WO2020179781A1 - 五環式化合物の塩およびそれらの結晶 - Google Patents

五環式化合物の塩およびそれらの結晶 Download PDF

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WO2020179781A1
WO2020179781A1 PCT/JP2020/008889 JP2020008889W WO2020179781A1 WO 2020179781 A1 WO2020179781 A1 WO 2020179781A1 JP 2020008889 W JP2020008889 W JP 2020008889W WO 2020179781 A1 WO2020179781 A1 WO 2020179781A1
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thieno
compound
diffraction
crystals
powder
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PCT/JP2020/008889
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English (en)
French (fr)
Japanese (ja)
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賢史 吉田
芳章 大橋
環 星川
信明 佐藤
郁雄 櫛田
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エーザイ・アール・アンド・ディー・マネジメント株式会社
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Priority to JP2021504108A priority Critical patent/JP7508441B2/ja
Priority to MX2021009774A priority patent/MX2021009774A/es
Priority to AU2020233452A priority patent/AU2020233452A1/en
Priority to CN202080014060.2A priority patent/CN113646046B/zh
Priority to KR1020217025603A priority patent/KR20210135223A/ko
Priority to EP20766851.8A priority patent/EP3936189A4/en
Priority to BR112021015979-7A priority patent/BR112021015979A2/pt
Priority to CA3129764A priority patent/CA3129764A1/en
Publication of WO2020179781A1 publication Critical patent/WO2020179781A1/ja
Priority to US17/021,544 priority patent/US11420980B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • 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 present invention presents pharmaceutically acceptable salts of pentacyclic compounds and crystals of pentacyclic compounds and pharmaceutically acceptable salts thereof, which have cholinergic neuronal activation and / or neuroprotective effects. Regarding.
  • the present invention also relates to a pharmaceutical composition containing the above salt or crystal as an active ingredient.
  • Non-Patent Document 1 cholinergic neurons that release acetylcholine as transmitters project widely from the Nucleus basalis and septal nucleus of the basal forebrain to the hippocampus, amygdala, and cerebral cortex, and memory, learning, and cognition. It is responsible for the regulation of attention.
  • Non-Patent Document 2 cholinergic neurons in the pedunculopontine nucleus and dorsolateral tegmental nucleus of the brain stem project to the striatum, nucleus accumbens, substantia nigra and thalamus, and are thought to be involved in motivation and regulation of wakefulness.
  • Non-Patent Documents 8-12 the role of cholinergic neurons in the basal portion of the forebrain has been clarified by analysis using many disorder model animals. Among them, it has been shown in a disorder model animal that the dysfunction of cholinergic neurons is correlated with the decrease in memory learning (Non-Patent Document 5-7), and the amount of acetylcholine is increased by a cholinesterase inhibitor to increase the amount of acetylcholine in cholinergic neurons. It has been shown that cognitive function is improved by increasing the function (Non-Patent Documents 8-12).
  • NGF Nerve Growth Factor
  • AD Alzheimer's dementia
  • cholinergic neuron loss is seen from the early stage of onset, which is one of the pathological features of AD.
  • senile plaque accumulation due to deposition of amyloid ⁇ and changes in neurofibrils due to aggregation of tau are also pathological features, and it is known that changes in neurofibrils increase with the progression of pathological conditions and cause nerve cell death.
  • Changes in neurofibrils have been observed in the Nucleus basalis and the entorhinal infield cortex from the early stage of AD onset.
  • Non-Patent Document 16-17 cholinergic neurons present in the Nucleus basalis are shed due to tau accumulation from an early stage, and their shedding and cognitive function It has been reported that the decrease in score correlates (Non-Patent Document 16-17).
  • a genetically modified mouse Human tau P301S transgenic mouse
  • a tau gene having a P301S mutation found in familial frontotemporal dementia hyperphosphorylation and abnormal accumulation of tau were observed as in AD. Get up.
  • changes in neurofibrils which are pathological features of AD, occur (Non-Patent Document 18), causing cognitive dysfunction due to synaptic disorders, neurodegeneration, and neuronal loss.
  • Human tau P301S transgenic mice are widely used as AD-like model animals (Non-patent documents 19-22), and by suppressing AD-like pathological changes in Human tau P301S transgenic mice. , It can be expected to improve the cognitive decline of Alzheimer's disease and suppress the progression of pathology.
  • Non-Patent Document 23-25 analysis using a plurality of genetically modified mice and disorder model animals suggests axonal transport disorder as one of the causes of cholinergic nerve cell shedding.
  • the hippocampal fornix amputation model impairs the axonal transport of cholinergic neurons that project from the septal field to the hippocampus, causing cell shedding by impairing the retrograde transport of molecules involved in survival and function ( Non-Patent Documents 26-28).
  • This impaired retrograde transport is also seen in genetically modified mice (Non-Patent Documents 23 and 24), and the loss of cholinergic neurons due to hippocampal fornix amputation reflects one aspect of the pathology. Therefore, by suppressing / ameliorating the loss of cholinergic neurons in this disorder model, the effects of improving cognitive decline in Alzheimer's disease and suppressing the progression of pathological conditions can be expected.
  • Lewy bodies In dementia with Lewy bodies (DLB; Dementia with Lewis bodies) and Parkinson's disease (PD; Parkinson disease), abnormal inclusion bodies (Lewy bodies) whose main component is ⁇ -synuclein appear in nerve cells, and nerve cells It is a progressive neurodegenerative disease that causes degeneration and shedding.
  • a large distribution of Lewy bodies in the cerebral cortex causes cognitive dysfunction, and a large distribution in the brainstem causes Parkinsonism.
  • psychiatric symptoms such as vision, hallucinations, delusions, and depressive symptoms, sleep disorders, and autonomic nervous symptoms are observed.
  • Lewy body dementia is diagnosed if dementia occurs before or within 1 year of onset of Parkinsonism, but Parkinson's disease with dementia occurs if Parkinsonism has been present for more than 1 year before the onset of dementia. (PDD; Parkinson disease with with mentia) is diagnosed.
  • PDD Parkinson disease with with mentia
  • LBD Lewy body disease
  • Non-Patent Documents 29-31 In dementia with Lewy bodies and Parkinson's disease with dementia, nerve cells of Meinert's basal ganglia, which is the origin of acetylcholinergic nerves, are degenerated and lost as in Alzheimer's disease. It has been reported that functional neuronal damage is observed (Non-Patent Documents 29-31). In addition, the progression of cholinergic nerve cell damage and cognitive decline are correlated (Non-Patent Document 29), and it has been shown that a cholinesterase inhibitor improves cognitive function. From these, it is shown that cognitive function is improved by improving the function of cholinergic neurons, and suppressing / improving the loss of cholinergic neurons in multiple disorder models is Alzheimer's dementia. Similarly, the effects of improving dementia of Lewy bodies and dementia of Parkinson's disease associated with dementia and suppressing the progression of disease state can be expected.
  • the cognitive decline caused by the functional decline of cholinergic neurons can be improved by achieving the functional activation and / or neuroprotection of cholinergic neurons in clinical practice.
  • Lapchak PA et al. “Effect of recombinant human nerve growth factor on presynaptic cholinergic function in rat hippocampal slices following partial septohippocampal lesions: measurements of [3H] acetylcholine -49.
  • Gilmor ML et al. “Coordinate expression of the vesicular acetylcholine transporter and choline acetyltransferase following septohippocampal pathwaylesions” J.Neurochem. 71 (1998) 2411-20. Gu Het al.
  • compound (I) The compound represented by the following formula (I) (5,10-dimethyl-5,6,9,10,11,12-hexahydropyrido [4'', 3'': 4', 5'] thieno [2] ',3':4,5]pyrimido[1,2-a]thieno[3,2-f][1,4]diazepine-4,13-dione, hereinafter also referred to as "compound (I)").
  • the present inventors have found that they have a cholinergic nerve cell activating effect and / or a neuroprotective effect. Therefore, compound (I) has the potential as an ameliorating agent for cognitive decline caused by functional decline of cholinergic neurons.
  • the present invention relates to the following ⁇ 1> to ⁇ 35>.
  • ⁇ 1> 5,10-Dimethyl-5,6,9,10,11,12-hexahydropyrido[4′′,3′′:4′,5′]thieno[represented by the formula (I) 2',3':4,5]Pyrimido[1,2-a]thieno[3,2-f][1,4]diazepine-4,13-dione monohydrochloride or hydrobromide.
  • E-type crystal of compound (I) monohydrochloride having the powder X-ray diffraction pattern of FIG. 6 in powder X-ray diffraction using CuK ⁇ as an X-ray source.
  • the pharmaceutical composition according to ⁇ 16> which is a cholinergic neuron protective agent.
  • a therapeutic agent for cognitive impairment which comprises the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15>.
  • a method for treating cognitive dysfunction wherein the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15> is administered to a patient.
  • ⁇ 23> Use of the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15> for producing a therapeutic agent for cognitive dysfunction.
  • An Alzheimer's disease therapeutic agent comprising the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15>.
  • ⁇ 25> A method for treating Alzheimer's disease, wherein the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15> is administered to a patient.
  • ⁇ 26> The salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15>, which is used for treating Alzheimer's disease.
  • ⁇ 27> Use of the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15> for producing a therapeutic agent for Alzheimer's disease.
  • a therapeutic agent for dementia with Lewy bodies which comprises the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15>.
  • ⁇ 29> A method for treating dementia with Lewy bodies, wherein the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15> is administered to a patient.
  • ⁇ 31> Use of the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15> for producing a therapeutic agent for dementia with Lewy bodies.
  • a therapeutic agent for Parkinson's disease associated with dementia which comprises the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15>.
  • ⁇ 33> A method for treating Parkinson's disease associated with dementia, wherein the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15> is administered to a patient.
  • ⁇ 34> The salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15>, which is used for treating Parkinson's disease associated with dementia.
  • ⁇ 35> Use of the salt according to ⁇ 1> or the crystal according to any one of ⁇ 2> to ⁇ 15> for producing a therapeutic agent for Parkinson's disease associated with dementia.
  • FIG. 1 is a powder X-ray diffraction pattern of the crystal of compound (I) obtained in Example 1.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 2 is a powder X-ray diffraction pattern of the A-type crystal of compound (I) monohydrochloride obtained in Example 2.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 3 is a powder X-ray diffraction pattern of the B-type crystal of compound (I) monohydrochloride obtained in Example 4.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 1 is a powder X-ray diffraction pattern of the crystal of compound (I) obtained in Example 1.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 4 is a powder X-ray diffraction pattern of the C-type crystal of compound (I) monohydrochloride obtained in Example 3.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 5 is a powder X-ray diffraction pattern of the D-type crystal of compound (I) monohydrochloride obtained in Example 5.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 6 is a powder X-ray diffraction pattern of the E-type crystal of compound (I) monohydrochloride obtained in Example 6.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 5 is a powder X-ray diffraction pattern of the D-type crystal of compound (I) monohydrochloride obtained in Example 5.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical
  • FIG. 7 is a powder X-ray diffraction pattern of the F-type crystal of compound (I) monohydrochloride obtained in Example 7.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 8 is a powder X-ray diffraction pattern of the crystals of compound (I) hydrobromide obtained in Example 8.
  • the horizontal axis represents the diffraction angle (2 ⁇ ), and the vertical axis represents the peak intensity.
  • FIG. 9 is a 13 C solid-state NMR spectrum of the A-type crystal of compound (I) monohydrochloride obtained in Example 2.
  • the horizontal axis represents the chemical shift ( ⁇ ) and the vertical axis represents the peak intensity.
  • FIG. 10 is a 13 C solid-state NMR spectrum of the B-type crystal of compound (I) monohydrochloride obtained in Example 4.
  • the horizontal axis represents the chemical shift ( ⁇ ) and the vertical axis represents the peak intensity.
  • FIG. 11 is a 13 C solid-state NMR spectrum of the C-type crystal of compound (I) monohydrochloride obtained in Example 3.
  • the horizontal axis represents the chemical shift ( ⁇ ) and the vertical axis represents the peak intensity.
  • FIG. 12 is a thermal analysis TG-DTA chart of the Form A crystal of compound (I) monohydrochloride obtained in Example 2.
  • the horizontal axis shows the temperature
  • the left vertical axis shows the weight change of TG
  • the right vertical axis shows the heat flow rate of DTA.
  • FIG. 13 is a thermal analysis TG-DTA chart of the B-type crystal of the compound (I) monohydrochloride obtained in Example 4.
  • the horizontal axis shows the temperature, the left vertical axis shows the weight change of TG, and the right vertical axis shows the heat flow rate of DTA.
  • FIG. 14 is a thermal analysis TG-DTA chart of the C-type crystal of the compound (I) monohydrochloride obtained in Example 3.
  • the horizontal axis shows the temperature, the left vertical axis shows the weight change of TG, and the right vertical axis shows the heat flow rate of DTA.
  • FIG. 15 is a thermal analysis TG-DTA chart of the D-type crystal of the compound (I) monohydrochloride obtained in Example 5.
  • FIG. 16 is a thermal analysis TG-DTA chart of the E type crystal of the compound (I) monohydrochloride obtained in Example 6.
  • the horizontal axis shows the temperature, the left vertical axis shows the weight change of TG, and the right vertical axis shows the heat flow rate of DTA.
  • FIG. 17 is a thermal analysis TG-DTA chart of the F type crystal of the compound (I) monohydrochloride obtained in Example 7.
  • the horizontal axis shows the temperature, the left vertical axis shows the weight change of TG, and the right vertical axis shows the heat flow rate of DTA.
  • FIG. 16 is a thermal analysis TG-DTA chart of the E type crystal of the compound (I) monohydrochloride obtained in Example 6.
  • the horizontal axis shows the temperature, the left vertical axis shows the weight change of TG, and the right vertical axis shows the heat flow rate of DTA.
  • FIG. 17 is a thermal analysis TG-DTA chart of the F type crystal of the compound (
  • FIG. 18 is a thermal analysis TG-DTA chart of the crystal of the compound (I) monohydrobromide obtained in Example 8.
  • the horizontal axis shows the temperature
  • the left vertical axis shows the weight change of TG
  • the right vertical axis shows the heat flow rate of DTA.
  • FIG. 19 shows a Raman spectrum of a type A crystal of compound (I) monohydrochloride obtained in Example 2.
  • salt means a chemical substance consisting of compound (I), which is a basic component, and an acid having a specific equivalent number with respect to compound (I).
  • salts used in the present specification include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like, and among them, a pharmaceutically acceptable salt is preferable.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitrate, phosphoric acid and the like
  • examples of salts with organic acids include acetic acid, succinic acid and fumal.
  • Salts with organic carboxylic acids such as acids, maleic acid, tartaric acid, malic acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid (mesylic acid), ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid
  • Examples thereof include salts with organic sulfonic acids such as (tosyl acid), and among them, hydrochloric acid, hydrobromic acid and phosphoric acid are preferable.
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
  • the salt of the present invention may be anhydrous, hydrate or solvate.
  • the hydrate or solvate refers to a solid formed by combining compound (I) or a salt thereof and a water molecule or a solvent molecule, respectively, even if the solid is a crystal.
  • the solvent of the solvent mixture is, for example, a ketone solvent such as acetone, 2-butanone, cyclohexanone; an ester solvent such as methyl acetate or ethyl acetate; 1,2-dimethoxyethane, t-butyl methyl ether and the like.
  • Ether-based solvents such as methanol, ethanol, 1-propanol and isopropanol
  • polar solvents such as N-methyl-2-pyrrolidone, N, N-dimethylformamide and dimethylsulfoxide
  • the number of water molecules or solvent molecules with respect to compound (I) or a salt thereof is not particularly limited, and may be, for example, one molecule or two molecules.
  • crystal means an anhydride or hydrate crystal of compound (I) or a salt thereof.
  • preferable compounds (I) and crystals of the hydrochloride and hydrobromide of compound (I) include: A crystal of compound (I) having diffraction peaks at diffraction angles (2 ⁇ 0.2°) of 9.0°, 11.1° and 23.6° in powder X-ray diffraction; In powder X-ray diffraction, the diffraction angle (2 ⁇ ⁇ 0.2 °) 9.0 °, 11.1 °, 14.5 °, 18.1 °, 20.0 °, 21.9 °, 23.6 ° , A crystal of compound (I) having diffraction peaks at 24.4°, 24.9° and 28.5°; A-type crystal of compound (I) monohydrochloride having diffraction peaks at diffraction angles (2 ⁇ ⁇ 0.2 °) of 11.6 °, 20.8 ° and 25.7 ° in powder X-ray diffraction; In powder X-ray diffraction, the diffraction angles (2 ⁇ ⁇ 0.2 °) of 9.
  • the diffraction peaks in the powder X-ray diffraction described above, the chemical shifts in the 13C solid-state NMR spectrum, and the Raman shift peaks in Raman spectroscopy are the crystals of compound (I), the A to F type crystals of compound (I) monochloride, and It is peculiar to each crystal of compound (I) hydromonobromide, and is a peak characteristic of the crystal.
  • the diffraction angle (2 ⁇ ) in powder X-ray diffraction may have an error within the range of ⁇ 0.2 °, so the above diffraction angle value is assumed to include a value within the range of about ⁇ 0.2 °. Need to be understood. Therefore, in a specific compound or a salt thereof, not only the crystals in which the peak diffraction angles in powder X-ray diffraction are completely the same, but also the crystals in which the peak diffraction angles are the same with an error of about ⁇ 0.2 ° are the same. , Included in the present invention.
  • the peak intensity or full width at half maximum of the diffraction angle (2 ⁇ ) in powder X-ray diffraction has different measurement conditions and the size and shape of each particle of the powder crystal used as a measurement sample even if the crystal shape is the same. Due to variability, it varies from measurement to measurement and does not always show a constant peak intensity or full width at half maximum. Therefore, in the comparison of powder X-ray diffraction patterns, even if there is a difference in peak intensity or full width at half maximum at the same diffraction angle (2 ⁇ ), the difference does not mean that it is derived from a different crystal form.
  • the crystal of the powder X-ray diffraction pattern having such a difference with respect to the diffraction peak characteristic of the specific crystal of the present invention has the same crystal form as the crystal of the present invention.
  • "having the powder X-ray diffraction pattern of FIG. 1" means that the powder X-ray diffraction pattern having a characteristic diffraction peak is ⁇ 0.
  • the powder X-ray diffraction pattern represented by FIG. not only in the case of matching within the error range of 2 °, but also in the case of powder X-ray diffraction patterns in which the characteristic diffraction angles match within the error range of ⁇ 0.2 ° but the peak intensity or half value width is different.
  • all the crystals showing the powder X-ray diffraction pattern shown in FIG. 1 are the same crystals as the crystals of the present invention.
  • chemical shift ( ⁇ 0.5 ppm) 164.0 ppm, 129.6 ppm and 36.5 ppm means “ 13 C under normal measurement conditions or substantially the same conditions as in the present specification”.
  • a solid-state NMR spectrum measurement is performed, and each has a peak substantially equivalent to a chemical shift ( ⁇ 0.5 ppm) of 164.0 ppm, 129.6 ppm, and 36.5 ppm”.
  • the chemical shift ⁇ in the 13 C solid state NMR spectrum may cause an error within a range of ⁇ 0.5 ppm, and thus the above-mentioned chemical shift value Needs to be understood as including numerical values in the range of about ⁇ 0.5 ppm. Therefore, the present invention includes not only a crystal whose chemical shifts in the 13 C solid state NMR spectrum completely match, but also a crystal whose chemical shifts match with an error of about ⁇ 0.5 ppm.
  • “having a peak at a chemical shift ( ⁇ 0.5 ppm) of 164.0 ppm” means having a peak in the range of a chemical shift ( ⁇ ) of 163.5 ppm to 164.5 ppm. This means the same for other chemical shifts in the 13 C solid-state NMR spectrum.
  • the Raman shift peak (cm -1 ) in Raman spectroscopy can have an error within the range of ⁇ 2 cm -1 , so the above peak value is understood to include the value within the range of ⁇ 2 cm -1. Needs to be done. Therefore, in a specific compound or a salt thereof, not only the crystals in which the Raman shift peaks in Raman spectroscopy are completely matched but also the crystals in which the Raman shift peaks are matched with an error of about ⁇ 2 cm -1 are the same. included.
  • the peak intensity or full width at half maximum of Raman shift in Raman spectroscopy is measured due to differences in measurement conditions and variations in the size and shape of each particle of the powder crystal used as a measurement sample, even if the crystal shapes are the same. It varies from one to another and does not always show a constant peak intensity or full width at half maximum. Therefore, in comparison of Raman spectroscopic measurements, differences in peak intensity or full width at half maximum for the same Raman shift peak (cm -1 ) do not mean that the differences are derived from different crystal forms. .. Therefore, the Raman spectrum having such a difference with respect to the Raman shift peak characteristic of the particular crystal of the present invention means that the crystal has the same crystal form as the crystal of the present invention.
  • “having the spectrum of FIG. 19 in Raman spectroscopy measurement” means that the Raman spectrum having a characteristic Raman shift peak (cm -1 ) is ⁇ 2 cm with respect to the Raman spectrum represented by FIG. not only if it matches within an error range of -1, even if the peak intensity or half width of those characteristic Raman shift peaks are matched within an error range of ⁇ 2 cm -1 different Raman spectrum, FIG. It means that all the crystals showing the Raman spectrum represented by 19 are the same crystals as the crystals of the present invention.
  • Compound (I) may be produced by a method well known to those skilled in the art.
  • compound (I) can be synthesized by the method described in Reference Examples described below.
  • the salt of compound (I) according to the present invention can be obtained by a method for producing a normal salt. Specifically, for example, compound (I) is suspended or dissolved in a solvent by heating, if necessary, and then an acid is added to the resulting suspension or solution, followed by room temperature or cooling. However, it can be produced by stirring or leaving for several minutes to several days.
  • the salt of compound (I) can be obtained as crystalline or amorphous. Further, the amorphous substance can be obtained by further performing an operation such as freeze-drying on these production methods, if necessary.
  • solvents examples include alcohol solvents such as ethanol, 1-propanol and isopropanol; acetonitrile; ketone solvents such as acetone and 2-butanone; ester solvents such as ethyl acetate; saturated carbonization such as hexane and heptane. Hydrogen solvent; ether solvent such as t-butyl methyl ether or water can be mentioned. These solvents may be used alone or in combination of two or more.
  • a crystal of compound (I) or a salt thereof can be produced by the above-mentioned method for producing compound (I) or a method for producing a salt thereof, or It can also be produced by heating and dissolving I) or a salt thereof in a solvent, cooling with stirring and crystallizing.
  • the compound (I) or a salt thereof used for crystallization may be in any form, may be a solvate or a hydrate or an anhydrous, and may be amorphous or crystalline (from a plurality of polymorphs). It may be a mixture of these.
  • Solvents used for crystallization include, for example, alcohol solvents such as methanol, ethanol, isopropanol, 1-propanol; acetonitrile; amide solvents such as N,N-dimethylformamide; ester solvents such as ethyl acetate; hexane and heptane. Examples thereof include saturated hydrocarbon solvents such as; ketone solvents such as acetone and 2-butanone; ether solvents such as t-butyl methyl ether; and water. Further, these solvents may be used alone or in combination of two or more.
  • the amount of the solvent used can be appropriately selected with the lower limit being the amount at which the compound (I) or its salt is dissolved by heating or the amount at which the suspension can be agitated, and the upper limit being the amount at which the crystal yield does not significantly decrease. ..
  • seed crystals may or may not be added.
  • the temperature at which the seed crystal is added is not particularly limited, but is preferably 0 to 80 ° C.
  • the temperature at which compound (I) or a salt thereof is dissolved by heating may be appropriately selected depending on the solvent, but the recrystallization solvent is preferably from 50 ° C. It is in the range of the temperature at which reflux is started, and more preferably 55 to 80 ° C.
  • Cooling at the time of crystallization may include crystals (polymorphs) having different aspects when rapidly cooled, so it is desirable to appropriately adjust the cooling rate in consideration of the influence on the quality and particle size of the crystals. , Preferably, for example, cooling at a rate of 5-40 ° C./hour. More preferably, for example, cooling at a rate of 5 to 25 ° C./hour.
  • the final crystallization temperature can be appropriately selected depending on the crystal yield and quality, but is preferably -25 to 30°C.
  • the crystallized crystals can be separated by a normal filtration operation, the separated crystals can be washed with a solvent if necessary, and the crystals can be further dried to obtain the desired crystals.
  • a solvent e.g., ethanol, acetone, 2-butanone, ethyl acetate, diethyl ether, t-butyl methyl ether, hexane and the like can be mentioned. Further, these solvents may be used alone or in combination of two or more.
  • the crystals separated by the filtration operation can be appropriately dried by leaving them in the air or in a nitrogen stream, or by heating.
  • the drying time the time until the residual solvent falls below a predetermined amount may be appropriately selected according to the production amount, the drying device, the drying temperature, etc.
  • drying can be performed under ventilation or under reduced pressure.
  • the degree of decompression may be appropriately selected according to the production amount, the drying apparatus, the drying temperature, and the like. After drying, the obtained crystals can be left in the air if necessary.
  • the crystals of the compound (I) and the salt of the compound (I) obtained by the production method described above have a cholinergic neuron activating effect and / or as shown in the activity data in the pharmacological test examples described later. It has a neuroprotective effect and can be used as an ameliorating agent for cognitive decline caused by functional decline of cholinergic neurons.
  • [Pharmaceutical composition] Another embodiment of the invention is a pharmaceutical composition containing crystals of compound (I) and pharmaceutically acceptable additives.
  • the pharmaceutical composition can be prepared by mixing a pharmaceutically acceptable additive with the crystals of compound (I).
  • the pharmaceutical composition according to the present invention can be produced according to a known method such as the method described in the 17th revised Japanese Pharmacopoeia General Formulation Regulations.
  • the pharmaceutical composition according to this embodiment can be appropriately administered to a patient according to its dosage form.
  • the dose of compound (I) according to the present invention varies depending on the degree of symptoms, age, sex, body weight, administration form / salt type, specific type of disease, etc., but is usually 1 for adults.
  • the crystal of compound (I) of the present invention can be produced, for example, by the method described in the following Examples, and the effect of the compound can be confirmed by the method described in the following Test Examples. it can.
  • the sample was precisely weighed in an aluminum sample pan and measured under the following conditions. (Measurement condition) Atmosphere: 100 mL / min Nitrogen gas Airflow Control: Empty aluminum sample pan Temperature rise rate: 10 ° C / min Sampling interval: 1 sec Measurement temperature range: room temperature to 320°C
  • the 13 C solid-state NMR spectrum of the crystal was measured under the following conditions with a solid sample enclosed in a sample tube in an amount of about 300 mg.
  • Equipment used Avance 400MHz (manufactured by Bruker) 7mm-CPMAS probe (manufactured by Bruker) Measurement nucleus: 13 C (resonance frequency 100.6248425 MHz) Measurement temperature: Room temperature Pulse mode: CPTOSS Measurement rotation speed: 5000 Hz Pulse repetition time: 3 sec Contact time: 1 msec Number of integrations: 5120 times Reference substance: Glycine (external standard: 176.03 ppm)
  • the Raman spectrum of the crystal was measured under the following measurement conditions by placing the sample on the sample table of a microscopic Raman spectrometer.
  • Diffraction grating 1200 lines/mm
  • Objective lens 50x scanning style: Continuous exposure time: 5 seconds
  • Total number of times 5 times Measurement range: 400 to 1800 cm -1 (Raman shift) Error: ⁇ 2cm -1
  • Root temperature in the following examples and reference examples usually indicates about 10 ° C to about 35 ° C. % Indicates weight percent unless otherwise specified.
  • Initiator TM or Initiator+ TM manufactured by Biotage was used.
  • the silica gel used is Merck's Silica Gel60 (70-230 mesh ASTM) or Fuji Silysia Chemical's PSQ60B, or a prepack column ⁇ column: YAMAZEN's Hi-Flash TM Column (Silicagel), size: S ( 16 x 60 mm), M (20 x 75 mm), L (26 x 100 mm), 2 L (26 x 150 mm), 3 L (46 x 130 mm), or Biotage TM SNAP Ultra Silica Gel, size: 10 g , 25 g, or 50 g ⁇ was used.
  • NH silica gel For NH silica gel, use CHROMATOREX NH-DM2035 manufactured by Fuji Silysia Chemical Ltd., or prepack column ⁇ column: Hi-Flash TM Column (Amino) manufactured by YAMAZEN, size: S (16 x 60 mm), M (20 x 75 mm). ), L (26 x 100 mm), 2 L (26 x 150 mm), 3 L (46 x 130 mm), or Wako Pure Chemical Industries, Ltd.
  • Example 1 Preparation of crystals of compound (I) To 1.5 L of 0.3 M hydrochloric acid, 152.08 g of compound (I) was added, 450 ml of ethyl acetate was added to this solution, and the mixture was stirred for 5 minutes. The aqueous layer was separated, washed with 450 ml of ethyl acetate, and the insoluble material was filtered off. 100 ml of a 1N aqueous sodium hydroxide solution was added to the filtrate in a water bath at 20 ° C., and the mixture was stirred for 15 minutes.
  • Example 2 Preparation of A-type Crystals of Compound (I) Monohydrochloride 101 mg of Compound (I) was added to a screw cap test tube. 0.2 mL of 1.5 M hydrochloric acid was added and dissolved. 1.8 mL of IPA was added, and after ultrasonic irradiation, the mixture was stirred at 40 ° C. for one day using a stirrer. After stirring at room temperature for an additional 1 hour, the sample was filtered using a filter (0.2 ⁇ m), rinsed with 0.5 mL of IPA/water (9/1, v/v), and ventilated under a nitrogen stream. Dried. The crystals were dried at 70 ° C. for about 1 hour to obtain the title crystals (103 mg).
  • Powder X-ray diffraction peak (transmission method, 2 ⁇ 0.2°): 6.1°, 7.8°, 11.6°, 16.2°, 19.9°, 20.8°, 25.2 °, 25.7°, 26.9°, 29.9° 13 C-NMR (100MHz, solid state) ⁇ (ppm): 164.0, 162.5, 160.5, 153.9, 151.6, 150.7, 133.6, 131.1, 129.6 , 128.4, 126.9, 125.2, 123.7, 121.3, 120.3, 119.5, 53.7, 52.0, 50.9, 44.7, 36.5, 22 .6
  • Raman shift peak (cm -1 ): 409,587,763,976,1428,1493,1688
  • the powder X-ray diffraction pattern of the A-type crystal of compound (I) monohydrochloride obtained by the above method is shown in FIG. 2, the 13 C-solid-state NMR spectrum is shown in FIG. 9, and the thermogravimetric TG-DTA chart
  • Example 3 Preparation of C-type Crystals of Compound (I) Monohydrochloride 1020 mg of Compound (I) was added to a screw cap test tube. 1.5 equivalents of hydrochloric acid (353 ⁇ L) was dissolved in 20 mL of methanol and added to the sample. The mixture was stirred at room temperature for 2 days using a stirrer. A sample was collected by filtration using a filter (0.2 ⁇ m). The obtained solid was dried under reduced pressure for about 2 hours and then dried at 70 ° C. for 1 hour to obtain the title crystals (1048 mg).
  • Powder X-ray diffraction peak (transmission method, 2 ⁇ ⁇ 0.2 °): 6.0 °, 7.7 °, 9.7 °, 11.4 °, 15.8 °, 16.9 °, 18.1 °, 23.2°, 25.4°, 27.6° 13 C-NMR (100 MHz, solid state) ⁇ (ppm): 162.5, 160.5, 159.6, 153.8, 151.1, 134.1, 131.6, 128.4, 127.6. , 125.6, 120.0, 54.0, 52.6, 50.9, 44.3, 43.5, 38.9, 32.3, 22.4
  • the powder X-ray diffraction pattern of the C-type crystal of compound (I) monohydrochloride obtained by the above method is shown in FIG. 4, the 13 C-solid-state NMR spectrum is shown in FIG. 11, and the thermogravimetric TG-DTA chart is shown in FIG. ..
  • Example 4 Preparation of B-type Crystals of Compound (I) Monohydrochloride 303 mg of the hydrochloride crystals obtained in Example 3 was added to a platinum crucible and heated at 160 ° C. for 15 minutes to obtain the title crystals (293 mg). Powder X-ray diffraction peak (transmission method, 2 ⁇ ⁇ 0.2 °): 6.3 °, 9.7 °, 10.1 °, 17.9 °, 19.0 °, 19.4 °, 23.4 °, 26.3°, 27.3°, 32.0° 13 C-NMR (100 MHz, solid state) ⁇ (ppm): 162.0, 160.1, 153.8, 151.1, 133.4, 130.7, 128.3, 126.9, 125.6.
  • Example 5 Preparation of Form D Crystals of Compound (I) Monohydrochloride 227 mg of the mixture of hydrochloride crystals obtained in each of Examples 2 and 3 and 8 mL of ethanol were added to a screw cap test tube. The mixture was stirred at 65 ° C. using a stirrer. After about 1 hour, ultrasonic waves were applied and the mixture was stirred at the same temperature for one day. The sample was collected by filtration using a filter (0.2 ⁇ m) to obtain the title crystal (203 mg).
  • FIG. 5 shows a powder X-ray diffraction pattern of a D-type crystal of compound (I) monohydrochloride obtained by the above method
  • FIG. 15 shows a thermal analysis TG-DTA chart.
  • Example 6 Preparation of Form E Crystal of Compound (I) Monohydrochloride 108 mg of the hydrochloride crystal obtained in Example 2 and 5 mL of acetonitrile were added to a screw cap test tube. The mixture was stirred at 60 ° C. for one day using a stirrer, and the sample was collected by filtration using a filter (0.2 ⁇ m). The obtained solid and 5 mL of acetonitrile were added to the screw cap test tube again, and the mixture was stirred at 60 ° C. for one day using a stirrer. The crystals were collected by filtration under a nitrogen stream using a filter (0.2 ⁇ m) to obtain the title crystals (89.7 mg).
  • FIG. 6 shows the powder X-ray diffraction pattern of the E type crystal of the compound (I) monohydrochloride obtained by the above method
  • FIG. 16 shows the thermal analysis TG-DTA chart.
  • Example 7 Preparation of Form F Crystals of Compound (I) Monohydrochloride Hydrochloride crystals 101 mg obtained in Example 2 and 5 mL of ethanol were added to a screw cap test tube. The mixture was stirred at 60 ° C. for one day using a stirrer. A sample was collected by filtration using a filter (0.2 ⁇ m). The obtained solid and 5 mL of ethanol were added to the screw cap test tube again, and the mixture was stirred at 60 ° C. for 4 hours using a stirrer. The crystals were collected by filtration using a filter (0.2 ⁇ m) to obtain the title crystals (75.0 mg).
  • Powder X-ray diffraction peak (transmission method, 2 ⁇ 0.2°): 5.9°, 7.3°, 9.3°, 10.7°, 13.8°, 15.6°, 16.4 °, 18.7°, 25.1°, 26.8°
  • the powder X-ray diffraction pattern of the F type crystal of the compound (I) monohydrochloride obtained by the above method is shown in FIG. 7, and the thermal analysis TG-DTA chart is shown in FIG.
  • Example 8 Preparation of Crystals of Compound (I) Hydrohydrobromide
  • Compound (I) 933 mg was added to a screw cap test tube.
  • 1.5 equivalents (434 ⁇ L) of hydrobromic acid was dissolved in 20 mL of methanol and added to the sample. It stirred at room temperature for 3 days using the stirrer. The sample was collected by filtration using a filter (0.2 ⁇ m) and dried at 60 ° C. for 1 hour to obtain the title crystal (1111 mg).
  • Powder X-ray diffraction peak (transmission method, 2 ⁇ 0.2°): 6.0°, 7.8°, 10.0°, 11.7°, 17.8°, 20.8°, 23.5 °, 24.5°, 25.2°, 27.3°
  • a powder X-ray diffraction pattern of the compound (I) monohydrobromide obtained by the above method is shown in FIG. 8, and a thermal analysis TG-DTA chart is shown in FIG.
  • the collected septal field is enzymatically treated with an enzyme solution containing 0.25% trypsin (15050-065, Thermo Fisher Scientific) and 0.01% DNase (D5025-150KU, Sigma) at 37 ° C. for 30 minutes. By doing so, the cells were dispersed. At this time, the enzymatic reaction was stopped by adding deactivated horse serum (26050-088, Thermo Fisher Scientific). The enzyme-treated solution was centrifuged at 1000 rpm for 3 minutes to remove the supernatant. 10 mL of medium was added to the obtained cell mass.
  • Dulbecco's Modified Eagle's Medium (044-29765, WAKO) was supplemented with N2 supplements (17502-048, Thermo Fisher Scientific 122/140) and 1 mM Sodium pyruvic (S60) 10% (11360-070). , Thermo Fisher Scientific) was used.
  • the cell mass to which the medium had been added was redispersed by gentle pipetting operation, and then centrifuged again at 1000 rpm for 3 minutes to remove the supernatant. 10 mL of medium was added to the obtained cell mass, and this cell dispersion was filtered through a 40 ⁇ m nylon mesh (Cell Strainer) to remove the cell mass to obtain a nerve cell suspension.
  • the neuronal suspension was diluted with medium and 10% deactivated bovine serum (26140-079, Thermo Fisher Scientific) and 10% deactivated horse serum were added. Then, 100 ⁇ L/well was seeded in a 96-well incubator (354461, CORNING) previously coated with poly-D-lysine at an initial culture density of 1.4 ⁇ 10 5 cells/cm 2 . Seeded cells 5% CO 2 -95% air under were cultured two days at in 37 ° C. incubator, the medium was changed total volume of fresh medium 120 [mu] L, were incubated subsequently for 5 days. (2) Compound addition On the 7th day of the culture, drug addition was carried out as follows.
  • the DMSO solution of the test compound was diluted in medium to 10 times the final concentration.
  • NGF 450-01, PEPRO TECH, INC.
  • the final DMSO concentration was 0.1% or less.
  • only DMSO and NGF were added to the control group.
  • a buffer containing 10 ⁇ M choline, 10 ⁇ M physostigmine and 6 mM KCl was added.
  • the buffer was 125 mM NaCl, 25 mM 4-(2-hydroxyethyl)-1-piperazinecinethenesulfonic acid, 1.2 mM KH 2 PO 4 , 1.2 mM MgSO 4 , 2.2 mM CaCl 2 (2H 2 O), and 10 mM Glucose in sterile water.
  • the final pH of the solution was adjusted to 7.4. After incubating the 96-well incubator with buffer under 5% CO 2 -95% air for 40 minutes in a 37° C. incubator, 80 ⁇ L was collected.
  • ChAT choline acetyltransferase
  • RNA purification was performed by the method described in the package insert of the kit. After RNA purification, total RNA concentration was measured by QIAexpert Instrument (QIAGEN). The cDNA was prepared using the SuperScript® VILO TM cDNA Synthesis Kit (# 11754: Thermo Fisher Scientific). The cDNA was prepared by the method described in the kit package insert. The prepared cDNA was diluted 4-fold with RNase free water, and the diluted cDNA solution was used as a sample.
  • Taqman registered trademark
  • Universal PCR Master Mix #43044437: Thermo Fisher Scientific
  • Taqman registered trademark
  • Gene Expression ResorpLass Rhs INVENTORIhsRhsRh
  • Inventor RheaRs INVENTORIhEhRhsRs
  • INVENTORIhedRs INVENTORIhedRs
  • INVENTORIEDT #4331182
  • 5 ⁇ l each were mixed to prepare a measurement sample solution.
  • Quantitative prism chain reaction qPCR was performed by fluorescent probe method using ABI PRISM® 7900HT (Thermo Fisher Scientific). The analysis was performed by SDS2.4 (Thermo Fisher Scientific).
  • the result was 56.4% at 10 mg / kg when the increase in the ChAT mRNA expression level of the compound-administered group of Reference Example 1 was calculated as a percentage with respect to the ChAT mRNA expression level of the vehicle-administered group.
  • Acetylcholine (ACh) amount in rat Cerebrospinal fluid (CSF) (1) Background It has been clarified from rodent studies that the increase and decrease of neurotransmitters in the brain and in Cerebrospinal fluid (CSF) are correlated, and that the correlation is also understood in humans. (Lowe S et al. Psychopharmacology 219 (2012) 959-70.). Therefore, in order to detect the change in the amount of acetylcholine in the brain due to the test compound, the change in the amount of acetylcholine in CSF was evaluated. (2) Compound administration In this test, male Fischer 344 strain rats (Japan Charles River) having a body weight of about 150 to 250 g were used.
  • the test compound was orally administered once a day for 3 days at 10 mg/kg.
  • the medium used was 0.01N hydrochloric acid.
  • CSF was collected from the cisterna in a tube containing an AChE inhibitor under pentobarbital anesthesia.
  • the collected CSF was centrifuged at 3500 xg at 4 ° C. for 10 minutes, and the supernatant was collected.
  • the recovered supernatant was frozen in liquid nitrogen and then stored at ⁇ 80 ° C.
  • ChAT Choline acetyltransferase
  • the number of ChAT-positive cells present along the main axis of the medial septum was measured by (Keyence). The results showed the number of ChAT-positive cells in the medium-administered group and the test compound-administered group as a percentage when the number of ChAT-positive cells in the administration start group (4 months old) was 100%. The results are expressed as the average value ⁇ standard error.
  • the difference between the administration start group and the vehicle administration group (significant difference: *) and the difference between the vehicle administration group and the test compound group (significant difference: #) were analyzed by unpaired t-test. p ⁇ 0.05 was judged as a statistically significant difference. Statistical analysis was performed using GraphPad Prism version 7.02. The results are shown in Table 1.
  • rat hippocampal fimbria fornix transection model a Sprague-Dawley male rat (Charles River Laboratories, Japan) weighing about 250-350 g was used. Rats were anesthetized by mixing three kinds of subcutaneous administration of midazolam (2 mg/kg), medetomidine hydrochloride (0.15 mg/kg) and butorphanol tartrate (2.5 mg/kg), and the rats were fixed on a stereotaxic apparatus (Narishige Co., Ltd.).
  • the skull was exposed and the right skull was drilled to a width of 5 mm from the midline 2 mm posterior to Bregma.
  • a razor with a width of 4 mm was inserted into the depth of 5.5 mm from Bregma to cut the hippocampal fimbria-fornix. After hemostasis, the scalp was sutured and the rat was returned to the cage after surgery to recover from anesthesia.
  • the group in which the right skull was drilled to a width of 5 mm from the midline 2 mm behind Bregma and the razor was not inserted was defined as the sham surgery group.
  • test compound was orally administered once a day for 5 to 9 days (Example 1: 10 mg / kg) or 7 days to 14 days (Example 3: 3 mg / kg).
  • vehicle 0.01 N hydrochloric acid was used, and in the sham-operated group, the vehicle was orally administered once a day like the compound.
  • a brain coronal frozen section with a thickness of 30 ⁇ m was obtained from a sample of the forebrain including the medial septal area using a sliding microtome (Leica, SM2000R). Made.
  • ChAT Choline acetyltransferase positive cells
  • VAChT vesicular acetylcholine transporter
  • DAV staining DAB PERO XIDASE SUBSTRATE KIT (Vector, SK-4100) was performed using a VAChT antibody (Merck Millipore, ABN100).
  • the number of ChAT-positive cells or OD of hippocampal VAChT in the vehicle-administered group and the test compound-administered group was shown as a percentage when the medial septal area ChAT-positive cells or hippocampal VAChT OD in the sham-operated group was defined as 100%. ..
  • the results are expressed as mean ⁇ standard error.
  • the difference between the vehicle administration group and the test compound group (significant difference: #) was analyzed by unpaired t-test. p ⁇ 0.05 was judged as a statistically significant difference.
  • Statistical analysis was performed using GraphPad Prism version 7.02. The results are shown in Tables 2 and 3.

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