CN112876475A - Salts of octahydropyrrolo [3,4-c ] pyrrole derivatives - Google Patents

Abstract

The present invention relates to salts of octahydropyrrolo [3,4-c ] pyrrole derivatives. The invention also relates to a pharmaceutical composition comprising the salt and the use of the salt or the pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of diseases related to orexin receptors.

Description

Salts of octahydropyrrolo [3,4-c ] pyrrole derivatives

Technical Field

The invention belongs to the technical field of medicines, relates to a salt of an octahydropyrrolo [3,4-c ] pyrrole derivative, and particularly relates to a salt of (5- (5-chlorobenzo [ d ] oxazole-2-yl) hexahydropyrrolo [3,4-c ] pyrrole-2 (1H) -yl) (2-fluoro-6- (2H-1,2, 3-triazole-2-yl) phenyl) methanone and an application thereof, and further relates to a pharmaceutical composition containing the salt.

Background

Orexin (orexin), also known as hypothalamin, orexin, which includes orexin a and orexin B (or hypothalamin-1 and hypothalamin-2), is a neuropeptide secreted by the hypothalamus with its main physiological roles: 1. appetite regulation, orexin is able to activate feeding-regulating neurons, significantly promote feeding, and have a dose-dependent response; 2. participating in the regulation of energy metabolism, the orexin can obviously increase the metabolic rate; 3. participating in sleep-wake regulation, orexin can inhibit rapid eye movement sleep, prolong wake time, and block orexin effect to promote sleep; 4. participating in endocrine regulation, and the influence of the orexin on the endocrine of pituitary hormone is obvious; 5. associated with sense of reward, learning, and memory; 6. promoting gastric acid secretion; 7. promoting the increase of drinking water; 8. raising blood pressure; 9. plays an important role in reward systems and drug addiction mechanisms, etc. (Piper et al, The novel blue neuroepidep, orexin-A, models The sleep-wave cycle of rates. Eur. J. Neurosis, 2000,12(2), 726-730; and Sakurai, T.et al, The neural circuit of orexin. Nature Review Neurosis, 2007,8: 171181).

Orexin produces physiological effects by acting on orexin receptors (OXR). The orexin receptor is a G-protein coupled receptor of two types, respectively called OX₁Receptors and OX₂Receptor of which OX₁The receptor selectively binds orexin A, and OX₂Receptors bind orexin A and orexin B (Sakurai T.et al, Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate the binding of behavior. cell,1998,92(4): 573-585). OX₁Receptors and OX₂Receptors are present almost exclusively in brain tissue and are selectively expressed in the brain, where OX₁The receptor is expressed in high density in locus coeruleus (blue spot), which is the initiation of noradrenergic neurons, and OX₂Receptors are expressed in high density in the tuberomamillary nucleus, which is the initiation nucleus of histaminergic neurons. OX₁Receptors and OX₂The expression of both receptors can be seen in the nucleus raphe, which is the initiation of serotonergic neurons; OX₁Receptors and OX₂Expression of both receptors is also seen in the ventral tegmental region, which is the initiation of dopaminergic neurons. In addition, OX₂Receptor expression can also be seen in and has an effect on nuclear activity in brainstem cholinergic neurons responsible for modulating rapid eye movement sleep (Marcus, j.n. et al, Differential expression of organ receptors 1and 2in the rate bridge.j.comp.neurol., 2001,435(1): 6-25; and Trivedi, p.et al, Distribution of organ receptor mRNA in the rate bridge.febs., 1998,438(1-2): 71-75).

Thus, it can be seen that orexin receptors are pathologically important in relation to a variety of diseases such as sleep disorders, depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, affective neuropathies, depressive neuropathies, anxiety neuropathies, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorders, sexual dysfunction, psychosis, schizophrenia, manic depression, confusion, dementia, drug dependence, addiction, cognitive disorders, alzheimer's disease, parkinson's disease, movement disorders, eating disorders, headache, migraine, pain, digestive system diseases, epilepsy, inflammation, cardiovascular diseases, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases and hypertension.

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.

International application WO 2017088759a1 discloses the compound (5- (5-chlorobenzo [ d ] oxazol-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2-fluoro-6- (2H-1,2, 3-triazol-2-yl) phenyl) methanone, which has orexin receptor antagonistic activity. However, the prior art has investigated crystalline forms of the compound or salts thereof.

Disclosure of Invention

Prior art WO 2017088759a1 discloses compounds of formula (I) as pale yellow solids, but does not specifically disclose the specific solid form or salt thereof. Through a large number of experimental researches, the inventor finds that the salt of the compound shown in the formula (I) has good stability, good water solubility, good pharmacokinetic property in organisms and high preparation purity of products, namely, the physical properties and various properties of the salt are more beneficial to the development of preparations, so that the salt has more excellent drugability.

In particular, the invention relates to a salt of a compound shown in formula (I) and application of the salt or a pharmaceutical composition containing the salt in preparing a medicament for preventing, treating or alleviating diseases related to an orexin receptor. The salts of the present invention may have a stable crystalline structure, and the salts 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 some embodiments, the inorganic acid salts of the present invention include, but are not limited to, hydrochloride, hydrobromide, phosphate or sulfate salts; the organic acid salt includes, but is not limited to, acetate, oxalate, maleate, tartrate, citrate, succinate, camphorsulfonate, malonate, benzoate, benzenesulfonate, methanesulfonate, or p-toluenesulfonate.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, wherein the p-toluenesulfonate salt is p-toluenesulfonate salt form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 θ angles: 4.95 ° ± 0.2 °,9.88 ° ± 0.2 °,11.11 ° ± 0.2 °,13.60 ° ± 0.2 °,14.87 ° ± 0.2 °,15.78 ° ± 0.2 °,16.44 ° ± 0.2 °,16.88 ° ± 0.2 °,18.27 ° ± 0.2 °,18.85 ° ± 0.2 °,19.71 ° ± 0.2 °,20.23 ° ± 0.2 °,20.47 ° ± 0.2 °,21.01 ° ± 0.2 °,21.31 ° ± 0.2 °,22.36 ° ± 0.2 °,23.25 ° ± 0.2 °,23.62 ° ± 0.2 ° ± 0.12 ° ± 0.2 °,24.47 ° ± 0.2 °,25.10 ° ± 0.2 °,25.53 ° ± 0.2 °, 3626.58 ° ± 0.24 ° ± 0.2 °,23.2 ° ± 0.2 ° ± 0.9 ° ± 0.2 °, 360.2 ° ± 0.2 °, 30.9 ° ± 0.2.2.42 ° ± 0.2.2 °,25 ° ± 0.2.2 °,25.2 ° ± 0.2 °.

In some embodiments, the salt of the invention is a camphorsulfonate salt, wherein the camphorsulfonate salt is camphorsulfonate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 4.42 ° ± 0.2 °,8.80 ° ± 0.2 °,11.89 ° ± 0.2 °,12.69 ° ± 0.2 °,13.22 ° ± 0.2 °,14.57 ° ± 0.2 °,15.49 ° ± 0.2 °,16.03 ° ± 0.2 °,16.62 ° ± 0.2 °,17.49 ° ± 0.2 °,18.31 ° ± 0.2 °,18.62 ° ± 0.2 °,19.42 ° ± 0.2 °,20.18 ° ± 0.2 °,20.81 ° ± 0.2 °,21.72 ° ± 0.2 °,23.72 ° ± 0.2 °,24.57 ° ± 0.25 ° ± 0.2 °,25.92 ° ± 0.2 °,26.41 ° ± 0.73 °, 26.13.13 ° ± 0.2.61 ° ± 0.2 °,27 ° ± 0.2 ° ± 0.25 ° ± 0.2 °,25 ° ± 0.2 °,25.2 °,25.92 ° ± 0.2 °,26.41 ° ± 0.2 °, 26.73.2 °,26.2 ° ± 0.2 °, 26.2.2 °, 26.13 ° ± 0.2 °, 27.13.2 ° ± 0.2.2.2 ° ± 0.2 °,2 °.

In some embodiments, the salt of the invention is a maleate salt, wherein the maleate salt is maleate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 8.39 ° ± 0.2 °,9.78 ° ± 0.2 °,10.67 ° ± 0.2 °,11.06 ° ± 0.2 °,11.30 ° ± 0.2 °,11.62 ° ± 0.2 °,12.00 ° ± 0.2 °,12.40 ° ± 0.2 °,12.63 ° ± 0.2 °,12.94 ° ± 0.2 °,13.85 ° ± 0.2 °,14.21 ° ± 0.2 °,14.51 ° ± 0.2 °,15.58 ° ± 0.2 °,16.20 ° ± 0.2 °,16.85 ° ± 0.2 °,17.22 ° ± 0.2 °,17.63 ° ± 0.2 °,17.95 ° ± 0.2 °,18.48 ° ± 0.2 °,18.80 ° ± 0.66 ° ± 0.2 °,20.01 ° ± 0.2.36 ° ± 0.2 °, 360.2 ° ± 0.2 °,2 ° ± 0.2.2 °, 2.2 ° ± 0.2 °, 2.2.2 ° ± 0.2 °, 18.2.2 °,18 ° ± 0.2 °, 18.2.2.2 °, 19.2.2 ° ± 0.2 °,19 ° ± 0.2.2.2.2 °,3 ° ± 0.2 °,3 ° ± 0.2.2.2.26 °,3 ° ± 0.2.2 °,3 ° ± 0.2 °,3 ° ± 0.2.2.2.2..

In some embodiments, the salt of the invention is an oxalate salt, wherein the oxalate salt is oxalate form a having a diffraction peak at the following 2 Θ angles in an X-ray powder diffraction pattern: 7.79 ° ± 0.2 °,8.37 ° ± 0.2 °,10.64 ° ± 0.2 °,11.95 ° ± 0.2 °,12.72 ° ± 0.2 °,13.68 ° ± 0.2 °,15.60 ° ± 0.2 °,16.79 ° ± 0.2 °,17.22 ° ± 0.2 °,17.54 ° ± 0.2 °,18.30 ° ± 0.2 °,18.64 ° ± 0.2 °,19.11 ° ± 0.2 °,19.60 ° ± 0.2 °,20.39 ° ± 0.2 °,21.48 ° ± 0.2 °,21.68 ° ± 0.2 °,21.98 ° ± 0.2 °,22.46 ° ± 0.2 °,22.72 ° ± 0.2 °,23.35 ° ± 0.2 °,24.02 ° ± 0.2 °,24.53 ° ± 0.2.26 ° ± 0.2 °, 21.2 ° ± 0.2 °, 22.25 ° ± 0.2 °,22.2 ° ± 0.2 °,22.2 °,22.72 ° ± 0.2.2 ° ± 0.2.2.2 °,23.2 ° ± 0.2 °,23.35 ° ± 0.2.2 °,2 ° ± 0.2 °,2.

In some embodiments, the salt of the invention is a mesylate salt, wherein the mesylate salt is mesylate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.51 ° ± 0.2 °,10.40 ° ± 0.2 °,12.28 ° ± 0.2 °,13.52 ° ± 0.2 °,15.88 ° ± 0.2 °,16.57 ° ± 0.2 °,17.89 ° ± 0.2 °,18.22 ° ± 0.2 °,19.92 ° ± 0.2 °,20.59 ° ± 0.2 °,21.09 ° ± 0.2 °,23.06 ° ± 0.2 °,24.58 ° ± 0.2 °,25.91 ° ± 0.2 °,26.51 ° ± 0.2 °,26.81 ° ± 0.2 °,27.31 ° ± 0.2 °,28.85 ° ± 0.2 °,29.99 ° ± 0.2 °,30.54 ° ± 0.2 °,31.10 ° ± 0.2 °.

In some embodiments, the salt of the invention is a benzenesulfonate salt, characterized in that the benzenesulfonate salt is benzenesulfonate salt form a having X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.26 ° ± 0.2 °,13.93 ° ± 0.2 °,14.92 ° ± 0.2 °,15.77 ° ± 0.2 °,16.73 ° ± 0.2 °,17.29 ° ± 0.2 °,18.43 ° ± 0.2 °,19.46 ° ± 0.2 °,20.03 ° ± 0.2 °,21.02 ° ± 0.2 °,21.39 ° ± 0.2 °,21.78 ° ± 0.2 °,22.10 ° ± 0.2 °,22.46 ° ± 0.2 °,23.18 ° ± 0.2 °,24.11 ° ± 0.2 °,24.97 ° ± 0.2 °,25.97 ° ± 0.2 °,26.29 ° ± 0.2 °,27.45 ° ± 0.2 °,29.49 ° ± 0.2 °,30.22 ° ± 0.2 °,30.86 ° ± 0.2 °.

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 6.51 +/-0.2 degrees, 8.79 +/-0.2 degrees, 10.59 +/-0.2 degrees, 11.70 +/-0.2 degrees, 12.64 +/-0.2 degrees, 13.01 +/-0.2 degrees, 14.21 +/-0.2 degrees, 15.92 +/-0.2 degrees, 17.61 +/-0.2 degrees, 18.00 +/-0.2 degrees, 19.19 +/-0.2 degrees, 19.57 +/-0.2 degrees, 19.89 +/-0.2 degrees, 20.52 +/-0.2 degrees, 21.40 +/-0.2 degrees, 22.55 +/-0.2 degrees, 23.04 +/-0.2 degrees, 23.49 +/-0.2 degrees, 23.78 +/-0.2 degrees, 24.66 +/-0.2 degrees, 25.17 +/-0.2 degrees, 25.85 +/-0.2 degrees, 26.53 +/-0.2 degrees, 23.49 +/-0.2 degrees, 27.2 degrees, 0.2 degrees, 0.3 +/-0.2 degrees, 30.2 degrees, 0.2 degrees, 30.2 degrees, 0.2 degrees, 0..

In some embodiments, the salt of the invention is a sulfate salt, characterized in that the sulfate salt is sulfate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 Θ angles: 5.77 ° ± 0.2 °,12.75 ° ± 0.2 °,13.59 ° ± 0.2 °,15.82 ° ± 0.2 °,17.21 ° ± 0.2 °,19.58 ° ± 0.2 °,20.08 ° ± 0.2 °,21.75 ° ± 0.2 °,23.03 ° ± 0.2 °,23.89 ° ± 0.2 °,25.02 ° ± 0.2 °,26.84 ° ± 0.2 °,27.71 ° ± 0.2 °,30.63 ° ± 0.2 °,34.12 ° ± 0.2 °. .

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, characterized in that the p-toluenesulfonate salt is form a p-toluenesulfonate salt having an X-ray powder diffraction pattern substantially as shown in fig. 1.

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

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

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

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

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

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride salt form a having 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 form a sulfate salt having an X-ray powder diffraction pattern substantially as shown in figure 8.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, characterized in that the p-toluenesulfonate salt is form a p-toluenesulfonate salt, the differential scanning calorimetry trace of which comprises an endothermic peak at 234.33 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a camphorsulfonate salt, characterized in that the camphorsulfonate salt is camphorsulfonate form a having a differential scanning calorimetry trace comprising an endothermic peak at 279.12 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a maleate salt characterized in that the maleate salt is form a maleate salt having a differential scanning calorimetry pattern comprising an endothermic peak at 138.28 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is an oxalate salt, characterized in that the oxalate salt is form a oxalate, and a differential scanning calorimetry trace of form a of the oxalate salt comprises endothermic peaks at 118.72 ℃ ± 3 ℃ and 151.73 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a mesylate salt, characterized in that the mesylate salt is form a mesylate salt, the differential scanning calorimetry trace of which comprises an endothermic peak at 197.42 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a benzenesulfonate salt, characterized in that the benzenesulfonate salt is benzenesulfonate salt form a having a differential scanning calorimetry pattern that comprises an endothermic peak at 221.45 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a hydrochloride salt, characterized in that the hydrochloride salt is hydrochloride form a having a differential scanning calorimetry trace comprising an endothermic peak at 212.52 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a sulfate salt, characterized in that the sulfate salt is form a sulfate salt, the differential scanning calorimetry trace of which comprises endothermic peaks at 226.27 ℃ ± 3 ℃ and 255.54 ℃ ± 3 ℃.

In some embodiments, the salt of the invention is a p-toluenesulfonate salt, characterized in that the p-toluenesulfonate salt is form a p-toluenesulfonate salt having a differential scanning calorimetry trace substantially as shown in fig. 9.

In some embodiments, the salt of the invention is a camphorsulfonate salt, wherein the camphorsulfonate salt is camphorsulfonate form a having a differential scanning calorimetry trace substantially as shown in figure 10.

In some embodiments, the salt of the invention is a maleate salt characterized in that the maleate salt is maleate form a having a differential scanning calorimetry pattern substantially as shown in figure 11.

In some embodiments, the salt of the invention is a mesylate salt, wherein the mesylate salt is mesylate salt form a having a differential scanning calorimetry pattern substantially as shown in figure 12.

In some embodiments, the salt of the invention is a benzenesulfonate salt, characterized in that the benzenesulfonate salt is in benzenesulfonate salt form a having a differential scanning calorimetry pattern substantially as shown in fig. 13.

In some embodiments, the salt of the invention is a sulfate salt, wherein the sulfate salt is form a sulfate salt having a differential scanning calorimetry pattern substantially as shown in figure 14.

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 a disease or a disorder related to the orexin receptor.

In some such embodiments, the orexin receptor-related disorder of the invention is a sleep disorder, depression, anxiety disorder, panic disorder, obsessive compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorders, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, delirium, dementia, drug dependence, addiction, cognitive disorder, alzheimer's disease, parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, a disease of the digestive system, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or hypertension.

In another aspect, the invention relates to the use of said salt or said pharmaceutical composition for the preparation of a medicament for antagonizing orexin receptors.

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 salt has good stability and water solubility, so the salt 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.

"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. 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 on the sample preparationMany factors are related to instrument geometry. 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 invention relates to crystalline forms of the salts of (5- (5-chlorobenzo [ d ] oxazol-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2-fluoro-6- (2H-1,2, 3-triazol-2-yl) phenyl) methanone, present 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 (XRPD).

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.

Compositions, formulations, administration and uses of the salts of the invention

The pharmaceutical composition of the present invention is characterized by comprising a salt of the compound represented by formula (I) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. 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 the 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 and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising salts of the compounds of the present invention may 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 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. The 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 diseases mentioned herein by administering to a patient in need thereof a safe and effective amount of a salt or crystalline form of a compound of the present invention or a pharmaceutical composition comprising a salt or crystalline form of a compound of the present invention.

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 salt comprising 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, such as absorption, distribution and half-life, of the salt of the compound or the crystalline form thereof, which can be determined by the skilled person. In addition, a suitable dosing regimen 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, 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 adjustments to the subject's response to the dosage regimen, or the need for changes in the subject's patient over time, may be required.

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 together with them in the form of pharmaceutical compositions.

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. 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, weight, age and condition of the subject, 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 or a crystalline form thereof 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 alleviating diseases related to the orexin receptors in mammals including human beings, and can also be used for preparing medicaments for antagonizing the orexin receptors.

In particular, the amount of the compound in the composition of the present invention is effective to detectably and selectively antagonize orexin receptors, and the salt of the compound of the present invention or a crystalline form thereof is useful as a medicament for treating diseases associated with orexin receptors.

The salts of the compounds of the present invention or their crystalline forms can be used in, but are in no way limited to, the administration of an effective amount of a salt of a compound of the present invention or its crystalline form or composition to a patient for the prevention, treatment or alleviation of orexin receptor related disorders. The diseases related to orexin receptors are sleep disorders, depression, anxiety disorders, panic disorders, obsessive compulsive disorders, affective neuropathies, depressive neuropathies, anxiety neuropathies, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorders, sexual dysfunction, psychosis, schizophrenia, manic depression, confusion, dementia, drug dependence, addiction, cognitive disorders, Alzheimer's disease, Parkinson's disease, movement disorders, eating disorders, headache, migraine, pain, digestive system diseases, epilepsy, inflammation, cardiovascular diseases, diabetes, metabolic diseases, immune-related diseases, endocrine-related diseases or hypertension, etc.

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

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

Fig. 2 is an X-ray powder diffraction (XRPD) pattern of crystalline form a of camphorsulfonate of the compound of formula (I).

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

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

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

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

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

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

FIG. 9 is a Differential Scanning Calorimetry (DSC) profile of crystalline form A of p-toluenesulfonate of the compound of formula (I).

FIG. 10 is a Differential Scanning Calorimetry (DSC) profile of camphorsulfonate form A of the compound of formula (I).

FIG. 11 is a Differential Scanning Calorimetry (DSC) profile of maleate form A of the compound of formula (I).

FIG. 12 is a Differential Scanning Calorimetry (DSC) profile of the mesylate salt form A of the compound of formula (I).

FIG. 13 is a Differential Scanning Calorimetry (DSC) profile of besylate salt form A of the compound of formula (I).

FIG. 14 is a Differential Scanning Calorimetry (DSC) profile of the sulfate salt form A 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) analysis method: acetonitrile-mobile phase a ═ 70: 30 (V: V), runtime: for 10 minutes.

Detailed description of the invention

A compound of formula (I): (5- (5-chlorobenzo [ d ] oxazol-2-yl) hexahydropyrrolo [3,4-c ] pyrrol-2 (1H) -yl) (2-fluoro-6- (2H-1,2, 3-triazol-2-yl) phenyl) methanone, the specific synthesis method refers to example 3 in International application WO 2017088759A 1.

Examples

Example 1 crystalline form a of p-toluenesulfonate according to the invention

1. Preparation of p-toluenesulfonate form A

Adding a compound (45mg) shown in the formula (I) into EA (1.5mL), adding p-toluenesulfonic acid (24mg), reacting at room temperature overnight, performing suction filtration, and drying to obtain white solid powder which is p-toluenesulfonic acid salt crystal form A.

2. Identification of p-toluenesulfonate 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: 4.95 °,9.88 °,11.11 °,13.60 °,14.87 °,15.78 °,16.44 °,16.88 °,18.27 °,18.85 °,19.71 °,20.23 °,20.47 °,21.01 °,21.31 °,22.36 °,23.25 °,23.62 °,24.12 °,24.47 °,25.10 °,25.53 °,26.58 °,27.24 °,27.58 °,28.22 °,28.96 °,29.79 °,30.78 °,33.84 °,35.99 °, 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 234.33 ℃, with a margin of error of ± 3 ℃.

Example 2 camphorsulfonate form a of the present invention

1. Preparation of camphorsulfonate Crystal form A

The compound of formula (I) (45mg) was added to EA (1.5mL), camphorsulfonic acid (28mg) was added, and the reaction was allowed to proceed overnight at room temperature, filtered off with suction, and dried to give a white-like solid powder as camphorsulfonate form A.

2. Identification of camphorsulfonate 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: 4.42 °,8.80 °,11.89 °,12.69 °,13.22 °,14.57 °,15.49 °,16.03 °,16.62 °,17.49 °,18.31 °,18.62 °,19.42 °,20.18 °,20.81 °,21.72 °,23.72 °,24.57 °,25.49 °,25.92 °,26.41 °,26.73 °,27.13 °,27.61 °,27.84 °,28.58 °,29.44 °,29.92 °,30.53 °,32.99 °,35.32 °,37.06 °, 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 279.12 ℃, with a margin of error of ± 3 ℃.

Example 3 maleate form a of the invention

1. Preparation of maleate form a

Adding a compound (45mg) shown in the formula (I) into EA (1.5mL), adding maleic acid (24mg), reacting at room temperature overnight, performing suction filtration, and drying to obtain off-white solid powder which is maleate crystal form A.

2. Identification of maleate 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: 8.39 °,9.78 °,10.67 °,11.06 °,11.30 °,11.62 °,12.00 °,12.40 °,12.63 °,12.94 °,13.85 °,14.21 °,14.51 °,15.58 °,16.20 °,16.85 °,17.22 °,17.63 °,17.95 °,18.48 °,18.80 °,19.66 °,20.01 °,20.36 °,21.08 °,21.55 °,20.03 °,22.21 °,22.65 °,23.69 °,24.16 °,24.84 °,25.60 °,25.85 °,26.18 °,26.91 °,27.49 °,27.78 °,28.18 °,29.71 °,30.48 °, with an error 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 138.28 ℃, with a margin of error of ± 3 ℃.

Example 4 crystalline form A of the oxalate salt of the invention

1. Preparation of oxalate form A

Adding a compound shown as a formula (I) (45mg) into EA (1.5mL), adding oxalic acid (18mg), reacting at room temperature overnight, performing suction filtration, and drying to obtain off-white solid powder which is oxalate crystal form A.

2. Identification of oxalate 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: 7.79 °,8.37 °,10.64 °,11.95 °,12.72 °,13.68 °,15.60 °,16.79 °,17.22 °,17.54 °,18.30 °,18.64 °,19.11 °,19.60 °,20.39 °,21.48 °,21.68 °,21.98 °,22.46 °,22.72 °,23.35 °,24.02 °,24.53 °,25.26 °,25.93 °,26.65 °,27.56 °,27.81 °,28.64 °,29.45 °,30.33 °,30.62 °, 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 118.72 ℃ and 151.73 ℃, with a margin of error of ± 3 ℃.

Example 5 mesylate form a of the invention

1. Preparation of mesylate salt form A

Adding the compound (900mg) shown in the formula (I) into EA (15mL), adding methanesulfonic acid (240mg), reacting at room temperature overnight, performing suction filtration, and drying to obtain off-white solid powder which is mesylate crystal form A.

2. Identification of mesylate 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: 5.51 °,10.40 °,12.28 °,13.52 °,15.88 °,16.57 °,17.89 °,18.22 °,19.92 °,20.59 °,21.09 °,23.06 °,24.58 °,25.91 °,26.51 °,26.81 °,27.31 °,28.85 °,29.99 °,30.54 °,31.10 °, 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 197.42 ℃, with a margin of error of ± 3 ℃.

Example 6 besylate crystalline form a of the invention

1. Preparation of besylate crystal form a

Adding the compound (900mg) shown in the formula (I) into EA (15mL), adding benzenesulfonic acid (360mg), reacting at room temperature overnight, performing suction filtration, and drying to obtain off-white solid powder which is benzenesulfonate crystal form A.

2. Identification of besylate Crystal 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: 5.26 °,13.93 °,14.92 °,15.77 °,16.73 °,17.29 °,18.43 °,19.46 °,20.03 °,21.02 °,21.39 °,21.78 °,22.10 °,22.46 °,23.18 °,24.11 °,24.97 °,25.97 °,26.29 °,27.45 °,29.49 °,30.22 °,30.86 °, 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 221.45 ℃, with a margin of error of ± 3 ℃.

Example 7 hydrochloride form a of the invention

1. Preparation of hydrochloride form a

Adding the compound shown in the formula (I) (900mg) into EA (15mL), adding hydrochloric acid (240mg), reacting at room temperature overnight, performing suction filtration, and drying to obtain off-white solid powder which is hydrochloride crystal form A.

2. Identification of hydrochloride 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: 6.51 °,8.79 °,10.59 °,11.70 °,12.64 °,13.01 °,14.21 °,15.92 °,17.61 °,18.00 °,19.19 °,19.57 °,19.89 °,20.52 °,21.40 °,22.55 °,23.04 °,23.49 °,23.78 °,24.66 °,25.17 °,25.85 °,26.53 °,26.97 °,27.26 °,27.91 °,28.57 °,29.05 °,29.57 °,29.83 °,30.20 °,30.60 °,31.10 °, 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 212.52 ℃, with a margin of error of ± 3 ℃.

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

1. Preparation of sulfate form A

Adding the compound (900mg) shown in the formula (I) into EA (15mL), adding sulfuric acid (240mg), reacting at room temperature overnight, performing suction filtration, and drying to obtain off-white solid powder which is sulfate crystal form A.

2. Identification of sulfate 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: 5.77 °,12.75 °,13.59 °,15.82 °,17.21 °,19.58 °,20.08 °,21.75 °,23.03 °,23.89 °,25.02 °,26.84 °,27.71 °,30.63 °,34.12 °, with a tolerance of ± 0.2 °.

(2) Identification by TA Q2000 Differential Scanning Calorimetry (DSC) analysis: the scan rate was 10 ℃/min, contained endothermic peaks at 226.27 ℃ and 255.54 ℃, with a margin of error of ± 3 ℃.

Example 9 pharmacokinetic experiments of the salts of the invention

The test samples were encapsulated for oral administration.

3 male Beagle dogs (8-12 kg) were orally administered to 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. Pharmacokinetic parameters were calculated according to the drug concentration-time curve using the WinNonLin 6.3 software non-compartmental model method. Experiments prove that the salt has higher exposure in beagle dogs and better pharmacokinetic property.

EXAMPLE 10 stability test of salts according to the invention

Taking a proper amount of sample to be tested, and respectively irradiating the sample under the condition of (4500 +/-500 lx and ultraviolet light is more than or equal to 0.7 w/m)²) Placing the sample under the conditions of high humidity (25 ℃, 75% +/-5% RH, 90% +/-5% RH) and high temperature (40 ℃ +/-2 ℃, 60 ℃ +/-2 ℃ and humidity control), carrying out influencing factor experiments, sampling respectively on days 5, 10, 15 and 30, carrying out XRPD detection, and inspecting the stability of the sample.

Experiments prove that the salt has good stability under various lofting conditions and is suitable for pharmaceutical application under high temperature (40 ℃ or 60 ℃), high humidity (25 ℃, RH 75% +/-5% or RH 90% +/-5%) and illumination conditions.

Example 11 solubility testing of salts of the invention

Placing a sample to be detected in water at 37 ℃ to prepare supersaturated turbid liquid, shaking for 24h, filtering, taking filtrate, and detecting the solubility of a target sample in the water by using an HPLC method. The experimental result shows that the salt has higher solubility in water, so the salt has better drug forming property and is suitable for the development of preparations.

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 (9)

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 or sulfate salt; the organic acid salt is acetate, oxalate, maleate, tartrate, citrate, succinate, camphorsulfonate, malonate, benzoate, 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: 4.95 ° ± 0.2 °,9.88 ° ± 0.2 °,11.11 ° ± 0.2 °,13.60 ° ± 0.2 °,14.87 ° ± 0.2 °,15.78 ° ± 0.2 °,16.44 ° ± 0.2 °,16.88 ° ± 0.2 °,18.27 ° ± 0.2 °,18.85 ° ± 0.2 °,19.71 ° ± 0.2 °,20.23 ° ± 0.2 °,20.47 ° ± 0.2 °,21.01 ° ± 0.2 °,21.31 ° ± 0.2 °,22.36 ° ± 0.2 °,23.25 ° ± 0.2 °,23.62 ° ± 0.2 ° ± 0.12 ° ± 0.2 °,24.47 ° ± 0.2 °,25.10 ° ± 0.2 °,25.53 ° ± 0.2 °, 3626.58 ° ± 0.24 ° ± 0.2 °,23.2 ° ± 0.9 ° ± 0.2 ± 0.9 ° ± 0.42 ° ± 0.2.2 °,25.2 ° ± 0.2 ° ± 0.36 ° ± 0.2 ° ± 0.9.9 ° ± 0.2 ° ± 0.2.2 ° ± 0.9.2 ° ±;

the camphorsulfonate is a camphorsulfonate form a having an X-ray powder diffraction pattern with diffraction peaks at the following 2 theta angles: 4.42 ° ± 0.2 °,8.80 ° ± 0.2 °,11.89 ° ± 0.2 °,12.69 ° ± 0.2 °,13.22 ° ± 0.2 °,14.57 ° ± 0.2 °,15.49 ° ± 0.2 °,16.03 ° ± 0.2 °,16.62 ° ± 0.2 °,17.49 ° ± 0.2 °,18.31 ° ± 0.2 °,18.62 ° ± 0.2 °,19.42 ° ± 0.2 °,20.18 ° ± 0.2 °,20.81 ° ± 0.2 °,21.72 ° ± 0.2 °,23.72 ° ± 0.2 °,24.57 ° ± 0.25 ° ± 0.2 °,25.92 ° ± 0.2 °,26.41 ° ± 0.73 °, 0.2.13.27.2 ° ± 0.61 ° ± 0.25 ° ± 0.2 °,25.2 °,25.92 ° ± 0.2 °,26.41 ° ± 0.2 °,26.73 ° ± 0.25 ° ± 0.2.2 °, 25.25 ° ± 0.2.2 °,25.2 °, 25.2.25 ° ± 0.2.2 °, 2.29.2 ° ± 0.2 ° ± 0.2.2 ° ± 0.2 °, 26.25 ° ± 0;

the maleate is a maleate crystal form A, and an X-ray powder diffraction pattern of the maleate crystal form A has diffraction peaks at the following 2 theta angles: 8.39 ° ± 0.2 °,9.78 ° ± 0.2 °,10.67 ° ± 0.2 °,11.06 ° ± 0.2 °,11.30 ° ± 0.2 °,11.62 ° ± 0.2 °,12.00 ° ± 0.2 °,12.40 ° ± 0.2 °,12.63 ° ± 0.2 °,12.94 ° ± 0.2 °,13.85 ° ± 0.2 °,14.21 ° ± 0.2 °,14.51 ° ± 0.2 °,15.58 ° ± 0.2 °,16.20 ° ± 0.2 °,16.85 ° ± 0.2 °,17.22 ° ± 0.2 °,17.63 ° ± 0.2 °,17.95 ° ± 0.2 °,18.48 ° ± 0.2 °,18.80 ° ± 0.2 °,19.66 ° ± 0.2 °,20.01 ° ± 0.2.36 ° ± 0.2 °, 360.2 ° ± 0.2 °, 19.2 ° ± 0.2 °,19 ° ± 0.26 ° ± 0.2.2.2 °, 360.2 ° ± 0.2.2.2 °,19 ° ± 0.2.2 °,3 ° ± 0.2.2 °, 3.2.2 ° ± 0.2.2.26 ° ± 0.2 °,3 ° ± 0.2.2.2.2.2.2.2 °,3 ° ± 0.2 ° ± 0.2.2.2.2 °,3 ° ± 0.2.2.2 °,3 ° ± 0.2 °,3 ° ± 0.2.2.2.2.2.2.2 °,3 °;

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: 7.79 ° ± 0.2 °,8.37 ° ± 0.2 °,10.64 ° ± 0.2 °,11.95 ° ± 0.2 °,12.72 ° ± 0.2 °,13.68 ° ± 0.2 °,15.60 ° ± 0.2 °,16.79 ° ± 0.2 °,17.22 ° ± 0.2 °,17.54 ° ± 0.2 °,18.30 ° ± 0.2 °,18.64 ° ± 0.2 °,19.11 ° ± 0.2 °,19.60 ° ± 0.2 °,20.39 ° ± 0.2 °,21.48 ° ± 0.2 °,21.68 ° ± 0.2 °,21.98 ° ± 0.2 °,22.46 ° ± 0.2 °,22.72 ° ± 0.2 °,23.35 ° ± 0.2 °,24.02 ° ± 0.2 °,24.53 ° ± 0.2.26 ° ± 0.2 °, 21.2 ° ± 0.2 °,22.46 ° ± 0.2 °,22.2 ° ± 0.2 °,22.72 ° ± 0.2.2 °,23.35 ° ± 0.2.2 ° ± 0.2 °, 27.2.2 ° ± 0.2 ° ± 0.2.2 ° ± 0.30.30 ° ± 0.27.2 ° ± 0.2 °;

the mesylate is mesylate crystal form A, and the X-ray powder diffraction pattern of the mesylate crystal form A has diffraction peaks at the following 2 theta angles: 5.51 ° ± 0.2 °,10.40 ° ± 0.2 °,12.28 ° ± 0.2 °,13.52 ° ± 0.2 °,15.88 ° ± 0.2 °,16.57 ° ± 0.2 °,17.89 ° ± 0.2 °,18.22 ° ± 0.2 °,19.92 ° ± 0.2 °,20.59 ° ± 0.2 °,21.09 ° ± 0.2 °,23.06 ° ± 0.2 °,24.58 ° ± 0.2 °,25.91 ° ± 0.2 °,26.51 ° ± 0.2 °,26.81 ° ± 0.2 °,27.31 ° ± 0.2 °,28.85 ° ± 0.2 °,29.99 ° ± 0.2 °,30.54 ° ± 0.2 °,31.10 ° ± 0.2 °;

the benzenesulfonate is a benzenesulfonate crystal form A, and an X-ray powder diffraction pattern of the benzenesulfonate crystal form A has diffraction peaks at the following 2 theta angles: 5.26 ° ± 0.2 °,13.93 ° ± 0.2 °,14.92 ° ± 0.2 °,15.77 ° ± 0.2 °,16.73 ° ± 0.2 °,17.29 ° ± 0.2 °,18.43 ° ± 0.2 °,19.46 ° ± 0.2 °,20.03 ° ± 0.2 °,21.02 ° ± 0.2 °,21.39 ° ± 0.2 °,21.78 ° ± 0.2 °,22.10 ° ± 0.2 °,22.46 ° ± 0.2 °,23.18 ° ± 0.2 °,24.11 ° ± 0.2 °,24.97 ° ± 0.2 °,25.97 ° ± 0.2 °,26.29 ° ± 0.2 °,27.45 ° ± 0.2 °,29.49 ° ± 0.2 °,30.22 ° ± 0.2 °,30.86 ° ± 0.2 ° ±;

the hydrochloride is hydrochloride form A, and an X-ray powder diffraction pattern of the hydrochloride form A has diffraction peaks at the following 2 theta angles: 6.51 ° ± 0.2 °,8.79 ° ± 0.2 °,10.59 ° ± 0.2 °,11.70 ° ± 0.2 °,12.64 ° ± 0.2 °,13.01 ° ± 0.2 °,14.21 ° ± 0.2 °,15.92 ° ± 0.2 °,17.61 ° ± 0.2 °,18.00 ° ± 0.2 °,19.19 ° ± 0.2 °,19.57 ° ± 0.2 °,19.89 ° ± 0.2 °,20.52 ° ± 0.2 °,21.40 ° ± 0.2 °,22.55 ° ± 0.2 °,23.04 ° ± 0.2 °,23.49 ° ± 0.2 °,23.78 ° ± 0.2 °,24.66 ° ± 0.2 °,25.17 ° ± 0.2 °,25.85 ° ± 0.2 °,26.53 ° ± 0.2.2 °,23.49 ° ± 0.27.2 ° ± 0.2 °, 30.83 ° ± 0.2 ° ± 0.2.2 ° ± 0.2.27 ° ± 0.2 °, 25.2.2 ° ± 0.2.2.2 ° ± 0.2 ° 30.2 ° ± 0.2 ° ± 30.2.2 ° ± 0.2 ° ± 30.2 ° ±;

the sulfate is a sulfate crystal form A, and an X-ray powder diffraction pattern of the sulfate crystal form A has diffraction peaks at the following 2 theta angles: 5.77 ° ± 0.2 °,12.75 ° ± 0.2 °,13.59 ° ± 0.2 °,15.82 ° ± 0.2 °,17.21 ° ± 0.2 °,19.58 ° ± 0.2 °,20.08 ° ± 0.2 °,21.75 ° ± 0.2 °,23.03 ° ± 0.2 °,23.89 ° ± 0.2 °,25.02 ° ± 0.2 °,26.84 ° ± 0.2 °,27.71 ° ± 0.2 °,30.63 ° ± 0.2 °,34.12 ° ± 0.2 °.

4. The salt of claim 2 or 3, wherein the p-toluenesulfonate salt is form A p-toluenesulfonate salt having an X-ray powder diffraction pattern substantially as shown in FIG. 1;

the camphorsulfonate salt is camphorsulfonate form a having an X-ray powder diffraction pattern substantially as shown in figure 2;

the maleate is in maleate form a having an X-ray powder diffraction pattern substantially as shown in figure 3;

the oxalate salt is oxalate form a having an X-ray powder diffraction pattern substantially as shown in figure 4;

the mesylate salt is in mesylate form a, the mesylate form a having an X-ray powder diffraction pattern substantially as shown in figure 5;

the benzenesulfonate salt in benzenesulfonate salt form a having an X-ray powder diffraction pattern substantially as shown in fig. 6;

the hydrochloride salt is hydrochloride form a having an X-ray powder diffraction pattern substantially as shown in figure 7;

the sulfate is sulfate form a having an X-ray powder diffraction pattern substantially as shown in figure 8.

5. The salt of claim 2, wherein the p-toluenesulfonate salt is form a p-toluenesulfonate salt, and wherein a differential scanning calorimetry trace of form a of the p-toluenesulfonate salt comprises an endothermic peak at 234.33 ℃ ± 3 ℃;

the camphorsulfonate is camphorsulfonate form A, the differential scanning calorimetry trace of which comprises an endothermic peak at 279.12 ℃ ± 3 ℃;

the maleate is maleate form A, and a differential scanning calorimetry trace of the maleate form A comprises an endothermic peak at 138.28 ℃ ± 3 ℃;

the oxalate is oxalate form A, and a differential scanning calorimetry chart of the oxalate form A comprises endothermic peaks at 118.72 ℃ +/-3 ℃ and 151.73 ℃ +/-3 ℃;

the mesylate salt is mesylate salt form A, and a differential scanning calorimetry trace of the mesylate salt form A comprises an endothermic peak at 197.42 ℃ ± 3 ℃;

the benzenesulfonate is benzenesulfonate form A, and a differential scanning calorimetry trace of benzenesulfonate form A contains an endothermic peak at 221.45 ℃ + -3 ℃;

the hydrochloride salt is the hydrochloride form a, and a differential scanning calorimetry trace of the hydrochloride form a comprises an endothermic peak at 212.52 ℃ ± 3 ℃;

the sulfate salt is sulfate form a having a differential scanning calorimetry trace comprising endothermic peaks at 226.27 ℃ ± 3 ℃ and 255.54 ℃ ± 3 ℃.

6. The salt of claim 5, wherein the p-toluenesulfonate is form A p-toluenesulfonate having a differential scanning calorimetry pattern substantially as shown in FIG. 9;

the camphorsulfonate salt is camphorsulfonate form a having a differential scanning calorimetry pattern substantially as shown in figure 10;

the maleate salt is maleate form a having a differential scanning calorimetry pattern substantially as shown in figure 11;

the mesylate salt is mesylate salt form a having a differential scanning calorimetry trace substantially as shown in figure 12;

the benzenesulfonate salt in benzenesulfonate salt form a having a differential scanning calorimetry pattern substantially as shown in fig. 13;

the sulfate salt is sulfate form a having a differential scanning calorimetry pattern substantially as shown in figure 14.

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 in the manufacture of a medicament for the prevention, treatment or alleviation of a disease or a disorder related to the orexin receptor.

9. The use according to claim 8, wherein the orexin receptor-related disease is sleep disorder, depression, anxiety disorder, panic disorder, obsessive compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorders, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, delirium, dementia, drug dependence, addiction, cognitive disorder, alzheimer's disease, parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease or hypertension.

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