WO2021104294A1 - CRYSTAL FORMS OF OCTAHYDROPYRROLO [3,4-c] PYRROLE DERIVATIVES - Google Patents

CRYSTAL FORMS OF OCTAHYDROPYRROLO [3,4-c] PYRROLE DERIVATIVES Download PDF

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WO2021104294A1
WO2021104294A1 PCT/CN2020/131410 CN2020131410W WO2021104294A1 WO 2021104294 A1 WO2021104294 A1 WO 2021104294A1 CN 2020131410 W CN2020131410 W CN 2020131410W WO 2021104294 A1 WO2021104294 A1 WO 2021104294A1
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crystal form
disorder
disease
present
neuropathy
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French (fr)
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Chuanfei JIN
Tengfei XU
Yingjun Zhang
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Sunshine Lake Pharma Co., Ltd.
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • A61P25/04—Centrally acting analgesics, e.g. opioids
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    • A61P25/16—Anti-Parkinson drugs
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    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A61P5/00—Drugs for disorders of the endocrine system
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    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of medicine, and relates to a crystal form of octahydropyrrolo [3, 4-c] pyrrole derivatives.
  • the invention specifically relates to a crystal form of (5- (5-chlorobenzo [d] oxazol-2-yl) hexahydropyrrolo [3, 4-c] pyrrole-2 (1H) -yl) (2-fluoro-6- (2H-1, 2, 3-triazol-2-yl) phenyl) methanone and the use thereof, and further relates to a pharmaceutical composition comprising the crystal form.
  • Orexin also known as hypothalamic secretin, includes orexin A and orexin B (or hypothalamic secretin-1 and hypothalamic secretin-2) , which is a neuropeptide secreted by the hypothalamus.
  • the main physiological functions are as follows: 1. regulating food intake: orexin can activate the neurons that regulate eating, obviously promote eating, and has a dose-dependent response; 2. participating in the regulation of energy metabolism: orexin can significantly increase the metabolic rate; 3. participating in the regulation of sleep-wakefulness: orexin can inhibit rapid eye movement sleep and prolong the time of wakefulness; and blocking the effect of orexin can promote sleep; 4. participating in endocrine regulation: orexin has a significant effect on the endocrine of pituitary hormones; 5.
  • Orexin produces physiological effects by acting on orexin receptor (OXR) .
  • Orexin receptor is a G-protein coupled receptor. There are two types, called OX 1 receptor and OX 2 receptor.
  • OX 1 receptor selectively binds orexin A
  • OX 2 receptor can 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 feeding behavior. Cell, 1998, 92 (4) : 573-585) .
  • OX 1 receptor and OX 2 receptor are almost exclusively found in brain tissues, and are selectively expressed in the brain.
  • OX 1 receptor is expressed at high density in locus coeruleus, which is the nuclei originis of noradrenergic neurons; while OX 2 receptor is expressed at high density in the nodular papillary nucleus, which is the nuclei originis of histaminergic neurons.
  • the expression of both OX 1 receptor and OX 2 receptor can be found in the raphe nucleus, which is the nuclei originis of serotonergic neurons; the expression of both OX 1 receptor and OX 2 receptor can also be found in the ventral tegmental area, which is the nuclei originis of dopaminergic neurons.
  • OX 2 receptor can also be found in brainstem cholinergic neurons responsible for regulating REM sleep and has an impact on its nuclear activity (Marcus, J.N. et al., Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol., 2001, 435 (1) : 6-25; and Trivedi, P. et al., Distribution of orexin receptor mRNA in the rat brain. FEBS Lett., 1998, 438 (1-2) : 71-75) .
  • orexin receptors are of great significance in pathology and are related to many diseases, such as sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease and high blood pressure.
  • diseases such as sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson
  • Different solid forms of pharmaceutical active ingredients may have different properties. Different solid forms may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may have different effects on the stability, bioavailability and efficacy of the drug. Therefore, the solid form of drug should be fully considered in drug research and development.
  • the compound has poor water solubility, low oral bioavailability, poor stability, and poor druggability. Therefore, it is necessary to find a solid form with better druggability.
  • the inventor found that the crystal form II of the compound having formula (I) has good stability, high exposure in the organism after oral administration, high bioavailability, and high preparation purity of the product, that is, the physical properties and various properties of the crystal form II of the present invention are more conducive to the development of preparations, and thus have better druggability.
  • the present invention relates to a crystal form of the compound having formula (I) , and the use of the crystal form or the pharmaceutical composition comprising the crystal form in the manufacture of a medicament for the prevention, treatment or alleviation of orexin receptor-related diseases.
  • the crystal form of the present invention may also be in the form of a solvate, such as a hydrate form.
  • the present invention provides a crystal form of the compound having formula (I) ,
  • the crystal form described in the present invention is crystal form I.
  • the crystal form I of the present invention wherein the X-ray powder diffraction pattern of the crystal form I comprises peaks expressed as 2 ⁇ at 7.44° ⁇ 0.2°, 7.78° ⁇ 0.2°, 8.24° ⁇ 0.2°, 12.69° ⁇ 0.2°, 12.95° ⁇ 0.2°, 14.08° ⁇ 0.2°, 14.75° ⁇ 0.2°, 15.03° ⁇ 0.2°, 17.75° ⁇ 0.2°, 19.71° ⁇ 0.2°, 20.12° ⁇ 0.2°, 20.81° ⁇ 0.2°, 21.30° ⁇ 0.2°, 21.89° ⁇ 0.2°, 22.18° ⁇ 0.2°, 23.27° ⁇ 0.2°, 25.49° ⁇ 0.2°, 25.85° ⁇ 0.2°, 26.08° ⁇ 0.2°, 26.60° ⁇ 0.2°, 27.21° ⁇ 0.2°, 27.44° ⁇ 0.2°, 27.70° ⁇
  • the crystal form I of the present invention wherein the crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
  • the crystal form I of the present invention wherein the differential scanning calorimetry of the crystal form I comprises an endothermic peak at 159.96 °C ⁇ 3 °C.
  • the crystal form I of the present invention wherein the crystal form I has a differential scanning calorimetry diagram substantially as shown in FIG. 2.
  • the crystal form described in the present invention is crystal form II.
  • the crystal form II of the present invention wherein the X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2 ⁇ at 10.43° ⁇ 0.2°, 12.31° ⁇ 0.2°, 15.92° ⁇ 0.2°, 16.90° ⁇ 0.2°, 17.90° ⁇ 0.2°, 20.52° ⁇ 0.2°, 21.04° ⁇ 0.2°, 26.53° ⁇ 0.2°, 26.83° ⁇ 0.2°.
  • the crystal form II of the present invention wherein the X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2 ⁇ at 10.43° ⁇ 0.2°, 12.31° ⁇ 0.2°, 14.49° ⁇ 0.2°, 15.92° ⁇ 0.2°, 16.00° ⁇ 0.2°, 16.90° ⁇ 0.2°, 17.90° ⁇ 0.2°, 18.42° ⁇ 0.2°, 20.52° ⁇ 0.2°, 21.04° ⁇ 0.2°, 21.45° ⁇ 0.2°, 23.59° ⁇ 0.2°, 24.00° ⁇ 0.2°, 24.26° ⁇ 0.2°, 24.75° ⁇ 0.2°, 25.07° ⁇ 0.2°, 26.26° ⁇ 0.2°, 26.53° ⁇ 0.2°, 26.83° ⁇ 0.2°, 30.03° ⁇ 0.2°, 31.20° ⁇ 0.2°, 31.56° ⁇ 0.2°, 34.24°
  • the crystal form II of the present invention wherein the X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2 ⁇ at 10.43° ⁇ 0.2°, 12.31° ⁇ 0.2°, 13.08° ⁇ 0.2°, 14.49° ⁇ 0.2°, 15.18° ⁇ 0.2°, 15.92° ⁇ 0.2°, 16.00° ⁇ 0.2°, 16.61° ⁇ 0.2°, 16.90° ⁇ 0.2°, 17.90° ⁇ 0.2°, 18.42° ⁇ 0.2°, 20.52° ⁇ 0.2°, 21.04° ⁇ 0.2°, 21.45° ⁇ 0.2°, 23.59° ⁇ 0.2°, 24.00° ⁇ 0.2°, 24.26° ⁇ 0.2 °, 24.75° ⁇ 0.2°, 25.07° ⁇ 0.2°, 26.26° ⁇ 0.2°, 26.53° ⁇ 0.2°, 26.83° ⁇ 0.2°, 28.02° ⁇ 0.2
  • the crystal form II of the present invention wherein the crystal form II has an X-ray powder diffraction pattern substantially as shown in FIG. 4.
  • the crystal form II of the present invention wherein the differential scanning calorimetry of the crystal form II comprises an endothermic peak at 182.86 °C ⁇ 3 °C.
  • the crystal form II of the present invention wherein the crystal form II has a differential scanning calorimetry diagram substantially as shown in FIG. 5.
  • the crystal form described in the present invention is crystal form X.
  • the crystal form X of the present invention wherein the X-ray powder diffraction pattern of the crystal form X comprises peaks expressed as 2 ⁇ at 7.97° ⁇ 0.2°, 12.20° ⁇ 0.2°, 13.82° ⁇ 0.2°, 15.68° ⁇ 0.2°, 16.79° ⁇ 0.2°, 17.48° ⁇ 0.2°, 18.42° ⁇ 0.2°, 20.05° ⁇ 0.2°, 20.85° ⁇ 0.2°, 22.33° ⁇ 0.2°, 23.03° ⁇ 0.2°, 23.87° ⁇ 0.2°, 24.61° ⁇ 0.2°, 25.72° ⁇ 0.2°, 26.97° ⁇ 0.2°, 27.48° ⁇ 0.2°, 28.05° ⁇ 0.2°, 28.77° ⁇ 0.2°, 29.49° ⁇ 0.2°, 30.29° ⁇ 0.2°, 32.05° ⁇ 0.2°, 32.96° ⁇ 0.2°, 33.
  • the crystal form X of the present invention wherein the crystal form X has an X-ray powder diffraction pattern substantially as shown in FIG. 6.
  • the crystal form X of the present invention wherein the differential scanning calorimetry of the crystal form X comprises an endothermic peak at 176.58 °C ⁇ 3 °C.
  • the crystal form X of the present invention wherein the crystal form X has a differential scanning calorimetry diagram substantially as shown in FIG. 7.
  • the crystal form described in the present invention is crystal form XI.
  • the crystal form XI of the present invention wherein the X-ray powder diffraction pattern of the crystal form XI comprises peaks expressed as 2 ⁇ at 7.44° ⁇ 0.2°, 7.76° ⁇ 0.2°, 8.28° ⁇ 0.2°, 12.69° ⁇ 0.2°, 14.14° ⁇ 0.2°, 15.05° ⁇ 0.2°, 16.55° ⁇ 0.2°, 17.44° ⁇ 0.2°, 17.77° ⁇ 0.2°, 19.12° ⁇ 0.2°, 19.35° ⁇ 0.2°, 19.69° ⁇ 0.2°, 20.14° ⁇ 0.2°, 20.45° ⁇ 0.2°, 20.74° ⁇ 0.2°, 21.35° ⁇ 0.2°, 21.95° ⁇ 0.2°, 22.20° ⁇ 0.2°, 23.25° ⁇ 0.2°, 23.82° ⁇ 0.2°, 24.90° ⁇ 0.2°, 25.46° ⁇ 0.2°, 25.82°
  • the crystal form XI of the present invention wherein the crystal form XI has an X-ray powder diffraction pattern substantially as shown in FIG. 8.
  • the crystal form XI of the present invention wherein the differential scanning calorimetry of the crystal form XI comprises endothermic peaks at 149.48 °C ⁇ 3 °C and 160.27 °C ⁇ 3 °C.
  • the crystal form XI of the present invention wherein the crystal form XI has a differential scanning calorimetry diagram substantially as shown in FIG. 9.
  • the crystal form described in the present invention is crystal form XII.
  • the crystal form XII of the present invention wherein the X-ray powder diffraction pattern of the crystal form XII comprises peaks expressed as 2 ⁇ at 6.36° ⁇ 0.2°, 7.25° ⁇ 0.2° , 11.41° ⁇ 0.2°, 11.89° ⁇ 0.2°, 13.32° ⁇ 0.2°, 13.76° ⁇ 0.2°, 14.15° ⁇ 0.2°, 15.10° ⁇ 0.2°, 16.67° ⁇ 0.2°, 18.06° ⁇ 0.2°, 18.23° ⁇ 0.2°, 18.86° ⁇ 0.2°, 19.04° ⁇ 0.2°, 19.35° ⁇ 0.2°, 20.09° ⁇ 0.2°, 20.43° ⁇ 0.2°, 20.72° ⁇ 0.2°, 21.42° ⁇ 0.2°, 22.61° ⁇ 0.2°, 23.48° ⁇ 0.2°, 23.65° ⁇ 0.2°, 23.86° ⁇ 0.2°, 24.
  • the crystal form XII of the present invention wherein the crystal form XII has an X-ray powder diffraction pattern substantially as shown in FIG. 10.
  • the crystal form XII of the present invention wherein the differential scanning calorimetry of the crystal form XII comprises an endothermic peak at 162.58 °C ⁇ 3 °C.
  • the crystal form XII of the present invention wherein the crystal form XII has a differential scanning calorimetry diagram substantially as shown in FIG. 11.
  • the crystal form described in the present invention is crystal form XIII.
  • the crystal form XIII of the present invention wherein the X-ray powder diffraction pattern of the crystal form XIII comprises peaks expressed as 2 ⁇ at 7.18° ⁇ 0.2°, 8.28° ⁇ 0.2°, 12.37° ⁇ 0.2°, 13.45° ⁇ 0.2°, 14.26° ⁇ 0.2°, 14.87° ⁇ 0.2°, 17.48° ⁇ 0.2°, 17.90° ⁇ 0.2°, 19.35° ⁇ 0.2°, 19.95° ⁇ 0.2°, 20.71° ⁇ 0.2°, 21.23° ⁇ 0.2°, 21.45° ⁇ 0.2°, 22.11° ⁇ 0.2°, 23.16° ⁇ 0.2°, 24.95° ⁇ 0.2°, 25.55° ⁇ 0.2°, 26.82° ⁇ 0.2°, 27.07° ⁇ 0.2°, 27.35° ⁇ 0.2°, 28.40° ⁇ 0.2°, 28.94° ⁇ 0.2°, 29
  • the crystal form XIII of the present invention wherein the crystal form XIII has an X-ray powder diffraction pattern substantially as shown in FIG. 12.
  • the crystal form XIII of the present invention wherein the differential scanning calorimetry of the crystal form XIII comprises endothermic peaks at 146.79 °C ⁇ 3°C and 164.21 °C ⁇ 3°C.
  • the crystal form XIII of the present invention wherein the crystal form XIII has a differential scanning calorimetry diagram substantially as shown in FIG. 13.
  • the crystal form described in the present invention is crystal form XIV.
  • the crystal form XIV of the present invention wherein the X-ray powder diffraction pattern of the crystal form XIV comprises peaks expressed as 2 ⁇ at 7.25° ⁇ 0.2°, 8.06° ⁇ 0.2°, 12.62° ⁇ 0.2°, 14.02° ⁇ 0.2°, 14.79° ⁇ 0.2°, 17.28° ⁇ 0.2°, 17.65° ⁇ 0.2°, 19.69° ⁇ 0.2°, 19.87° ⁇ 0.2°, 20.64° ⁇ 0.2°, 20.80° ⁇ 0.2°, 21.62° ⁇ 0.2°, 23.22° ⁇ 0.2°, 24.31° ⁇ 0.2°, 25.46° ⁇ 0.2°, 25.77° ⁇ 0.2°, 26.71° ⁇ 0.2°, 27.23° ⁇ 0.2°, 28.42° ⁇ 0.2°, 28.74° ⁇ 0.2°, 29.82° ⁇ 0.2°, 30.78° ⁇ 0.2°,
  • the crystal form XIV of the present invention wherein the crystal form XIV has an X-ray powder diffraction pattern substantially as shown in FIG. 14.
  • the crystal form XIV of the present invention wherein the differential scanning calorimetry of the crystal form XIV comprises endothermic peaks at 124.04 °C ⁇ 3 °C and 163.38 °C ⁇ 3 °C.
  • the crystal form XIV of the present invention wherein the crystal form XIV has a differential scanning calorimetry diagram substantially as shown in FIG. 15.
  • the crystal form described in the present invention is crystal form XV.
  • the crystal form XV of the present invention wherein the X-ray powder diffraction pattern of the crystal form XV comprises peaks expressed as 2 ⁇ at 7.37° ⁇ 0.2°, 8.03° ⁇ 0.2°, 12.72° ⁇ 0.2°, 13.89° ⁇ 0.2°, 14.85° ⁇ 0.2°, 17.26° ⁇ 0.2°, 17.58° ⁇ 0.2°, 17.77° ⁇ 0.2°, 19.72° ⁇ 0.2°, 20.20° ⁇ 0.2°, 20.47° ⁇ 0.2°, 20.99° ⁇ 0.2°, 21.45° ⁇ 0.2°, 21.64° ⁇ 0.2°, 23.12° ⁇ 0.2°, 24.30° ⁇ 0.2°, 25.26° ⁇ 0.2°, 25.57° ⁇ 0.2°, 27.09° ⁇ 0.2°, 27.23° ⁇ 0.2°, 28.28° ⁇ 0.2°, 28.91° ⁇ 0.2°, 29
  • the crystal form XV of the present invention wherein the crystal form XV has an X-ray powder diffraction pattern substantially as shown in FIG. 16.
  • the crystal form XV of the present invention wherein the differential scanning calorimetry of the crystal form XV comprises endothermic peaks at 127.06 °C ⁇ 3 °C and 165.38 °C ⁇ 3 °C.
  • the crystal form XV of the present invention wherein the crystal form XV has a differential scanning calorimetry diagram substantially as shown in FIG. 17.
  • the invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any one of the crystal forms described in the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
  • the present invention relates to use of the crystal form or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, treating or lessening a disease related to orexin receptors in a subject.
  • the disease related to orexin receptors of the present invention is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
  • the present invention relates to a method of preventing, treating or lessening a disease related to orexin receptors in a subject comprising administering to the subject a therapeutically effective amount of the crystal form or the pharmaceutical composition disclosed herein.
  • the disease related to orexin receptors of the present invention is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
  • the present invention relates to the crystal form or the pharmaceutical composition disclosed herein for use in preventing, treating or lessening a disease related to orexin receptors in a subject.
  • the disease related to orexin receptors of the present invention is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
  • the present invention relates to use of the crystal form or the pharmaceutical composition in the manufacture of a medicament for antagonizing orexin receptors.
  • the present invention also provides an amorphous form of the compound having formula (I) , which has an X-ray powder diffraction pattern substantially as shown in FIG. 3.
  • the present invention also relates to the preparation method of the crystal form or amorphous form of the compound having formula (I) .
  • the solvent used in the preparation method of the crystal form or amorphous form of the invention is not particularly restricted, and any solvent which dissolves the starting material to a degree and does not affect its properties is contained in the present invention. Additionally, many similar modifications in the art, equivalent replacements, or solvent, solvent composition and different proportions of the solvent composition which are equivalent to those described in the invention, all are deemed to be included in the present invention.
  • the present invention gives the preferred solvent for each reaction step.
  • the preparation of the crystal forms of the present invention will be described in detail in the examples section. Meanwhile, the present invention provides pharmacological properties test experiments (e.g., pharmacokinetic experiments) , solubility experiments, stability experiments, and moisture absorption experiments of the crystal form.
  • pharmacological properties test experiments e.g., pharmacokinetic experiments
  • solubility experiments e.g., solubility experiments
  • stability experiments e.g., solubility experiments
  • moisture absorption experiments of the crystal form e.g., moisture absorption experiments.
  • the crystal form II of the present invention has unexpected technical advantages: 1) the crystal form II is very stable and can not undergo transformation under general conditions (such as open storage at room temperature or stirring in water at room temperature) , and it is also very stable under high temperature and high humidity conditions, and there is basically no change in crystal morphology, appearance and purity; 2) compared with the compound represented by formula (I) disclosed in the prior art, it has a higher blood concentration and exposure level in dogs by oral capsule administration, thereby having better pharmacokinetic properties. Therefore, the crystal form II of the present invention has better pharmacological properties, higher stability, and is more suitable for pharmaceutical use.
  • Crystal form or “crystalline form” refers to a solid having a highly regular chemical structure, including, but not limited to, mono-or multi-component crystals, and/or polymorphic compounds of compounds, solvates, hydrates, clathrates, eutecticum, salt, solvate of the salt, hydrate of the salt.
  • the crystalline form of the material can be obtained by a number of methods known in the field.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in defined space, for example, in nanopores or capillaries, on a surface or template, for example, on a polymer, in the presence of additives such as co-crystallization counterions, crystallization, removing solvent, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding and solvent drop milling, etc.
  • additives such as co-crystallization counterions, crystallization, removing solvent, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding and solvent drop milling, etc.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid) .
  • Solvents for use in the practice of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like
  • Anti-solvent refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent.
  • the anti-solvent may comprise a cold gas, or a fluid that promotes the precipitation by chemical reaction or 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 liquid different from the solvent.
  • Solvate refers to a compound that has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice.
  • the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N, N-dimethylacetamide, N, 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 the solvate is a hydrate in which the solvent on the surface, in the lattice or on the surface and in the lattice is water.
  • the hydrate On the surface, in the lattice or on the surface and in the lattic of the substance, the hydrate may or may not have any solvent other than water.
  • Crystal form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD) , infrared absorption spectroscopy (IR) , melting point method, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM) , quantitative analysis, solubility and dissolution rate.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • dissolution calorimetry scanning electron microscopy
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect changes in crystal form, crystallinity, crystal state and other information, and is a common means for identifying crystal form.
  • the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, which is substantially as shown in the XRPD pattern provided in the drawings of the present invention.
  • the 2 ⁇ of the XRPD pattern can be measured with an experimental error.
  • the measurement of 2 ⁇ of the XRPD pattern may be slightly different between the different instruments and the different samples. Therefore, the value of 2 ⁇ can not be regarded as absolute. According to the condition of the instrument used in this test, the diffraction peak has an error tolerance of ⁇ 0.2°.
  • Differential Scanning Calorimetry is a technique of measuring the energy difference between a sample and an inert reference (commonly used ⁇ -Al 2 O 3 ) varied with temperature by continuously heating or cooling under program control.
  • the endothermic peak of the DSC curve depends on many factors associated with sample preparation and instrument geometry.
  • the crystal form of the present invention is characterized by an DSC pattern having certain peak positions, which is substantially as shown in the DSC pattern provided in the drawings of the present invention.
  • the DSC pattern can be measured with an experimental error.
  • the peak position and peak value of DSC pattern may be slightly different between the different instruments and the different samples. Therefore, the peak position or the peak value of the DSC endothermic peak can not be regarded as absolute. According to the condition of the instrument used in this test, the endothermic peak has an error tolerance of ⁇ 3 °C.
  • Thermogravimetric analysis is a technique for measuring the change of quality of a substance varied with temperature under the control of a program. It is suitable for examining the process of the solvent loss or the samples sublimation and decomposition. It can be presumed that the crystal contains crystal water or crystallization solvent.
  • the quality variety of the TGA curve depends on a number of factors, containing the sample preparation and the instrument. The quality variety of the TGA test may be slightly different between the different instruments and between the different samples. According to the condition of the instrument used in this test, there is a ⁇ 0.1%error tolerance for the mass change.
  • the 2 ⁇ values in the X-ray powder diffraction pattern are in degrees (°) .
  • substantially as shown in the figure refers to 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 are shown in the X-ray powder diffraction pattern or DSC pattern or Raman spectra pattern or infrared spectra pattern.
  • the “peak” refers to a feature that a person skilled in the art can recognize without belonging to background noise when referring to a spectrum or/and data that appears in the figure.
  • the present invention relates to the crystal form of (5- (5-chlorobenzo [d] oxazol-2-yl) hexahydropyrrolo [3, 4-c] pyrrole-2 (1H) -yl) (2-fluoro-6- (2H-1, 2, 3 -triazol-2-yl) phenyl) methanone, which exists in a substantially pure crystalline form.
  • substantially pure means that a crystalline form is substantially free of another or more crystalline forms, which means the purity of 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%, or crystal form containing other crystal form.
  • the percentage of the other crystals in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • “Substantially free” means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • “Relative strength” (or “relative peak height” ) in the XRPD pattern means the ratio of the intensity of the other peaks to the intensity of the first strong peak when the intensity of the first strong peak in all the diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%.
  • the word when used or whether or not used the word, such as “about” , it means that within a given value or range of 10%, appropriately within 5%, especially within 1%. Or, for those of ordinary skill in the art, the term “about” means within an acceptable standard error range of the mean value.
  • any number within N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8%, or N +/-10% will be disclosed clearly, wherein “+/-” means plus or minus.
  • room temperature refers to the temperature from about 10 °C to about 40 °C. In some embodiments, “room temperature” refers to a temperature from about 20 °C to about 30 °C; in other embodiments, “room temperature” refers to 20 °C, 22.5 °C, 25 °C, 27.5 °C, and so on.
  • the pharmaceutical composition of the present invention characterized in that it includes the crystal form of the compound represented by formula (I) and a pharmaceutically acceptable carrier, adjuvant, or excipient.
  • the amount of the crystal form of the compound in the pharmaceutical composition of the present invention can effectively and detectably treat or alleviate the patient's central nervous system dysfunction.
  • the pharmaceutical composition of the present invention may also optionally contain other therapeutic and/or preventive components.
  • Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams &Wilkins, Philadelphia; Gennaro A.R. et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams &Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.
  • Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention.
  • resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington’s Pharmaceutical Sciences (Mack Publishing Company) , The Handbook of Pharmaceutical Additives (Gower Publishing Limited) , and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press) .
  • compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing Company) .
  • Another aspect of the present invention is related to a method for preparing a pharmaceutical composition
  • the pharmaceutical composition contains the crystal form of the compound disclosed herein and pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof, the method comprises mixing various ingredients.
  • the pharmaceutical composition containing the crystal form of the compound disclosed herein can be prepared by mixing for example at environment temperature and under barometric pressure.
  • dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalational administration such as aerosols, solutions, and dry powders; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
  • oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets
  • parenteral administration such as sterile solutions, suspensions, and powders for reconstitution
  • transdermal administration such as transdermal patches
  • rectal administration such as
  • the pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry-filled capsule (DFC) , consists of two sections, one slipping over the other, thus completely enclosing the active ingredient.
  • the soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl-and propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • the therapeutic methods disclosed herein comprise administrating to a patient in need of the treatment a safe and effective amount of the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form.
  • Each embodiment disclosed herein comprises the treatment of the above disorders or diseases comprising administrating to a patient in need a safe and effective amount of the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form.
  • the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered by any suitable route of administration, including both systemic administration and topical administration.
  • Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration.
  • Typical parenteral administration refers to routes of administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion.
  • Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhaled and intranasal administration.
  • the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered orally.
  • the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered by inhalation.
  • the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered intranasally.
  • the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time.
  • doses may be administered one, two, three, or four times per day.
  • a dose is administered once per day.
  • a dose is administered twice per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect.
  • Suitable dosing regimens for the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form depend on the pharmacokinetic properties of that compound or its crystal form, such as absorption, distribution, and half-life, which can be determined by the skilled artisan.
  • suitable dosing regimens, including the duration such regimens are administered, for the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form depend on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment for an individual patient’s response to the dosing regimen or over time as individual patient needs change.
  • the compounds of the present invention or its crystal form may be administered either simultaneously, or before or after, with one or more other therapeutic agents.
  • the compounds of the present invention or its crystal form may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition with the other agents.
  • the pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredients, or about 1-500 mg of active ingredients for a subject of about 50-70 kg.
  • the therapeutically effective dosage of a compound or its crystal form, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
  • the amount of the compound in the therapeutically effective dose of the compound of the present invention or its crystalline form is from about 0.1 mg to about 2,000 mg per day.
  • the pharmaceutical compositions should provide a dosage of from about 0.1 mg to about 2000 mg of the compound.
  • pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 2,000 mg, about 10 mg to about 1,000 mg of the active ingredient or a combination of essential ingredients per dosage unit form.
  • the compound or its crystal form and pharmaceutical composition provided by the present invention can be used to prepare medicines for the prevention, treatment or alleviation of orexin receptor-related diseases in mammals, including humans, and can also be used to prepare medicines for antagonizing orexin receptors.
  • the amount of the compound in the composition of the present invention can effectively, detectably and selectively antagonize the orexin receptor, and the compound or its crystal form of the present invention can be used as a medicine for treating diseases related to orexin receptor.
  • the compound of the present invention or its crystal form would be useful for, but is not limited to, preventing, treating or alleviating diseases related to orexin receptors by administering to the patient the compound of the present invention or its crystal form or a pharmaceutical composition disclosed herein in an effective amount.
  • the disease related to orexin receptors is sleep disorder, depression, anxiety, 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, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure, etc.
  • the compound of the present invention or its crystal form and pharmaceutical composition can also be useful for veterinary treatment of animals such as companion animals, exotic animals and farm animals.
  • animals such as companion animals, exotic animals and farm animals.
  • the animals disclosed herein include horses, dogs, and cats.
  • Figure 1 is an X-ray powder diffraction (XRPD) pattern of the crystal form I of the compound represented by formula (I) .
  • Figure 2 is a differential scanning calorimetry (DSC) pattern of the crystal form I of the compound represented by formula (I) .
  • Figure 3 is the X-ray powder diffraction (XRPD) pattern of the amorphous form of the compound represented by formula (I) .
  • Figure 4 is an X-ray powder diffraction (XRPD) pattern of the crystal form II of the compound represented by formula (I) .
  • Figure 5 is a differential scanning calorimetry (DSC) pattern of the crystal form II of the compound represented by formula (I) .
  • Figure 6 is an X-ray powder diffraction (XRPD) pattern of the crystal form X of the compound represented by formula (I) .
  • Figure 7 is a differential scanning calorimetry (DSC) pattern of the crystal form X of the compound represented by formula (I) .
  • Figure 8 is an X-ray powder diffraction (XRPD) pattern of the crystal form XI of the compound represented by formula (I) .
  • Figure 9 is a differential scanning calorimetry (DSC) pattern of the crystal form XI of the compound represented by formula (I) .
  • Figure 10 is an X-ray powder diffraction (XRPD) pattern of the crystal form XII of the compound represented by formula (I) .
  • Figure 11 is a differential scanning calorimetry (DSC) pattern of the crystal form XII of the compound represented by formula (I) .
  • Figure 12 is an X-ray powder diffraction (XRPD) pattern of the crystal form XIII of the compound represented by formula (I) .
  • Figure 13 is a differential scanning calorimetry (DSC) pattern of the crystal form XIII of the compound represented by formula (I) .
  • Figure 14 is an X-ray powder diffraction (XRPD) pattern of the crystal form XIV of the compound represented by formula (I) .
  • Figure 15 is a differential scanning calorimetry (DSC) pattern of the crystal form XIV of the compound represented by formula (I) .
  • Figure 16 is an X-ray powder diffraction (XRPD) pattern of the crystal form XV of the compound represented by formula (I) .
  • Figure 17 is a differential scanning calorimetry (DSC) pattern of the crystal form XV of the compound represented by formula (I) .
  • Figure 18 is the X-ray powder diffraction (XRPD) comparison chart of crystal form II of the compound represented by formula (I) according to the method of Example 11 Experiment B under high temperature, high humidity, and light conditions for 0 days and 10 days.
  • XRPD X-ray powder diffraction
  • Figure 19 is a dynamic vapour adsorption (DVS) diagram of the crystal form II of the compound represented by formula (I) .
  • the X-ray powder diffraction analysis in the present invention was performed on an Empyrean diffractometer, and an X-ray powder diffraction pattern was obtained using Cu-K ⁇ radiation (45 KV, 40 mA) .
  • the powdery sample was prepared as a thin layer on a monocrystalline silicon sample rack, placed on a specimen rotating holder, analyzed in the range of 3°-60° with a step size of 0.0167°.
  • Data Collector software was used to collect data
  • HighScore Plus software was used to process data
  • Data Viewer software was used to read data.
  • the differential scanning calorimetry (DSC) analysis method used in the present invention was using a TA Q2000 module equipped with a thermal analysis controller to perform differential scanning calorimetry. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of the sample was accurately weighed into a specially crafted aluminum crucible with a lid and analyzed from room temperature to about 300 °C using a linear heating device at 10 °C/min. During use, the DSC chamber was purged with dry nitrogen.
  • the hygroscopicity of the present invention was measured by DVS INT-Std dynamic vapor sorptionanalyzer from Surface Measurement Systems, UK.
  • the humidity test range was 0%-95%, airflow: 200 mL/min, temperature: 25°C, and test points: one test point was taken for every 5%increase in humidity.
  • the compound represented by formula (I) (307 g) was prepared.
  • the compound was dissolved in DMF (614 mL) , and the mixture was heated to 80°C and stirred for 0.5 h to make the solid completely dissolved, then slowly cooled down to room temperature, crystallized, filtered with suction.
  • the filter residue was washed with water (50 mL ⁇ 2) , and air-dried at 70°C to obtain off-white solid powder.
  • the crystal form I 500 mg of the compound represented by formula (I) was added to DCM (5.0 mL) and dissolved at room temperature, followed by rotary evaporation under reduced pressure to precipitate a solid, which was dried to obtain off-white solid powder.
  • the crystal form I (200 mg) of the compound represented by formula (I) was added into ethyl acetate (2.0 mL) . The mixture was stirred and heated to 75°C, and stirred in slurry for 24 h. Then the reaction was stopped. The mixture was filtered with suction and dried to obtain the target crystal form as off-white solid powder.
  • the crystal form I (60 mg) of the compound represented by formula (I) was added into ethylene glycol dimethyl ether (2.0 mL) . The mixture was stirred in slurry at room temperature for 5 days, then the reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
  • the crystal form I (60 mg) of the compound represented by formula (I) was added into acetonitrile (1.0 mL) . The mixture was stirred in slurry at room temperature for 5 days, then the reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
  • the amorphous form (50 mg) of the compound represented by formula (I) was added into 4-methyl-2-pentanone (1.0 mL) .
  • the mixture was stirred in slurry at room temperature for 24 h, then the reaction was stopped.
  • the mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
  • the crystal form I (50 mg) of the compound represented by formula (I) was added into acetone (1.0 mL) , and the mixture was stirred in slurry at 50°C for 24 h. The reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
  • the amorphous form (50 mg) of the compound represented by formula (I) was added to butanone (1.0 mL) , and the mixture was stirred in slurry at room temperature for 24 h. The reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
  • the amorphous form (50 mg) of the compound represented by formula (I) was added into ethyl formate (1.0 mL) , and the mixture was stirred in slurry at room temperature for 24 h. The reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
  • Example 10 The pharmacokinetics test of the crystal form of the present invention
  • test samples were filled into capsules for oral administration.
  • Example 11 The stability test of the crystal form of the present invention
  • the test samples were put into EP tubes, and water (1.5 mL) was added to each tube.
  • the mixtures were stirred in slurry at room temperature for 24 h, filtered with suction, dried, analyzed and identified by X-ray powder diffraction (XRPD) .
  • XRPD X-ray powder diffraction
  • the experimental results show that the crystal form II of the present invention is stirred in water at room temperature, the crystal form will not change, while other crystal forms, such as crystal forms XIII, XIV, XV, are also stirred in water, and the crystal structure will change. That is, the crystal structure of the crystal form II of the present invention is stable and suitable for industrial production and formulation development.
  • test sample was placed in light (4500 ⁇ 500 lx, ultraviolet light ⁇ 0.7 w/m 2 ) , high humidity (25 °C, 75% ⁇ 5%RH, 90% ⁇ 5%RH) , and at high temperature (40 °C ⁇ 2 °C, 60 °C ⁇ 2 °C, without humidity control) to conduct the influencing factor experiment.
  • a sample was taken on the 10th day for XRPD detection to investigate the stability of the crystal form of the sample. Results were as shown in FIG. 18.
  • the XRPD pattern of crystal form II of the present invention has no significant change, that is, the crystal structure of the crystal form II remains unchanged. Therefore, the crystal form II of the present invention has better stability under various storing conditions and is suitable for pharmaceutical applications.
  • Example 12 The hygroscopicity test of the crystal form of the present invention
  • test sample i.e., the crystal form of the present invention
  • dynamic vapour sorption was used to test the hygroscopicity.
  • the dynamic vapour adsorption (DVS) diagram of the hygroscopicity test of the crystal form II of the present invention was basically as shown in FIG. 19. It can be seen from FIG. 19 that the hygroscopicity of the crystal form II of the present invention under different humidity is very low, and the hygroscopicity weight gain is about 0.06%under the condition of 95%RH; according to the description of hygroscopicity characteristics and the definition standard for hygroscopicity weight gain (Chinese Pharmacopoeia 2015 Edition General Principles 9103 Guidelines for Drug Hygroscopicity Tests, see Table 2 for details) , the crystal form II of the present invention is non-hygroscopic. That is, the crystal form II of the present invention is not susceptible to deliquescence by influence of high humidity.

Abstract

Disclosed a crystal form of octahydropyrrolo [3,4-c] pyrrole derivatives. Disclosed a pharmaceutical composition comprising the crystal form, and the use of the crystal form or the pharmaceutical composition in the manufacture of a medicament for preventing, treating or alleviating diseases related to orexin receptors.

Description

CRYSTAL FORMS OF OCTAHYDROPYRROLO [3, 4-c] PYRROLE DERIVATIVES
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the priority and benefits of Chinese Patent Application No. 201911198247.8, filed with the State Intellectual Property Office of China on November 29, 2019, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The invention belongs to the technical field of medicine, and relates to a crystal form of octahydropyrrolo [3, 4-c] pyrrole derivatives. The invention specifically relates to a crystal form of (5- (5-chlorobenzo [d] oxazol-2-yl) hexahydropyrrolo [3, 4-c] pyrrole-2 (1H) -yl) (2-fluoro-6- (2H-1, 2, 3-triazol-2-yl) phenyl) methanone and the use thereof, and further relates to a pharmaceutical composition comprising the crystal form.
BACKGROUND OF THE INVENTION
Orexin, also known as hypothalamic secretin, includes orexin A and orexin B (or hypothalamic secretin-1 and hypothalamic secretin-2) , which is a neuropeptide secreted by the hypothalamus. The main physiological functions are as follows: 1. regulating food intake: orexin can activate the neurons that regulate eating, obviously promote eating, and has a dose-dependent response; 2. participating in the regulation of energy metabolism: orexin can significantly increase the metabolic rate; 3. participating in the regulation of sleep-wakefulness: orexin can inhibit rapid eye movement sleep and prolong the time of wakefulness; and blocking the effect of orexin can promote sleep; 4. participating in endocrine regulation: orexin has a significant effect on the endocrine of pituitary hormones; 5. relating to the sense of reward, learning and memory; 6. promoting gastric acid secretion; 7. promoting more drinking water; 8. raising blood pressure; 9. playing an important role in the reward system and drug addiction mechanism, etc. (Piper et al., The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur. J. Neuroscience, 2000, 12 (2) , 726-730; and Sakurai, T., et al., The neural circuit of orexin (hypocretin) : Maintaining sleep and wakefulness. Nature Review Neuroscience, 2007, 8: 171181) .
Orexin produces physiological effects by acting on orexin receptor (OXR) . Orexin receptor is a G-protein coupled receptor. There are two types, called OX 1 receptor and OX 2 receptor. OX 1 receptor selectively binds orexin A, while OX 2 receptor can 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 feeding behavior. Cell, 1998, 92 (4) : 573-585) . OX 1 receptor and OX 2 receptor are almost exclusively found in brain tissues, and are selectively expressed in the brain. Among them, OX 1 receptor is expressed at high density in locus coeruleus, which is the nuclei originis of noradrenergic neurons; while OX 2 receptor is expressed at high density in the nodular papillary nucleus, which is the nuclei originis of histaminergic neurons. The expression of both OX 1 receptor and OX 2 receptor can be found in the raphe nucleus, which is the nuclei originis of serotonergic neurons; the expression of both OX 1 receptor and OX 2 receptor can also be found in the ventral tegmental area, which is the nuclei originis of dopaminergic neurons. In addition, the expression of OX 2 receptor can also be found in brainstem cholinergic neurons responsible for regulating REM sleep and has an impact on its nuclear activity (Marcus, J.N. et al., Differential expression of  orexin receptors  1 and 2 in the rat brain. J. Comp. Neurol., 2001, 435 (1) : 6-25; and Trivedi, P. et al., Distribution of orexin receptor mRNA in the rat brain. FEBS Lett., 1998, 438 (1-2) : 71-75) .
It can be seen that orexin receptors are of great significance in pathology and are related to many diseases, such as sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease and high blood pressure.
Different solid forms of pharmaceutical active ingredients may have different properties. Different solid forms may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may have different effects on the stability, bioavailability and efficacy of the drug. Therefore, the solid form of drug should be fully considered in drug research and development.
International application WO 2017088759 A1 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 does not disclose the research on the crystal form of the compound.
When the inventors studied the compound, it was found that the compound has poor water solubility, low oral bioavailability, poor stability, and poor druggability. Therefore, it is necessary to find a solid form with better druggability.
SUMMARY OF THE INVENTION
Through a large number of experimental studies, the inventor found that the crystal form II of the compound having formula (I) has good stability, high exposure in the organism after oral administration, high bioavailability, and high preparation purity of the product, that is, the physical properties and various properties of the crystal form II of the present invention are more conducive to the development of preparations, and thus have better druggability.
Specifically, the present invention relates to a crystal form of the compound having formula (I) , and the use of the crystal form or the pharmaceutical composition comprising the crystal form in the manufacture of a medicament for the prevention, treatment or alleviation of orexin receptor-related diseases. The crystal form of the present invention may also be in the form of a solvate, such as a hydrate form.
In one aspect, the present invention provides a crystal form of the compound having formula (I) ,
Figure PCTCN2020131410-appb-000001
In some embodiments, the crystal form described in the present invention is crystal form I.
In some embodiments, the crystal form I of the present invention, wherein the X-ray powder diffraction pattern of the crystal form I comprises peaks expressed as 2θ at 7.44° ± 0.2°, 7.78° ± 0.2°, 8.24° ± 0.2°, 12.69° ± 0.2°, 12.95° ± 0.2°, 14.08° ± 0.2°, 14.75° ± 0.2°, 15.03°± 0.2°, 17.75° ± 0.2°, 19.71° ± 0.2°, 20.12° ± 0.2°, 20.81° ± 0.2°, 21.30° ± 0.2°, 21.89° ± 0.2°, 22.18° ± 0.2°, 23.27° ± 0.2°, 25.49° ± 0.2°, 25.85° ± 0.2°, 26.08° ± 0.2°, 26.60° ± 0.2°, 27.21° ± 0.2°, 27.44° ± 0.2°, 27.70° ± 0.2°, 28.53° ± 0.2°.
In some embodiments, the crystal form I of the present invention, wherein the crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
In some embodiments, the crystal form I of the present invention, wherein the differential scanning calorimetry of the crystal form I comprises an endothermic peak at 159.96 ℃ ± 3 ℃.
In some embodiments, the crystal form I of the present invention, wherein the crystal form I has a differential scanning calorimetry diagram substantially as shown in FIG. 2.
In some embodiments, the crystal form described in the present invention is crystal form II.
In some embodiments, the crystal form II of the present invention, wherein the  X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2θ at 10.43°± 0.2°, 12.31° ± 0.2°, 15.92° ± 0.2°, 16.90° ± 0.2°, 17.90° ± 0.2°, 20.52° ± 0.2°, 21.04° ± 0.2°, 26.53° ± 0.2°, 26.83° ± 0.2°.
In some embodiments, the crystal form II of the present invention, wherein the X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2θ at 10.43°± 0.2°, 12.31° ± 0.2°, 14.49° ± 0.2°, 15.92° ± 0.2°, 16.00° ± 0.2°, 16.90° ± 0.2°, 17.90° ± 0.2°, 18.42° ± 0.2°, 20.52° ± 0.2°, 21.04° ± 0.2°, 21.45° ± 0.2°, 23.59° ± 0.2°, 24.00° ± 0.2°, 24.26° ± 0.2°, 24.75° ± 0.2°, 25.07° ± 0.2°, 26.26° ± 0.2°, 26.53° ± 0.2°, 26.83° ± 0.2°, 30.03° ± 0.2°, 31.20° ± 0.2°, 31.56° ± 0.2°, 34.24° ± 0.2°, 38.78° ± 0.2°.
In some embodiments, the crystal form II of the present invention, wherein the X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2θ at 10.43°± 0.2°, 12.31° ± 0.2°, 13.08° ± 0.2°, 14.49° ± 0.2°, 15.18° ± 0.2°, 15.92° ± 0.2°, 16.00° ± 0.2°, 16.61° ± 0.2°, 16.90° ± 0.2°, 17.90° ± 0.2°, 18.42° ± 0.2°, 20.52° ± 0.2°, 21.04° ± 0.2°, 21.45° ±0.2°, 23.59° ± 0.2°, 24.00° ± 0.2°, 24.26° ± 0.2 °, 24.75° ± 0.2°, 25.07° ± 0.2°, 26.26° ± 0.2°, 26.53° ± 0.2°, 26.83° ± 0.2°, 28.02° ± 0.2°, 28.31° ± 0.2°, 29.31° ± 0.2°, 30.03° ± 0.2°, 30.42° ± 0.2°, 31.20° ± 0.2°, 31.56° ± 0.2°, 32.25° ± 0.2°, 32.80° ± 0.2°, 33.63° ± 0.2°, 34.24° ± 0.2°, 35.54° ± 0.2°, 36.41° ± 0.2°, 36.96° ± 0.2°, 38.33° ± 0.2°, 38.78° ± 0.2°.
In some embodiments, the crystal form II of the present invention, wherein the crystal form II has an X-ray powder diffraction pattern substantially as shown in FIG. 4.
In some embodiments, the crystal form II of the present invention, wherein the differential scanning calorimetry of the crystal form II comprises an endothermic peak at 182.86 ℃ ± 3 ℃.
In some embodiments, the crystal form II of the present invention, wherein the crystal form II has a differential scanning calorimetry diagram substantially as shown in FIG. 5.
In some embodiments, the crystal form described in the present invention is crystal form X.
In some embodiments, the crystal form X of the present invention, wherein the X-ray powder diffraction pattern of the crystal form X comprises peaks expressed as 2θ at 7.97°± 0.2°, 12.20° ± 0.2°, 13.82° ± 0.2°, 15.68° ± 0.2°, 16.79° ± 0.2°, 17.48° ± 0.2°, 18.42° ± 0.2°, 20.05° ± 0.2°, 20.85° ± 0.2°, 22.33° ± 0.2°, 23.03° ± 0.2°, 23.87° ± 0.2°, 24.61° ± 0.2°, 25.72° ± 0.2°, 26.97° ± 0.2°, 27.48° ± 0.2°, 28.05° ± 0.2°, 28.77° ± 0.2°, 29.49° ± 0.2°, 30.29° ± 0.2°, 32.05° ± 0.2°, 32.96° ± 0.2°, 33.35° ± 0.2°, 34.90° ± 0.2°, 36.21° ± 0.2°, 36.82° ± 0.2°, 39.33° ± 0.2°.
In some embodiments, the crystal form X of the present invention, wherein the crystal form X has an X-ray powder diffraction pattern substantially as shown in FIG. 6.
In some embodiments, the crystal form X of the present invention, wherein the differential scanning calorimetry of the crystal form X comprises an endothermic peak at 176.58 ℃ ± 3 ℃.
In some embodiments, the crystal form X of the present invention, wherein the crystal form X has a differential scanning calorimetry diagram substantially as shown in FIG. 7.
In some embodiments, the crystal form described in the present invention is crystal form XI.
In some embodiments, the crystal form XI of the present invention, wherein the X-ray powder diffraction pattern of the crystal form XI comprises peaks expressed as 2θ at 7.44°± 0.2°, 7.76° ± 0.2°, 8.28° ± 0.2°, 12.69° ± 0.2°, 14.14° ± 0.2°, 15.05° ± 0.2°, 16.55° ± 0.2°, 17.44° ± 0.2°, 17.77° ± 0.2°, 19.12° ± 0.2°, 19.35° ± 0.2°, 19.69° ± 0.2°, 20.14° ± 0.2°, 20.45° ± 0.2°, 20.74° ± 0.2°, 21.35° ± 0.2°, 21.95° ± 0.2°, 22.20° ± 0.2°, 23.25° ± 0.2°, 23.82° ± 0.2°, 24.90° ± 0.2°, 25.46° ± 0.2°, 25.82° ± 0.2°, 27.19° ± 0.2°, 27.41° ± 0.2°, 27.52° ± 0.2°, 29.58° ± 0.2°, 32.96° ± 0.2°, 35.29° ± 0.2°, 38.58° ± 0.2°.
In some embodiments, the crystal form XI of the present invention, wherein the crystal form XI has an X-ray powder diffraction pattern substantially as shown in FIG. 8.
In some embodiments, the crystal form XI of the present invention, wherein the differential scanning calorimetry of the crystal form XI comprises endothermic peaks at 149.48 ℃ ± 3 ℃ and 160.27 ℃ ± 3 ℃.
In some embodiments, the crystal form XI of the present invention, wherein the crystal form XI has a differential scanning calorimetry diagram substantially as shown in FIG. 9.
In some embodiments, the crystal form described in the present invention is crystal form XII.
In some embodiments, the crystal form XII of the present invention, wherein the X-ray powder diffraction pattern of the crystal form XII comprises peaks expressed as 2θ at 6.36° ± 0.2°, 7.25° ± 0.2° , 11.41° ± 0.2°, 11.89° ± 0.2°, 13.32° ± 0.2°, 13.76° ± 0.2°, 14.15° ± 0.2°, 15.10° ± 0.2°, 16.67° ± 0.2°, 18.06° ± 0.2°, 18.23° ± 0.2°, 18.86° ± 0.2°, 19.04° ± 0.2°, 19.35° ± 0.2°, 20.09° ± 0.2°, 20.43° ± 0.2°, 20.72° ± 0.2°, 21.42° ± 0.2°, 22.61° ± 0.2°, 23.48° ± 0.2°, 23.65° ± 0.2°, 23.86° ± 0.2°, 24.59° ± 0.2°, 25.22° ± 0.2°, 27.89° ± 0.2°, 28.49° ± 0.2°, 29.51° ± 0.2°, 30.22° ± 0.2°, 32.95° ± 0.2°.
In some embodiments, the crystal form XII of the present invention, wherein the crystal form XII has an X-ray powder diffraction pattern substantially as shown in FIG. 10.
In some embodiments, the crystal form XII of the present invention, wherein the differential scanning calorimetry of the crystal form XII comprises an endothermic peak at 162.58 ℃ ± 3 ℃.
In some embodiments, the crystal form XII of the present invention, wherein the crystal form XII has a differential scanning calorimetry diagram substantially as shown in FIG. 11.
In some embodiments, the crystal form described in the present invention is crystal form XIII.
In some embodiments, the crystal form XIII of the present invention, wherein the X-ray powder diffraction pattern of the crystal form XIII comprises peaks expressed as 2θ at 7.18° ± 0.2°, 8.28° ± 0.2°, 12.37° ± 0.2°, 13.45° ± 0.2°, 14.26° ± 0.2°, 14.87° ± 0.2°, 17.48° ± 0.2°, 17.90° ± 0.2°, 19.35° ± 0.2°, 19.95° ± 0.2°, 20.71° ± 0.2°, 21.23° ± 0.2°, 21.45° ± 0.2°, 22.11° ± 0.2°, 23.16° ± 0.2°, 24.95° ± 0.2°, 25.55° ± 0.2°, 26.82° ± 0.2°, 27.07° ± 0.2°, 27.35° ± 0.2°, 28.40° ± 0.2°, 28.94° ± 0.2°, 29.40° ± 0.2°, 29.99° ± 0.2°.
In some embodiments, the crystal form XIII of the present invention, wherein the crystal form XIII has an X-ray powder diffraction pattern substantially as shown in FIG. 12.
In some embodiments, the crystal form XIII of the present invention, wherein the differential scanning calorimetry of the crystal form XIII comprises endothermic peaks at 146.79 ℃ ± 3℃ and 164.21 ℃ ± 3℃.
In some embodiments, the crystal form XIII of the present invention, wherein the crystal form XIII has a differential scanning calorimetry diagram substantially as shown in FIG. 13.
In some embodiments, the crystal form described in the present invention is crystal form XIV.
In some embodiments, the crystal form XIV of the present invention, wherein the X-ray powder diffraction pattern of the crystal form XIV comprises peaks expressed as 2θ at 7.25° ± 0.2°, 8.06° ± 0.2°, 12.62° ± 0.2°, 14.02° ± 0.2°, 14.79° ± 0.2°, 17.28° ± 0.2°, 17.65° ± 0.2°, 19.69° ± 0.2°, 19.87° ± 0.2°, 20.64° ± 0.2°, 20.80° ± 0.2°, 21.62° ± 0.2°, 23.22° ± 0.2°, 24.31° ± 0.2°, 25.46° ± 0.2°, 25.77° ± 0.2°, 26.71° ± 0.2°, 27.23° ± 0.2°, 28.42° ± 0.2°, 28.74° ± 0.2°, 29.82° ± 0.2°, 30.78° ± 0.2°, 32.95° ± 0.2°, 24.26° ± 0.2°.
In some embodiments, the crystal form XIV of the present invention, wherein the crystal form XIV has an X-ray powder diffraction pattern substantially as shown in FIG. 14.
In some embodiments, the crystal form XIV of the present invention, wherein the differential scanning calorimetry of the crystal form XIV comprises endothermic peaks at 124.04 ℃ ± 3 ℃ and 163.38 ℃ ± 3 ℃.
In some embodiments, the crystal form XIV of the present invention, wherein the crystal form XIV has a differential scanning calorimetry diagram substantially as shown in FIG. 15.
In some embodiments, the crystal form described in the present invention is crystal form XV.
In some embodiments, the crystal form XV of the present invention, wherein the X-ray powder diffraction pattern of the crystal form XV comprises peaks expressed as 2θ at 7.37° ± 0.2°, 8.03° ± 0.2°, 12.72° ± 0.2°, 13.89° ± 0.2°, 14.85° ± 0.2°, 17.26° ± 0.2°, 17.58° ± 0.2°, 17.77° ± 0.2°, 19.72° ± 0.2°, 20.20° ± 0.2°, 20.47° ± 0.2°, 20.99° ± 0.2°, 21.45° ± 0.2°, 21.64° ± 0.2°, 23.12° ± 0.2°, 24.30° ± 0.2°, 25.26° ± 0.2°, 25.57° ± 0.2°, 27.09° ± 0.2°, 27.23° ± 0.2°, 28.28° ± 0.2°, 28.91° ± 0.2°, 29.98° ± 0.2°, 34.65° ± 0.2°.
In some embodiments, the crystal form XV of the present invention, wherein the crystal form XV has an X-ray powder diffraction pattern substantially as shown in FIG. 16.
In some embodiments, the crystal form XV of the present invention, wherein the differential scanning calorimetry of the crystal form XV comprises endothermic peaks at 127.06 ℃ ± 3 ℃ and 165.38 ℃ ± 3 ℃.
In some embodiments, the crystal form XV of the present invention, wherein the crystal form XV has a differential scanning calorimetry diagram substantially as shown in FIG. 17.
In another aspect, the invention relates to a pharmaceutical composition comprising any one of the crystal forms described in the present invention, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
In one aspect, the present invention relates to use of the crystal form or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, treating or lessening a disease related to orexin receptors in a subject.
In some embodiments, the disease related to orexin receptors of the present invention is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
In another aspect, the present invention relates to a method of preventing, treating or lessening a disease related to orexin receptors in a subject comprising administering to the subject a therapeutically effective amount of the crystal form or the pharmaceutical composition disclosed herein.
In some embodiments, the disease related to orexin receptors of the present invention is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
In another aspect, the present invention relates to the crystal form or the pharmaceutical composition disclosed herein for use in preventing, treating or lessening a disease related to orexin receptors in a subject.
In some embodiments, the disease related to orexin receptors of the present invention is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
In another aspect, the present invention relates to use of the crystal form or the pharmaceutical composition in the manufacture of a medicament for antagonizing orexin receptors.
In one aspect, the present invention also provides an amorphous form of the compound having formula (I) , which has an X-ray powder diffraction pattern substantially as shown in FIG. 3.
In another aspect, the present invention also relates to the preparation method of the crystal form or amorphous form of the compound having formula (I) .
The solvent used in the preparation method of the crystal form or amorphous form of the invention is not particularly restricted, and any solvent which dissolves the starting material to a degree and does not affect its properties is contained in the present invention. Additionally, many similar modifications in the art, equivalent replacements, or solvent, solvent composition and different proportions of the solvent composition which are equivalent to those described in the invention, all are deemed to be included in the present invention. The present  invention gives the preferred solvent for each reaction step.
The preparation of the crystal forms of the present invention will be described in detail in the examples section. Meanwhile, the present invention provides pharmacological properties test experiments (e.g., pharmacokinetic experiments) , solubility experiments, stability experiments, and moisture absorption experiments of the crystal form. Experiments have proved that the crystal form II of the present invention has unexpected technical advantages: 1) the crystal form II is very stable and can not undergo transformation under general conditions (such as open storage at room temperature or stirring in water at room temperature) , and it is also very stable under high temperature and high humidity conditions, and there is basically no change in crystal morphology, appearance and purity; 2) compared with the compound represented by formula (I) disclosed in the prior art, it has a higher blood concentration and exposure level in dogs by oral capsule administration, thereby having better pharmacokinetic properties. Therefore, the crystal form II of the present invention has better pharmacological properties, higher stability, and is more suitable for pharmaceutical use.
DEFINITIONS AND GENERAL TERMINOLOGY
Unless otherwise indicated, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications referred to herein are incorporated by reference in their entirety. Although any methods and materials similar or identical to those described herein may be used in the practice or testing of the invention, but the methods, apparatus and materials described in the invention are preferred.
“Crystal form” or “crystalline form” refers to a solid having a highly regular chemical structure, including, but not limited to, mono-or multi-component crystals, and/or polymorphic compounds of compounds, solvates, hydrates, clathrates, eutecticum, salt, solvate of the salt, hydrate of the salt. The crystalline form of the material can be obtained by a number of methods known in the field. Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in defined space, for example, in nanopores or capillaries, on a surface or template, for example, on a polymer, in the presence of additives such as co-crystallization counterions, crystallization, removing solvent, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reaction crystallization, anti-solvent addition, grinding and solvent drop milling, etc.
"Solvent” refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid) . Solvents for use in the practice of this invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene,  chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N, N-dimethylacetamide, N, N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, mesitylene, nitromethane, polyethylene glycol, propanol, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.
“Anti-solvent” refers to a fluid that promotes the precipitation of a product (or product precursor) from a solvent. The anti-solvent may comprise a cold gas, or a fluid that promotes the precipitation by chemical reaction or 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 liquid different from the solvent.
“Solvate” refers to a compound that has a solvent on the surface, in the crystal lattice, or on the surface and in the crystal lattice. The solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethylsulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N, N-dimethylacetamide, N, 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 the solvate is a hydrate in which the solvent on the surface, in the lattice or on the surface and in the lattice is water. On the surface, in the lattice or on the surface and in the lattic of the substance, the hydrate may or may not have any solvent other than water.
Crystal form can be identified by a variety of technical means, such as X-ray powder diffraction (XRPD) , infrared absorption spectroscopy (IR) , melting point method, differential scanning calorimetry (DSC) , thermogravimetric analysis (TGA) , nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM) , quantitative analysis, solubility and dissolution rate.
X-ray powder diffraction (XRPD) can detect changes in crystal form, crystallinity, crystal state and other information, and is a common means for identifying crystal form. In some embodiments, the crystalline form of the present invention is characterized by an XRPD pattern having certain peak positions, which is substantially as shown in the XRPD pattern provided in the drawings of the present invention. At the same time, the 2θ of the XRPD pattern can be measured with an experimental error. The measurement of 2θ of the XRPD pattern may be slightly different between the different instruments and the different samples. Therefore, the value of 2θ can not be regarded as absolute. According to the condition of the instrument used in this test, the diffraction peak has an error tolerance of ± 0.2°.
Differential Scanning Calorimetry (DSC) is a technique of measuring the energy  difference between a sample and an inert reference (commonly used α-Al 2O 3) varied with temperature by continuously heating or cooling under program control. The endothermic peak of the DSC curve depends on many factors associated with sample preparation and instrument geometry. Thus, in some embodiments, the crystal form of the present invention is characterized by an DSC pattern having certain peak positions, which is substantially as shown in the DSC pattern provided in the drawings of the present invention. At the same time, the DSC pattern can be measured with an experimental error. The peak position and peak value of DSC pattern may be slightly different between the different instruments and the different samples. Therefore, the peak position or the peak value of the DSC endothermic peak can not be regarded as absolute. According to the condition of the instrument used in this test, the endothermic peak has an error tolerance of ± 3 ℃.
Thermogravimetric analysis (TGA) is a technique for measuring the change of quality of a substance varied with temperature under the control of a program. It is suitable for examining the process of the solvent loss or the samples sublimation and decomposition. It can be presumed that the crystal contains crystal water or crystallization solvent. The quality variety of the TGA curve depends on a number of factors, containing the sample preparation and the instrument. The quality variety of the TGA test may be slightly different between the different instruments and between the different samples. According to the condition of the instrument used in this test, there is a ± 0.1%error tolerance for the mass change.
In the context of the present invention, the 2θ values in the X-ray powder diffraction pattern are in degrees (°) .
The term “substantially as shown in the figure” refers to 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 are shown in the X-ray powder diffraction pattern or DSC pattern or Raman spectra pattern or infrared spectra pattern.
The “peak” refers to a feature that a person skilled in the art can recognize without belonging to background noise when referring to a spectrum or/and data that appears in the figure.
The present invention relates to the crystal form of (5- (5-chlorobenzo [d] oxazol-2-yl) hexahydropyrrolo [3, 4-c] pyrrole-2 (1H) -yl) (2-fluoro-6- (2H-1, 2, 3 -triazol-2-yl) phenyl) methanone, which exists in a substantially pure crystalline form.
"Substantially pure” means that a crystalline form is substantially free of another or more crystalline forms, which means the purity of 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%, or crystal form  containing other crystal form. The percentage of the other crystals in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
“Substantially free” means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
“Relative strength” (or “relative peak height” ) in the XRPD pattern means the ratio of the intensity of the other peaks to the intensity of the first strong peak when the intensity of the first strong peak in all the diffraction peaks of the X-ray powder diffraction pattern (XRPD) is 100%.
In the context of the present invention, when used or whether or not used the word, such as “about” , it means that within a given value or range of 10%, appropriately within 5%, especially within 1%. Or, for those of ordinary skill in the art, the term “about” means within an acceptable standard error range of the mean value. When a number with an N value is disclosed, any number within N +/-1%, N +/-2%, N +/-3%, N +/-5%, N +/-7%, N +/-8%, or N +/-10%will be disclosed clearly, wherein “+/-” means plus or minus.
In the present invention, “room temperature” refers to the temperature from about 10 ℃ to about 40 ℃. In some embodiments, “room temperature” refers to a temperature from about 20 ℃ to about 30 ℃; in other embodiments, “room temperature” refers to 20 ℃, 22.5 ℃, 25 ℃, 27.5 ℃, and so on.
PHARMACEUTICAL COMPOSITIONS, FORMULATIONS, ADMINISTRATIONS AND USES OF THE CRYSTAL FORMS OF THE PRESENT INVENTION
The pharmaceutical composition of the present invention characterized in that it includes the crystal form of the compound represented by formula (I) and a pharmaceutically acceptable carrier, adjuvant, or excipient. The amount of the crystal form of the compound in the pharmaceutical composition of the present invention can effectively and detectably treat or alleviate the patient's central nervous system dysfunction. The pharmaceutical composition of the present invention may also optionally contain other therapeutic and/or preventive components.
Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel H.C. et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams &Wilkins, Philadelphia; Gennaro A.R. et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams &Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients  (2005) Pharmaceutical Press, Chicago.
Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington’s Pharmaceutical Sciences (Mack Publishing Company) , The Handbook of Pharmaceutical Additives (Gower Publishing Limited) , and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press) .
In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams &Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated by reference herein, various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof are disclosed. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component (s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing Company) .
Another aspect of the present invention is related to a method for preparing a pharmaceutical composition, the pharmaceutical composition contains the crystal form of the compound disclosed herein and pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or a combination thereof, the method comprises mixing various ingredients. The pharmaceutical composition containing the crystal form of the compound disclosed herein can be prepared by mixing for example at environment temperature and under barometric pressure.
The compound of the invention or its crystalline form will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalational administration such as  aerosols, solutions, and dry powders; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.
The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC) , consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, including methyl-and propyl-parabens, and sorbic acid. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
In one embodiment, the therapeutic methods disclosed herein comprise administrating to a patient in need of the treatment a safe and effective amount of the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form. Each embodiment disclosed herein comprises the treatment of the above disorders or diseases comprising administrating to a patient in need a safe and effective amount of the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form.
In one embodiment, the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration and rectal administration. Typical parenteral administration refers to routes of administration by injection or infusion, including intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin as well as intraocular, otic, intravaginal, inhaled and intranasal administration. In one embodiment, the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered orally. In another embodiment, the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered by inhalation. In a further embodiment, the compound of the invention or  its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered intranasally.
In one embodiment, the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. In one embodiment, a dose is administered once per day. In a further embodiment, a dose is administered twice per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form depend on the pharmacokinetic properties of that compound or its crystal form, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for the compound of the invention or its crystal form or the pharmaceutical composition containing the compound of the invention or its crystal form depend on the disorder being treated, the severity of the disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment for an individual patient’s response to the dosing regimen or over time as individual patient needs change.
The compounds of the present invention or its crystal form may be administered either simultaneously, or before or after, with one or more other therapeutic agents. The compounds of the present invention or its crystal form may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition with the other agents.
The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredients, or about 1-500 mg of active ingredients for a subject of about 50-70 kg. The therapeutically effective dosage of a compound or its crystal form, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease.
The above-cited dosage properties are demonstrable in vitro and in vivo tests using  advantageously mammals, e.g., mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
In one embodiment, the amount of the compound in the therapeutically effective dose of the compound of the present invention or its crystalline form is from about 0.1 mg to about 2,000 mg per day. The pharmaceutical compositions should provide a dosage of from about 0.1 mg to about 2000 mg of the compound. In a special embodiment, pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 2,000 mg, about 10 mg to about 1,000 mg of the active ingredient or a combination of essential ingredients per dosage unit form.
The compound or its crystal form and pharmaceutical composition provided by the present invention can be used to prepare medicines for the prevention, treatment or alleviation of orexin receptor-related diseases in mammals, including humans, and can also be used to prepare medicines for antagonizing orexin receptors.
Specifically, the amount of the compound in the composition of the present invention can effectively, detectably and selectively antagonize the orexin receptor, and the compound or its crystal form of the present invention can be used as a medicine for treating diseases related to orexin receptor.
The compound of the present invention or its crystal form would be useful for, but is not limited to, preventing, treating or alleviating diseases related to orexin receptors by administering to the patient the compound of the present invention or its crystal form or a pharmaceutical composition disclosed herein in an effective amount. The disease related to orexin receptors is sleep disorder, depression, anxiety, 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, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure, etc.
Besides being useful for human treatment, the compound of the present invention or its crystal form and pharmaceutical composition can also be useful for veterinary treatment of animals such as companion animals, exotic animals and farm animals. In other embodiments, the animals disclosed herein include horses, dogs, and cats.
DESCRIPTION OF THE DRAWINGS
Figure 1 is an X-ray powder diffraction (XRPD) pattern of the crystal form I of the compound represented by formula (I) .
Figure 2 is a differential scanning calorimetry (DSC) pattern of the crystal form I of the compound represented by formula (I) .
Figure 3 is the X-ray powder diffraction (XRPD) pattern of the amorphous form of the compound represented by formula (I) .
Figure 4 is an X-ray powder diffraction (XRPD) pattern of the crystal form II of the compound represented by formula (I) .
Figure 5 is a differential scanning calorimetry (DSC) pattern of the crystal form II of the compound represented by formula (I) .
Figure 6 is an X-ray powder diffraction (XRPD) pattern of the crystal form X of the compound represented by formula (I) .
Figure 7 is a differential scanning calorimetry (DSC) pattern of the crystal form X of the compound represented by formula (I) .
Figure 8 is an X-ray powder diffraction (XRPD) pattern of the crystal form XI of the compound represented by formula (I) .
Figure 9 is a differential scanning calorimetry (DSC) pattern of the crystal form XI of the compound represented by formula (I) .
Figure 10 is an X-ray powder diffraction (XRPD) pattern of the crystal form XII of the compound represented by formula (I) .
Figure 11 is a differential scanning calorimetry (DSC) pattern of the crystal form XII of the compound represented by formula (I) .
Figure 12 is an X-ray powder diffraction (XRPD) pattern of the crystal form XIII of the compound represented by formula (I) .
Figure 13 is a differential scanning calorimetry (DSC) pattern of the crystal form XIII of the compound represented by formula (I) .
Figure 14 is an X-ray powder diffraction (XRPD) pattern of the crystal form XIV of the compound represented by formula (I) .
Figure 15 is a differential scanning calorimetry (DSC) pattern of the crystal form XIV of the compound represented by formula (I) .
Figure 16 is an X-ray powder diffraction (XRPD) pattern of the crystal form XV of the compound represented by formula (I) .
Figure 17 is a differential scanning calorimetry (DSC) pattern of the crystal form XV of the compound represented by formula (I) .
Figure 18 is the X-ray powder diffraction (XRPD) comparison chart of crystal form  II of the compound represented by formula (I) according to the method of Example 11 Experiment B under high temperature, high humidity, and light conditions for 0 days and 10 days.
Figure 19 is a dynamic vapour adsorption (DVS) diagram of the crystal form II of the compound represented by formula (I) .
EXAMPLES
The invention will now be further illustrated by the following example without limiting the invention to the scope of the described examples.
The X-ray powder diffraction analysis in the present invention was performed on an Empyrean diffractometer, and an X-ray powder diffraction pattern was obtained using Cu-Kαradiation (45 KV, 40 mA) . The powdery sample was prepared as a thin layer on a monocrystalline silicon sample rack, placed on a specimen rotating holder, analyzed in the range of 3°-60° with a step size of 0.0167°. Data Collector software was used to collect data, HighScore Plus software was used to process data, and Data Viewer software was used to read data.
The differential scanning calorimetry (DSC) analysis method used in the present invention was using a TA Q2000 module equipped with a thermal analysis controller to perform differential scanning calorimetry. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of the sample was accurately weighed into a specially crafted aluminum crucible with a lid and analyzed from room temperature to about 300 ℃ using a linear heating device at 10 ℃/min. During use, the DSC chamber was purged with dry nitrogen.
The solubility of the present invention was determined by an Agilent 1200 High Performance Liquid Chromatograph DAD/VWD detector with an Agilent XDB-C18 model (4.6 × 50 mm, 5 μm) . Detection wavelength: 266 nm, flow rate: 1.0 mL/min, the column temperature: 35 ℃, mobile phase A: acetonitrile -0.01 M ammonium acetate = 10: 90 (V: V) , analysis methods: acetonitrile -mobile phase A = 70: 30 (V: V) , running time: 10 minutes.
The hygroscopicity of the present invention was measured by DVS INT-Std dynamic vapor sorptionanalyzer from Surface Measurement Systems, UK. The humidity test range was 0%-95%, airflow: 200 mL/min, temperature: 25℃, and test points: one test point was taken for every 5%increase in humidity.
EXAMPLES
The specific synthesis method of the compound represented by formula (I) (5- (5-chlorobenzo [d] oxazol-2-yl) hexahydropyrrolo [3, 4-c] pyrrole-2 (1H) -yl) (2-fluoro-6- (2H-1, 2, 3 -triazol-2-yl) phenyl) methanone referred to Example 3 in International Application WO 2017088759 A1.
Examples
Example 1 Crystal form I of the invention
1. Preparation of crystal form I
According to the method of Example 3 in International Application WO 2017088759 A1, the compound represented by formula (I) (307 g) was prepared. The compound was dissolved in DMF (614 mL) , and the mixture was heated to 80℃ and stirred for 0.5 h to make the solid completely dissolved, then slowly cooled down to room temperature, crystallized, filtered with suction. The filter residue was washed with water (50 mL×2) , and air-dried at 70℃ to obtain off-white solid powder.
2. Identification of crystal form I
(1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation with the following characteristic peaks expressed as 2θ at: 7.44°, 7.78°, 8.24°, 12.69°, 12.95°, 14.08°, 14.75°, 15.03°, 17.75°, 19.71°, 20.12°, 20.81°, 21.30°, 21.89°, 22.18°, 23.27°, 25.49°, 25.85°, 26.08°, 26.60°, 27.21°, 27.44°, 27.70° and 28.53°. There was an error tolerance of ± 0.2°.
(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10 ℃/min and comprised an endothermic peak at 159.96 ℃. There was an error tolerance of ± 3 ℃.
Example 2 Amorphous form of the invention
1. Preparation of amorphous form
The crystal form I (500 mg) of the compound represented by formula (I) was added to DCM (5.0 mL) and dissolved at room temperature, followed by rotary evaporation under reduced pressure to precipitate a solid, which was dried to obtain off-white solid powder.
2. Identification of amorphous form
Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation: its X-ray powder diffraction was essentially as shown in FIG. 3.
Example 3 Crystal form II of the invention
1. Preparation of crystal form II
The crystal form I (200 mg) of the compound represented by formula (I) was added  into ethyl acetate (2.0 mL) . The mixture was stirred and heated to 75℃, and stirred in slurry for 24 h. Then the reaction was stopped. The mixture was filtered with suction and dried to obtain the target crystal form as off-white solid powder.
2. Identification of crystal form II
(1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation with the following characteristic peaks expressed as 2θ at: 10.43°, 12.31°, 13.08°, 14.49°, 15.18°, 15.92°, 16.00°, 16.61°, 16.90°, 17.90°, 18.42°, 20.52°, 21.04°, 21.45°, 23.59°, 24.00°, 24.26°, 24.75°, 25.07°, 26.26°, 26.53°, 26.83°, 28.02°, 28.31°, 29.31°, 30.03°, 30.42°, 31.20°, 31.56°, 32.25°, 32.80°, 33.63°, 34.24°, 35.54°, 36.41°, 36.96°, 38.33° and 38.78°. There was an error tolerance of ± 0.2°.
(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10 ℃/min and comprised an endothermic peak at 182.86 ℃. There was an error tolerance of ± 3 ℃.
Example 4 Crystal form X of the invention
1. Preparation of crystal form X
The crystal form I (60 mg) of the compound represented by formula (I) was added into ethylene glycol dimethyl ether (2.0 mL) . The mixture was stirred in slurry at room temperature for 5 days, then the reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
2. Identification of crystal form X
(1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation with the following characteristic peaks expressed as 2θ at: 7.97°, 12.20°, 13.82°, 15.68°, 16.79°, 17.48°, 18.42°, 20.05°, 20.85°, 22.33°, 23.03°, 23.87°, 24.61°, 25.72°, 26.97°, 27.48°, 28.05°, 28.77°, 29.49°, 30.29°, 32.05°, 32.96°, 33.35°, 34.90°, 36.21°, 36.82° and 39.33°. There was an error tolerance of ± 0.2°.
(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10 ℃/min and comprised an endothermic peak at 176.58 ℃. There was an error tolerance of ± 3 ℃.
Example 5 Crystal form XI of the invention
1. Preparation of crystal form XI
The crystal form I (60 mg) of the compound represented by formula (I) was added into acetonitrile (1.0 mL) . The mixture was stirred in slurry at room temperature for 5 days, then the reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
2. Identification of crystal form XI
(1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation with the following characteristic peaks expressed as 2θ at: 7.44°, 7.76°, 8.28°, 12.69°, 14.14°, 15.05°, 16.55°, 17.44°, 17.77°, 19.12°, 19.35°, 19.69°, 20.14°, 20.45°, 20.74°, 21.35°, 21.95°, 22.20°, 23.25°, 23.82°, 24.90°, 25.46°, 25.82°, 27.19°, 27.41°, 27.52°, 29.58°, 32.96°, 35.29° and 38.58°. There was an error tolerance of ± 0.2°.
(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10 ℃/min and comprised the endothermic peaks at 149.48 ℃ and 160.27 ℃. There was an error tolerance of ± 3 ℃.
Example 6 Crystal form XII of the invention
1. Preparation of crystal form XII
The amorphous form (50 mg) of the compound represented by formula (I) was added into 4-methyl-2-pentanone (1.0 mL) . The mixture was stirred in slurry at room temperature for 24 h, then the reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
2. Identification of crystal form XII
(1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation with the following characteristic peaks expressed as 2θ at: 6.36°, 7.25°, 11.41°, 11.89°, 13.32°, 13.76°, 14.15°, 15.10°, 16.67°, 18.06°, 18.23°, 18.86°, 19.04°, 19.35°, 20.09°, 20.43°, 20.72°, 21.42°, 22.61°, 23.48°, 23.65°, 23.86°, 24.59°, 25.22°, 27.89°, 28.49°, 29.51°, 30.22° and 32.95°. There was an error tolerance of ± 0.2°.
(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10 ℃/min and comprised an endothermic peak at 162.58 ℃. There was an error tolerance of ± 3 ℃.
Example 7 Crystal form XIII of the invention
1. Preparation of crystal form XIII
The crystal form I (50 mg) of the compound represented by formula (I) was added into acetone (1.0 mL) , and the mixture was stirred in slurry at 50℃ for 24 h. The reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
2. Identification of crystal form XIII
(1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation with the following characteristic peaks expressed as 2θ at: 7.18°, 8.28°, 12.37°, 13.45°, 14.26°, 14.87°, 17.48°, 17.90°, 19.35°, 19.95°, 20.71°, 21.23°, 21.45°, 22.11°,  23.16°, 24.95°, 25.55°, 26.82°, 27.07°, 27.35°, 28.40°, 28.94°, 29.40° and 29.99°. There was an error tolerance of ± 0.2°.
(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10 ℃/min and comprised the endothermic peaks at 146.79 ℃ and 164.21 ℃. There was an error tolerance of ± 3 ℃.
Example 8 Crystal form XIV of the invention
1. Preparation of crystal form XIV
The amorphous form (50 mg) of the compound represented by formula (I) was added to butanone (1.0 mL) , and the mixture was stirred in slurry at room temperature for 24 h. The reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
2. Identification of crystal form XIV
(1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation with the following characteristic peaks expressed as 2θ at: 7.25°, 8.06°, 12.62°, 14.02°, 14.79°, 17.28°, 17.65°, 19.69°, 19.87°, 20.64°, 20.80°, 21.62°, 23.22°, 24.31°, 25.46°, 25.77°, 26.71°, 27.23°, 28.42°, 28.74°, 29.82°, 30.78°, 32.95° and 24.26°. There was an error tolerance of ± 0.2°.
(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10 ℃/min and comprised the endothermic peaks at 124.04 ℃ and 163.38 ℃. There was an error tolerance of ± 3 ℃.
Example 9 Crystal form XV of the invention
1. Preparation of crystal form XV
The amorphous form (50 mg) of the compound represented by formula (I) was added into ethyl formate (1.0 mL) , and the mixture was stirred in slurry at room temperature for 24 h. The reaction was stopped. The mixture was filtered with suction, and dried to obtain the target crystal form as off-white solid powder.
2. Identification of crystal form XV
(1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD) using Cu-Kα radiation with the following characteristic peaks expressed as 2θ at: 7.37°, 8.03°, 12.72°, 13.89°, 14.85°, 17.26°, 17.58°, 17.77°, 19.72°, 20.20°, 20.47°, 20.99°, 21.45°, 21.64°, 23.12°, 24.30°, 25.26°, 25.57°, 27.09°, 27.23°, 28.28°, 28.91°, 29.98° and 34.65°. There was an error tolerance of ± 0.2°.
(2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10 ℃/min and comprised the endothermic peaks at 127.06 ℃ and 165.38 ℃.  There is an error tolerance of ± 3 ℃.
Example 10 The pharmacokinetics test of the crystal form of the present invention
The test samples were filled into capsules for oral administration.
Three male Beagle dogs of 8-12 kg were orally given a capsule containing the test sample at a dose of 5 mg/kg. Blood was collected at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h. Standard curve was plotted based on concentrations of the samples in a suitable range, the concentration of the test sample in the plasma sample was measured and quantified by AB SCIEX API4000 in MRM mode. Pharmacokinetic parameters were calculated according to drug concentration-time curve using a noncompartmental model method by WinNonLin 6.3 software. Results were as shown in Table 1.
Table 1 Pharmacokinetic data of the crystal forms of the present invention
Test sample T max (h) C max (ng/ml) AUC last (h*ng/ml)
Example 3 (crystal form II) 11.3 433 4310
the compound having Formula (I) 1.5 108 661
Conclusion:
It can be seen from Table 1 that compared to the compound represented by formula (I) , the crystal form II of the present invention has a higher exposure in Beagle dogs and has better pharmacokinetic properties.
Example 11 The stability test of the crystal form of the present invention
1. Stability test experiment A
At room temperature, the test samples were put into EP tubes, and water (1.5 mL) was added to each tube. The mixtures were stirred in slurry at room temperature for 24 h, filtered with suction, dried, analyzed and identified by X-ray powder diffraction (XRPD) . The experimental results show that the crystal form II of the present invention is stirred in water at room temperature, the crystal form will not change, while other crystal forms, such as crystal forms XIII, XIV, XV, are also stirred in water, and the crystal structure will change. That is, the crystal structure of the crystal form II of the present invention is stable and suitable for industrial production and formulation development.
2. Stability test experiment B
An appropriate amount of test sample was placed in light (4500 ± 500 lx, ultraviolet light ≥ 0.7 w/m 2) , high humidity (25 ℃, 75%± 5%RH, 90%± 5%RH) , and at high temperature (40 ℃ ± 2 ℃, 60 ℃ ± 2 ℃, without humidity control) to conduct the influencing factor experiment. A sample was taken on the 10th day for XRPD detection to investigate the stability of the crystal form of the sample. Results were as shown in FIG. 18.
Conclusion: according to the experimental results, under high temperature (40 ℃ or 60 ℃) , high humidity (25 ℃, RH 75 ± 5%or RH 90%± 5%) , and light conditions, the XRPD pattern of crystal form II of the present invention has no significant change, that is, the crystal structure of the crystal form II remains unchanged. Therefore, the crystal form II of the present invention has better stability under various storing conditions and is suitable for pharmaceutical applications.
Example 12 The hygroscopicity test of the crystal form of the present invention
An appropriate amount of the test sample (i.e., the crystal form of the present invention) was taken, and the dynamic vapour sorption was used to test the hygroscopicity.
The dynamic vapour adsorption (DVS) diagram of the hygroscopicity test of the crystal form II of the present invention was basically as shown in FIG. 19. It can be seen from FIG. 19 that the hygroscopicity of the crystal form II of the present invention under different humidity is very low, and the hygroscopicity weight gain is about 0.06%under the condition of 95%RH; according to the description of hygroscopicity characteristics and the definition standard for hygroscopicity weight gain (Chinese Pharmacopoeia 2015 Edition General Principles 9103 Guidelines for Drug Hygroscopicity Tests, see Table 2 for details) , the crystal form II of the present invention is non-hygroscopic. That is, the crystal form II of the present invention is not susceptible to deliquescence by influence of high humidity.
Table 2 Description of the hygroscopicity feature and the definition of the hygroscopic weight gain (25 ℃ ± 1 ℃, 80%± 2%relative humidity)
Figure PCTCN2020131410-appb-000002
The foregoing description is merely a basic illustration of the present invention and any equivalent transformation made in accordance with the technical solution of the present invention is intended to be within the scope of the present invention.
Reference throughout this specification to “an embodiment” , “some embodiments” , “one embodiment” , “another example” , “an example” , “a specific example” , or “some examples” means 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 present disclosure. Thus, the appearances of the above terms throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.
Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.

Claims (13)

  1. The crystal form II of the compound having Formula (I) ,
    Figure PCTCN2020131410-appb-100001
    wherein the X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2θ at 10.43° ± 0.2°, 12.31° ± 0.2°, 15.92° ± 0.2°, 16.90° ± 0.2°, 17.90° ± 0.2°, 20.52° ± 0.2°, 21.04° ± 0.2°, 26.53° ± 0.2°, 26.83° ± 0.2°.
  2. The crystal form II according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2θ at 10.43° ± 0.2°, 12.31° ± 0.2°, 14.49° ± 0.2°, 15.92° ± 0.2°, 16.00° ± 0.2°, 16.90° ± 0.2°, 17.90° ± 0.2°, 18.42° ± 0.2°, 20.52° ± 0.2°, 21.04° ± 0.2°, 21.45° ± 0.2°, 23.59° ± 0.2°, 24.00° ± 0.2°, 24.26° ± 0.2°, 24.75° ± 0.2°, 25.07° ± 0.2°, 26.26° ± 0.2°, 26.53° ± 0.2°, 26.83° ± 0.2°, 30.03° ± 0.2°, 31.20° ± 0.2°, 31.56° ± 0.2°, 34.24° ± 0.2°, 38.78° ± 0.2°.
  3. The crystal form II according to claim 1 or 2, wherein the X-ray powder diffraction pattern of the crystal form II comprises peaks expressed as 2θ at 10.43° ± 0.2°, 12.31° ± 0.2°, 13.08° ± 0.2°, 14.49° ± 0.2°, 15.18° ± 0.2°, 15.92° ± 0.2°, 16.00° ± 0.2°, 16.61° ± 0.2°, 16.90° ± 0.2°, 17.90° ± 0.2°, 18.42° ± 0.2°, 20.52° ± 0.2°, 21.04° ± 0.2°, 21.45° ± 0.2°, 23.59° ± 0.2°, 24.00° ± 0.2°, 24.26° ± 0.2°, 24.75° ± 0.2°, 25.07° ± 0.2°, 26.26° ± 0.2°, 26.53° ± 0.2°, 26.83° ± 0.2°, 28.02° ± 0.2°, 28.31° ± 0.2°, 29.31° ± 0.2°, 30.03° ± 0.2°, 30.42° ± 0.2°, 31.20° ± 0.2°, 31.56° ± 0.2°, 32.25° ± 0.2°, 32.80° ± 0.2°, 33.63° ± 0.2°, 34.24° ± 0.2°, 35.54° ± 0.2°, 36.41° ± 0.2°, 36.96° ± 0.2°, 38.33° ± 0.2°, 38.78° ± 0.2°.
  4. The crystal form II according to any one of claims 1 to 3, wherein the crystal form II has an X-ray powder diffraction pattern substantially as shown in FIG. 4.
  5. The crystal form II according to any one of claims 1 to 4, wherein the differential scanning calorimetry of the crystal form II comprises an endothermic peak at 182.86 ℃ ± 3 ℃.
  6. The crystal form II according to any one of claims 1 to 5, wherein the crystal form II has a differential scanning calorimetry diagram substantially as shown in FIG. 5.
  7. A pharmaceutical composition comprising the crystal form II according to any one of claims 1 to 6, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
  8. Use of the crystal form II of any one of claims 1 to 6 or the pharmaceutical composition  of claim 7 in the manufacture of a medicament for preventing, treating or lessening a disease related to orexin receptors in a subject.
  9. The use of claim 8, wherein the disease related to orexin receptors is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
  10. A method of preventing, treating or lessening a disease related to orexin receptors in a subject comprising administering to the subject a therapeutically effective amount of the crystal form II according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7.
  11. The method of claim 10, wherein the disease related to orexin receptors is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
  12. The crystal form II of any one of claims 1 to 6 or the pharmaceutical composition of claim 7 for use in preventing, treating or lessening a disease related to orexin receptors in a subject.
  13. The crystal form II or the pharmaceutical composition of claim 12, wherein the disease related to orexin receptors is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress  disorder, sexual dysfunction, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson’s disease, dyskinesia, eating disorder, headache, migraine, pain, digestive system disease, epilepsy, inflammation, cardiovascular disease, diabetes, metabolic disease, immune-related disease, endocrine-related disease, or high blood pressure.
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