (XRPD) pattern of form a of the citrate salt of the compound of formula (I).

Figure 4 is an X-ray powder diffraction (XRPD) pattern of form B of the citrate salt of the compound of formula (I).

Figure 5 is an X-ray powder diffraction (XRPD) pattern of form C of the citrate salt of the compound of formula (I).

Figure 6 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form a of the compound of formula (I).

Figure 7 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form B of the compound of formula (I).

Figure 8 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form C of the compound of formula (I).

Figure 9 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form D of the compound of formula (I).

Figure 10 is an X-ray powder diffraction (XRPD) pattern of the sulfate salt form E of the compound of formula (I).

Figure 11 is an X-ray powder diffraction (XRPD) pattern of tartrate form a of the compound of formula (I).

Figure 12 is an X-ray powder diffraction (XRPD) pattern of tartrate form B of the compound of formula (I).

Figure 13 is an X-ray powder diffraction (XRPD) pattern of tartrate form C of the compound of formula (I).

Figure 14 is an X-ray powder diffraction (XRPD) pattern of crystalline form D of the tartrate salt of the compound of formula (I).

Figure 15 is an X-ray powder diffraction (XRPD) pattern of crystalline form E of the tartrate salt of the compound of formula (I).

FIG. 16 is a Differential Scanning Calorimetry (DSC) profile of acetate form A of the compound of formula (I).

FIG. 17 is a Differential Scanning Calorimetry (DSC) profile of acetate form B of the compound of formula (I).

Figure 18 is a Differential Scanning Calorimetry (DSC) profile of the citrate form a of the compound of formula (I).

Figure 19 is a Differential Scanning Calorimetry (DSC) profile of form B of the citrate salt of the compound of formula (I).

Figure 20 is a Differential Scanning Calorimetry (DSC) profile of the citrate form C of the compound of formula (I).

FIG. 21 is a Differential Scanning Calorimetry (DSC) profile of tartrate form A of the compound of formula (I).

FIG. 22 is a Differential Scanning Calorimetry (DSC) profile of tartrate form B of the compound of formula (I).

Figure 23 is a Differential Scanning Calorimetry (DSC) profile of tartrate form C of the compound of formula (I).

FIG. 24 is a Differential Scanning Calorimetry (DSC) profile of tartrate form D of the compound of formula (I).

FIG. 25 is a Differential Scanning Calorimetry (DSC) profile of tartrate form E of the compound of formula (I).

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

The X-ray powder diffraction analysis method used by the invention comprises the following steps: an Empyrean diffractometer, using Cu-Ka radiation (45KV,40mA) to obtain an X-ray powder diffraction pattern. The powdered sample was prepared as a thin layer 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 Collector software was used to collect Data, HighScore Plus software processed the Data, and Data Viewer software read the Data.

The Differential Scanning Calorimetry (DSC) analysis method used in the invention comprises the following steps: differential scanning calorimetry was performed using a TA Q2000 module with a thermoanalytical controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. About 1-5mg of the sample was accurately weighed into a specially made aluminum crucible with a lid and the sample analysis was performed from room temperature to about 300 c using a 10 c/min linear heating device. During use, the DSC cell was purged with dry nitrogen.

The solubility of the invention is measured by an Agilent 1200 high performance liquid chromatograph DAD/VWD detector, and the type of a chromatographic column is Agilent XDB-C18(4.6 multiplied by 50mm, 5 mu m). The detection wavelength is 266nm, the flow rate is 1.0mL/min, the column temperature is 35 ℃, and the ratio of mobile phase A: acetonitrile/0.01M ammonium acetate 10/90(V/V) analytical method: acetonitrile/mobile phase a ═ 70/30(V/V), run time: for 10 minutes.

Detailed description of the invention

A compound of formula (I): 3- (difluoromethyl) -1- ((3-fluorophenyl) sulfonyl) -4- (piperazin-1-yl) -1H-indole, the specific synthesis was as described in International application WO 2016004882A1, example 5.

Examples

Example 1 crystalline form a of acetate salt of the invention

1. Preparation of acetate form a

The compound represented by the formula (I) (24g,58.62mmol) was dissolved in ethyl acetate (200mL), and acetic acid (5.28g,88.0mmol,1.5eq) was added dropwise and reacted at room temperature overnight. The reaction was stopped, filtered, the filter residue was washed with methyl tert-butyl ether (50mL x 2) and dried to give an off-white solid powder as acetate form a.

2. Identification of acetate form a

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 5.50 °,10.16 °,12.82 °,13.40 °,14.49 °,16.01 °,16.59 °,16.94 °,17.83 °,18.93 °,19.34 °,19.95 °,20.14 °,20.45 °,21.25 °,21.77 °,22.19 °,22.66 °,24.34 °,26.20 °,27.01 °,27.84 °,33.00 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 162.89 ℃, with a margin of error of ± 3 ℃.

Example 2 crystalline form B of acetate salt of the invention

1. Preparation of acetate form B

Form A acetate (50mg) was dissolved in dimethyl sulfoxide (0.5mL), isopropanol (2mL) was added dropwise, and the reaction was allowed to proceed overnight at room temperature. Stopping the reaction, performing suction filtration, and drying to obtain off-white solid powder which is acetate crystal form B.

2. Identification of acetate form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 5.81 °,13.16 °,19.25 °,20.47 °,21.59 °,22.47 °,23.01 °,24.68 °,31.89 °,36.95 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 159.86 ℃, with a margin of error of ± 3 ℃.

Example 3 citrate form a of the invention

1. Preparation of citrate form a

The compound represented by the formula (I) (50mg) was added to methanol (2mL), and citric acid (45mg) was further added to react at room temperature overnight. Stopping reaction, performing suction filtration, and drying to obtain white solid powder which is citrate crystal form A.

2 identification of citrate form a

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.54 °,10.72 °,12.86 °,15.17 °,15.78 °,17.26 °,17.77 °,18.40 °,18.80 °,19.68 °,20.26 °,21.56 °,22.04 °,22.31 °,22.87 °,23.54 °,24.13 °,24.65 °,25.00 °,25.26 °,26.05 °,27.44 °,28.41 °,29.89 °,30.67 °,31.30 °,32.24 °, and an error tolerance of ± 0.2 ° exists.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 181.64 ℃, with a margin of error of ± 3 ℃.

Example 4 citrate form B of the invention

1. Preparation of citrate form B

The compound represented by the formula (I) (50mg) was added to methylene chloride (2mL), and citric acid (25mg) was further added to conduct a reaction at room temperature overnight. Stopping reaction, performing suction filtration, and drying to obtain white solid powder which is the citrate crystal form B.

2 identification of citrate form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 5.66 °,6.84 °,7.72 °,9.54 °,11.31 °,13.69 °,16.22 °,17.00 °,19.17 °,20.56 °,22.99 °,23.92 °,25.86 °,28.21 °,30.05 °,32.61 °,34.43 °,36.48 °,37.63 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 132.49 ℃, with a margin of error of ± 3 ℃.

Example 5 form C of citrate salt of the invention

1. Preparation of citrate form C

The compound represented by the formula (I) (50mg) was added to acetone (1mL) and water (1mL), and citric acid (25mg) was further added to conduct a reaction at room temperature overnight. Stopping reaction, performing suction filtration, and drying to obtain white solid powder which is the citrate crystal form C.

2 identification of citrate form C

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 7.72 °,10.92 °,12.35 °,13.05 °,14.75 °,15.35 °,15.97 °,17.20 °,17.47 °,17.95 °,18.60 °,18.95 °,19.87 °,20.72 °,21.72 °,22.20 °,22.50 °,2306 °,23.58 °,24.34 °,24.81 °,25.45 °,26.23 °,26.54 °,27.59 °,30.11 °,30.85 °, with an error tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 107.30 ℃ and 180.22 ℃, with a margin of error of ± 3 ℃.

Example 6 crystalline form a of the sulfate salt of the invention

1. Preparation of sulfate form A

Adding ethyl acetate (10mL) into a round-bottom flask of a compound (2g) shown in formula (I), heating to 50 ℃ to dissolve, then dropwise adding sulfuric acid (0.6g) (dissolving in 2mL of ethyl acetate, wherein the molar ratio of the compound shown in formula (I) to the sulfuric acid is 1/1.2), immediately precipitating a white solid, suspending for 12h, filtering and drying to obtain about 2.3g of a sulfate crystal form A product.

2. Identification of sulfate form a

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 9.76 ° ± 0.2 °,14.55 ° ± 0.2 °,15.65 ° ± 0.2 °,16.35 ° ± 0.2 °,17.95 ° ± 0.2 °,18.93 ° ± 0.2 °,19.37 ° ± 0.2 °,19.64 ° ± 0.2 °,20.22 ° ± 0.2 °,20.98 ° ± 0.2 °,21.38 ° ± 0.2 °,21.81 ° ± 0.2 °,22.18 ° ± 0.2 °,23.22 ° ± 0.2 °,23.60 ° ± 0.2 °,24.09 ° ± 0.2 °,25.24 ° ± 0.2 °,26.25 ° ± 0.2 °,27.62 ° ± 0.2 °,29.66 ° ± 0.2 °,29.96 ° ± 0.2 °,34.52 ° ± 0.2 °.

Example 7 crystalline form B of the sulfate salt of the invention

1. Preparation of sulfate form B

And (3) putting the sulfate crystal form A (50mg) into a test tube, adding water (2mL), suspending for 12h at room temperature, and filtering and drying to obtain a sulfate crystal form B.

2. Identification of sulfate form B

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 9.83 °,15.18 °,15.85 °,16.49 °,18.47 °,19.54 °,20.94 °,21.55 °,21.95 °,22.34 °,23.21 °,24.21 °,26.38 °,26.58 °,29.97 °,34.98 °, with a tolerance of ± 0.2 °.

Example 8 crystalline form C of the sulfate salt of the invention

1. Preparation of sulfate form C

Taking the sulfate crystal form A (50mg) in a test tube, adding 1, 4-dioxane (2mL), suspending for 12h at room temperature, and then filtering and drying to obtain the sulfate crystal form C.

2. Identification of sulfate form C

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 8.81 °,15.58 °,16.33 °,17.25 °,18.30 °,19.28 °,19.79 °,20.02 °,20.62 °,20.80 °,22.25 °,22.88 °,23.48 °,24.07 °,25.29 °,26.83 °,28.63 °,29.80 °,32.54 °, with a tolerance of ± 0.2 °.

Example 9 crystalline form D of the sulfate salt of the invention

1. Preparation of sulfate form D

And (3) putting the sulfate crystal form A (50mg) into a test tube, adding water (2mL), suspending for 48h at 60 ℃, and filtering and drying to obtain a sulfate crystal form D.

2. Identification of sulfate form D

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 9.44 °,10.64 °,14.33 °,15.20 °,15.54 °,15.82 °,18.18 °,18.89 °,19.23 °,19.74 °,20.22 °,21.20 °,21.54 °,21.87 °,22.21 °,22.74 °,23.27 °,24.80 °,26.50 °,27.16 °,28.54 °,31.37 °,33.90 °, with a tolerance of ± 0.2 °.

Example 10 crystalline form E of the sulfate salt of the invention

1. Preparation of sulfate form E

Dissolving the sulfate crystal form A (30mg) in methanol (1mL), dropwise adding the solution into isopropanol (2mL), suspending for 24h, separating out a solid, filtering and drying to obtain a sulfate crystal form E.

2. Identification of sulfate form E

Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 9.84 degrees, 10.51 degrees, 11.15 degrees, 14.99 degrees, 16.40 degrees, 18.54 degrees, 19.21 degrees, 20.49 degrees, 21.48 degrees, 21.91 degrees, 22.44 degrees, 23.62 degrees, 24.12 degrees, 24.40 degrees, 26.44 degrees, 27.64 degrees, 30.07 degrees, and error tolerance of +/-0.2 degrees exists.

Example 11 tartrate form a of the invention

1. Preparation of tartrate form a

The compound represented by the formula (I) (50mg) was added to acetonitrile (1mL), and tartaric acid (25mg) was further added to the mixture to conduct a reaction at room temperature overnight. Stopping the reaction, performing suction filtration, and drying to obtain off-white solid powder which is tartrate crystal form A.

2. Identification of tartrate form a

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.12 °,9.16 °,10.17 °,12.20 °,13.51 °,13.79 °,14.21 °,15.45 °,16.27 °,18.32 °,19.37 °,19.88 °,20.38 °,20.84 °,21.47 °,22.14 °,24.16 °,24.54 °,25.37 °,26.30 °,27.86 °,29.63 °,30.73 °,32.04 °,32.56 °,32.94 °,33.96 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 196.97 ℃, with a margin of error of ± 3 ℃.

Example 12 tartrate form B of the invention

1. Preparation of tartrate form B

The compound represented by the formula (I) (50mg) was added to butanone (2mL), and tartaric acid (25mg) was further added to the mixture, and the mixture was reacted at room temperature overnight. Stopping the reaction, performing suction filtration, and drying to obtain off-white solid powder which is tartrate crystal form B.

2. Identification of tartrate form B

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 3.42 °,6.74 °,7.76 °,8.87 °,10.09 °,11.67 °,12.78 °,13.46 °,14.06 °,15.47 °,17.09 °,17.37 °,17.87 °,18.30 °,19.01 °,19.50 °,19.82 °,20.23 °,20.90 °,21.99 °,22.32 °,22.86 °,23.44 °,23.71 °,24.04 °,24.92 °,25.27 °,29.28 °,29.59 °,34.68 °, and an error tolerance of ± 0.2 ° exists.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 84.06 ℃ and 194.68 ℃, with a margin of error of ± 3 ℃.

Example 13 tartrate form C of the invention

1. Preparation of tartrate form C

The compound represented by the formula (I) (50mg) was added to isopropanol (2mL), and tartaric acid (33mg) was further added to react at room temperature overnight. Stopping the reaction, performing suction filtration, and drying to obtain off-white solid powder which is tartrate crystal form C.

2. Identification of tartrate form C

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.16 °,9.27 °,13.22 °,13.97 °,15.10 °,15.80 °,16.64 °,18.69 °,19.20 °,19.65 °,20.58 °,20.83 °,21.01 °,21.85 °,22.29 °,23.09 °,23.80 °,25.05 °,25.93 °,27.72 °,28.81 °,30.67 °,31.13 °,34.63 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 192.69 ℃, with a margin of error of ± 3 ℃.

Example 14 crystalline form D of tartrate according to the invention

1. Preparation of tartrate form D

The compound represented by the formula (I) (50mg) was added to methylene chloride (2mL), and tartaric acid (23mg) was further added to the mixture, and the mixture was reacted at room temperature overnight. Stopping the reaction, performing suction filtration, and drying to obtain off-white solid powder which is tartrate crystal form D.

2. Identification of tartrate form D

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 6.15 °,7.75 °,9.61 °,11.36 °,13.45 °,14.47 °,15.56 °,16.96 °,18.32 °,18.71 °,19.28 °,20.18 °,21.01 °,21.53 °,22.26 °,23.67 °,24.13 °,25.35 °,26.78 °,28.19 °,29.04 °,30.59 °,31.90 °,32.95 °,35.82 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 196.10 ℃, with a margin of error of ± 3 ℃.

Example 15 tartrate form E of the invention

1. Preparation of tartrate form E

The compound represented by the formula (I) (50mg) was added to water (2mL), and tartaric acid (21mg) was further added to the mixture, followed by reaction at room temperature overnight. Stopping the reaction, performing suction filtration, and drying to obtain off-white solid powder which is tartrate crystal form E.

2. Identification of tartrate form E

(1) Identified by Empyrean X-ray powder diffraction (XRPD) analysis: using Cu-ka radiation, having the following characteristic peaks expressed in degrees 2 θ: 4.69 °,6.53 °,8.12 °,9.85 °,11.14 °,12.96 °,14.32 °,15.24 °,16.76 °,17.43 °,18.93 °,19.40 °,20.70 °,21.61 °,22.11 °,23.17 °,23.81 °,24.01 °,24.69 °,25.04 °,25.31 °,26.24 °,26.83 °,27.32 °,29.53 °,33.28 °,35.92 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained an endotherm peak at 195.27 ℃, with a margin of error of ± 3 ℃.

Example 16 pharmacokinetic experiments on the salt of the invention or its crystalline forms

The test sample (i.e., the salt of the invention or crystalline form thereof, or the compound of formula (I) of the invention) is filled into capsules for oral administration.

3 male beagle dogs of 8-12kg were orally administered with capsules containing test samples at a dose of 5mg/kg, and blood was collected at time points of 0.25,0.5,1.0,2.0,4.0,6.0,8.0 and 24 hours. A standard curve of the appropriate range is established based on the sample concentration, and the concentration of the test sample in the plasma sample is determined in MRM mode using LC-MS/MS model AB SCIEX API4000 and subjected to quantitative analysis. According to the drug concentration-time curve, pharmacokinetic parameters are calculated by adopting a WinNonLin 6.3 software non-compartmental model method. The results of the experiment are shown in table 1.

TABLE 1 pharmacokinetic experimental data for the salts of the invention or the crystalline forms thereof

Test sample	T_max(h)	C_max(ng/ml)	AUC_last(h*ng/ml)
				Example 1 (acetate form A)	6.67	226	3510
Example 2 (citrate form B)	5.33	67.5	986
				Example 3 (sulfate form A)	4.67	76.2	1190
A compound of formula (I)	18.7	104	1340

And (4) experimental conclusion:

as can be seen from table 1, compared to the compound of formula (I), the citrate crystal form B or the sulfate crystal form a of the compound of formula (I), the acetate crystal form a of the present invention has higher blood concentration and larger exposure in beagle, and has better pharmacokinetic properties.

Example 17 stability test of the salt of the invention or its crystalline forms

(1)High temperature experiment: taking a proper amount of a batch of samples to be tested, putting the samples into a flat weighing bottle, spreading the samples into a thin layer with the thickness less than or equal to 5mm, putting the weighing bottle into a constant temperature box with the temperature of 40 +/-2 ℃/75 +/-5% RH and the temperature of 60 +/-2 ℃/75 +/-5% RH, standing for 10 days, sampling on the 5 th day and the 10 th day, and detecting according to the key stability investigation items: the color change of the sample is observed, and the purity of the sample is detected by HPLC.

(2)High humidity experiment: a proper amount of a batch of samples to be tested are put into a flat weighing bottle, spread into a thin layer with the thickness less than or equal to 5mm, placed for 10 days at 25 ℃ under the condition of RH 75% +/-5% or RH 90% +/-5%, sampled on the 5 th and 10 th days, detected according to key stability investigation items, the color change of the samples is observed, and the purity of the samples is detected by HPLC.

(3)Light test: taking a proper amount of a batch of samples to be tested, putting the samples into a flat weighing bottle, spreading the samples into a thin layer with the thickness less than or equal to 5mm, and placing the thin layer in an open placeIn an illumination box (with an ultraviolet lamp), the illumination is 4500 +/-500 lx, and the ultraviolet light is more than or equal to 0.7 w.h/m²Was left for 16 days, sampled on

days

5, 10 and 16, and examined according to stability stress examination items: the color change of the sample is observed, and the purity of the sample is detected by HPLC.

The results of the stability experiments are shown in table 2:

table 2 stability test results for acetate form a of the present invention

And (4) experimental conclusion:

as can be seen from Table 2, the appearance and purity of the acetate form A of the present invention have no significant change under high temperature, high humidity and illumination conditions. Namely, the acetate crystal form A has good stability under various lofting conditions, and is suitable for pharmaceutical application.

EXAMPLE 18 hygroscopicity assay of a salt of the invention or crystalline forms thereof

1. Experimental methods

1) Placing a dried glass weighing bottle with a plug (outer diameter of 50mm, height of 15mm) in a constant temperature drier (ammonium chloride saturated solution placed at the lower part) at 25 + -1 deg.C in the previous day, and precisely weighing₁)。

2) Taking a proper amount of sample, spreading in the weighing bottle to obtain a sample with thickness of about 1mm, and precisely weighing (m)₂)。

3) The weighing bottle is opened and is placed under the constant temperature and humidity condition for 24 hours together with the bottle cap.

4) The weighing bottle cap is closed, and precision weighing is carried out (m)₃) And calculating: percent weight gain [ (% m)₃-m₂)/(m₂-m₁)×100％

5) The results of hygroscopicity were shown in Table 3.

TABLE 3 determination of hygroscopicity

2. The results of the hygroscopicity test are shown in table 4:

TABLE 4 hygroscopicity test results for acetate salt form A of the present invention

Experiment number	m₁(mg)	m₂(mg)	m₃(mg)	Wet induced weight gain (%)	Conclusion
						1	30.58512	31.67432	31.67497	0.06	No or almost no hygroscopicity
2	29.52900	30.73932	30.74009	0.06	No or almost no hygroscopicity

And (4) experimental conclusion:

according to experimental results, the acetate crystal form A has no or almost no hygroscopicity, and is not easy to deliquesce under the influence of high humidity.

Example 19 solubility testing of salts of the invention or crystalline forms thereof

Placing a sample to be tested in water with the temperature of 37 ℃ to prepare supersaturated turbid liquid, shaking for 24 hours, filtering, taking filtrate, and detecting the solubility of the target sample in the water by using an HPLC method. The results of the experiment are shown in Table 5.

TABLE 5 solubility test data for salts of the invention or crystalline forms thereof

And (4) experimental conclusion:

the experimental result shows that compared with the compound shown in the formula (I) and the citrate crystal form B or the sulfate crystal form A of the compound shown in the formula (I), the acetate crystal form A has higher solubility in water, so the compound has better drug forming property and is suitable for preparation development.

The above description is only a basic description of the present invention, and any equivalent changes made according to the technical solution of the present invention should fall within the protection scope of the present invention.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer 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, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims

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

characterized in that the salt is acetate; wherein the acetate is an acetate crystal form A, and an X-ray powder diffraction pattern of the acetate crystal form A has diffraction peaks at the following 2 theta angles: 5.50 ° ± 0.2 °,12.82 ° ± 0.2 °,17.83 ° ± 0.2 °,18.93 ° ± 0.2 °,20.14 ° ± 0.2 °,22.19 ° ± 0.2 °,22.66 ° ± 0.2 °,24.34 ° ± 0.2 °.

2. The salt of claim 1, wherein the acetate salt is form A acetate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 5.50 ° ± 0.2 °,10.16 ° ± 0.2 °,12.82 ° ± 0.2 °,14.49 ° ± 0.2 °,17.83 ° ± 0.2 °,18.93 ° ± 0.2 °,19.34 ° ± 0.2 °,20.14 ° ± 0.2 °,21.77 ° ± 0.2 °,22.19 ° ± 0.2 °,22.66 ° ± 0.2 °,24.34 ° ± 0.2 °.

3. The salt of claim 1, wherein the acetate salt is form A acetate salt having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 5.50 ° ± 0.2 °,10.16 ° ± 0.2 °,12.82 ° ± 0.2 °,13.40 ° ± 0.2 °,14.49 ° ± 0.2 °,16.01 ° ± 0.2 °,16.59 ° ± 0.2 °,16.94 ° ± 0.2 °,17.83 ° ± 0.2 °,18.93 ° ± 0.2 °,19.34 ° ± 0.2 °,19.95 ° ± 0.2 °,20.14 ° ± 0.2 °,20.45 ° ± 0.2 °,21.25 ° ± 0.2 °,21.77 ° ± 0.2 °,22.19 ° ± 0.2 °,22.66 ° ± 0.2 °,24.34 ° ± 0.2 °,26.20 ° ± 0.2 °,27.01 ° ± 0.2 °,27.84 ° ± 0.2 °,33.00 ° ± 0.2 °.

4. The salt of any one of claims 1-3, wherein the acetate salt is form A acetate salt having an X-ray powder diffraction pattern substantially as shown in figure 1.

5. The salt of claim 1, wherein the acetate salt is form A acetate salt and the differential scanning calorimetry trace of form A acetate salt comprises an endothermic peak at 162.89 ℃ ± 3 ℃.

6. The salt of claim 5, wherein the acetate salt is form A acetate salt having a differential scanning calorimetry pattern substantially as shown in FIG. 16.

7. A pharmaceutical composition comprising a salt of any one of claims 1-6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or combination thereof.

8. Use of a salt according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 7 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.