Compound useful as active ingredient of therapeutic agent for myelin sheath abnormality-related disease

Abstract

The present invention provides: a compound useful as an active ingredient of a therapeutic agent for myelin sheath abnormality-related disease; a therapeutic agent for myelin sheath abnormality-related disease; and a method for screening an active ingredient of a therapeutic agent for myelin sheath abnormality-related disease.　It was found that, among optical isomers of clemastine, an RS form and an RR form have a myelin sheath formation promoting effect. It was further found that the R form 1-(4-chlorophenyl)-1-phenylethane-1-ol, which is a shared skeleton of the RS form and the RR form, is important for a myelin sheath formation promoting effect, and that a novel compound synthesized using the R form 1-(4-chlorophenyl)-1-phenylethane-1-ol as a lead compound has a myelin sheath formation promoting effect.

Description

Compounds useful as active ingredients for therapeutic agents for myelin dysfunction-related diseases

[0001] The present invention relates to compounds useful as active ingredients in therapeutic agents for myelination-related diseases, therapeutic agents for myelination-related diseases, and methods for screening active ingredients in therapeutic agents for myelination-related diseases. This application claims priority from Japanese Patent Application No. 2024-089055, which is incorporated herein by reference.

[0002] Myelin is a structure that surrounds the axons of nerve cells and acts as an insulator, playing an important role in the fast and accurate transmission of nerve signals. Myelin formation is carried out by oligodendrocytes, a type of glial cell in the central nervous system. In vitro, animal model, and human cell tests suggest that clemastine, a known first-generation antihistamine, may stimulate the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes (Non-Patent Documents 1 and 2). Furthermore, Patent Documents 1 and 2 disclose methods for differentiating oligodendrocytes using clemastine and other agents.

[0003] The present inventors have discovered that clemastine, which has been approved as an anti-allergic drug for treating psychiatric disorders (increased anxiety / impulsivity, cognitive dysfunction) observed in alcoholic brain dysfunction and other conditions, improves abnormal oligodendrocyte differentiation and promotes myelination, thereby alleviating the disease (Patent Document 3).

[0004] Myelination abnormalities are widely recognized not only in alcohol-induced brain dysfunction but also in demyelinating diseases such as multiple sclerosis, and neuropsychiatric disorders such as schizophrenia and Alzheimer's disease. However, there have been no reports of the synthesis of novel compounds that are useful for treating these diseases by focusing on the myelination-promoting activity of clemastine.

[0005] International Publication No. WO2012 / 112933 International Publication No. WO2019 / 195742 International Publication No. WO2023 / 153055

[0006] Mei F et al., Nat Med., Aug, 201420(8):954-960Green AJ et al., Lancet, December 2,2017;390:2481-2489

[0007] An objective of the present invention is to provide compounds useful as active ingredients for therapeutic agents for myelination-related diseases, therapeutic agents for myelination-related diseases, and methods for screening active ingredients for therapeutic agents for myelination-related diseases.

[0008] The present inventors have conducted extensive research to achieve the above object and have found that, among the optical isomers of clemastine, the RS-isomer and the RR-isomer have the effect of promoting myelination. Furthermore, they have discovered that the R-isomer, 1-(4-chlorophenyl)-1-phenylethane-1-ol, which shares a common skeleton with the RS-isomer and the RR-isomer, is important for the myelination-promoting effect, and that novel compounds synthesized using the R-isomer, 1-(4-chlorophenyl)-1-phenylethane-1-ol, as a lead compound have the effect of promoting myelination, thereby completing the present invention.

[0009] That is, the present invention comprises the following: 1. A compound represented by the following formula (1), (2), (3) or (4) (excluding clemastine and its optical isomers) or a pharmacologically acceptable salt thereof. (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The portion excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). １ is the following formula (A1) or (B), and Z ２ is the following formula (C), and Z ３ is the following formula (D), and Z ４ 2. The compound according to item 1 above, which is represented by the following formula (E), (F) or (G), or a pharmacologically acceptable salt thereof. (In the formula, R １ is alkyl; X １ is carbon or a heteroatom; each R ２ are independently selected from the list including H, alkyl, =O; n １ is either 0 or 1.) (In the formula, R ３ is alkyl; X ２ and X ３ are each nitrogen or carbon; n ２ is 0.) (where n ３ is 0, 1 or 2; m １ is 1 or 2; R ４ is an alkyl group. (where n ４ is 0, 1 or 2; m ２ is 0 or 1; １ is 1 or 2; R ５ is an alkyl group. (where n ６ is 1 to 4; each R ６ are independently selected from the list including H, alkyl groups. (In formula (F), X ４is a complex number. In formula (G), R ７ and R ８ are each H or an alkyl group.) 3. Formula (A1) is selected from the following list: Formula (B) is selected from the list below: Formula (C) is selected from the list below: Formula (D) is selected from the list below; and Formula (E), (F) or (G) is selected from the following list: 3. A compound or a pharmacologically acceptable salt thereof according to the above item 1 or 2. 4. A compound represented by any one of the following formulas (6) to (8) or a pharmacologically acceptable salt thereof: (In formulas (6) to (8), (R) represents an asymmetric carbon atom of the R configuration.) 5. A therapeutic agent for a disease associated with myelination disorder, comprising, as an active ingredient, the compound according to any one of items 1 to 4 above or a pharmacologically acceptable salt thereof. 6. A therapeutic agent for a disease associated with myelination disorder, comprising, as an active ingredient, a compound represented by the following formula (5) or a pharmacologically acceptable salt thereof: (wherein (R) represents an asymmetric carbon atom in the R configuration.) 7. The therapeutic agent according to the above item 5 or 6, wherein the abnormal myelination-related disease is any one or more selected from the group consisting of demyelinating diseases and psychiatric disorders. 8. 8. The therapeutic agent according to any one of the preceding items 5 to 7, wherein the demyelinating disease is one or more selected from the group consisting of multiple sclerosis, Charcot-Marie-Tooth disease, diffuse sclerosis, generalized sclerosis, encephalitis, acute disseminated encephalomyelitis, acute cerebellitis, transverse myelitis, acute polyradiculitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Marchifava-Bignami disease, central pontine myelinolysis, central corpus callosum demyelination, neuromyelitis optica, Devic's disease, Barrow's disease, HIV myelopathy, HTLV myelopathy, progressive multifocal leukoencephalopathy, secondary demyelinating disease, subacute necrotizing myelitis, and adrenoleukodystrophy. 9. The therapeutic agent according to any one of the preceding items 5 to 8, wherein the psychiatric disorder is one or more selected from the group consisting of dementia, schizophrenia, alcohol use disorder, depression, bipolar disorder, anxiety disorder, impulsive disorder, bulimia, panic disorder, social anxiety disorder, insomnia, attention deficit hyperactivity disorder (ADHD), personality disorder, dissociative disorder, sleep apnea syndrome, and fibromyalgia. 10. A method for producing a compound represented by the following formula (1), (2), (3), or (4), or a pharmacologically acceptable salt thereof, characterized by using (R)-1-(4-chlorophenyl)-1-phenylethane-1-ol and / or a chemically modified product thereof as a starting material. (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form).) 11. 11. A method for screening active ingredients for therapeutic agents for myelination-related diseases, comprising using test compounds synthesized and / or designed using the R-isomer 1-(4-chlorophenyl)-1-phenylethane-1-ol as a lead compound and selecting compounds by one or more methods selected from the following 1) to 3): 1) adding a test compound to oligodendrocytes and culturing them, measuring the expression level of an oligodendrocyte marker in the cultured oligodendrocytes, and selecting a compound that increases the expression level of the oligodendrocyte marker compared to oligodendrocytes to which the test compound is not added; 2) collecting test samples from subjects, excluding humans, to which the test compound has been administered, measuring the expression level of an oligodendrocyte marker in the test samples, and selecting a compound that increases the expression level of the oligodendrocyte marker compared to subjects to which the test compound has not been administered; 3) selecting a compound that shows improvement, alleviation, mitigation, and / or suppression of symptoms caused by myelination in subjects, excluding humans, to which the test compound has been administered, compared to subjects to which the test compound has not been administered. 12. The screening method according to the preceding item 11, wherein the test compound is a compound represented by the following formula (1), (2), (3) or (4) (excluding clemastine) or a pharmacologically acceptable salt thereof: (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The stereochemistry of at least the asymmetric carbon atom of the portion excluding (R optical isomer) is R configuration.) 13. Use of a compound represented by the following formula (1), (2), (3), (4), (5), (6), (7) or (8) (excluding clemastine) or a pharmacologically acceptable salt thereof for the manufacture of a therapeutic agent for myelination-related diseases. (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, (R) represents an asymmetric carbon atom in the R configuration.) (In formulas (6) to (8), (R) represents an asymmetric carbon atom of R configuration.) 14. Use of a compound represented by the following formula (1), (2), (3), (4), (5), (6), (7) or (8) (excluding clemastine) or a pharmacologically acceptable salt thereof for the treatment of a myelination-related disease. (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, (R) represents an asymmetric carbon atom in the R configuration.) (In formulas (6) to (8), (R) represents an asymmetric carbon atom of R configuration.) 15. A compound represented by the following formula (1), (2), (3), (4), (5), (6), (7) or (8) (excluding clemastine) or a pharmacologically acceptable salt thereof for use in the treatment of a myelination-related disease. (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, (R) represents an asymmetric carbon atom in the R configuration.) (In formulas (6) to (8), (R) represents an asymmetric carbon atom of R configuration.) 16. A method for treating a myelination-related disease, which comprises administering to a subject an effective amount of a compound represented by the following formula (1), (2), (3), (4), (5), (6), (7) or (8) (excluding clemastine) or a pharmacologically acceptable salt thereof. (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, (R) represents an asymmetric carbon atom in the R configuration.) (In formulas (6) to (8), (R) represents an asymmetric carbon atom in the R configuration.)

[0010] The compounds of the present invention are useful as active ingredients for therapeutic agents for myelination-related diseases. Furthermore, the therapeutic agents for myelination-related diseases of the present invention can improve, alleviate, alleviate, and / or suppress symptoms of myelination-related diseases. Furthermore, the screening methods of the present invention can screen for active ingredients for therapeutic agents for myelination-related diseases.

[0011] 1 is a diagram showing the results of evaluating EAE symptoms in EAE (experimental autoimmune encephalomyelitis) model mice administered with the RR-, SS-, SR- or RS-form of clemastine. (Example 3) is a diagram showing the results of measuring the body weight of EAE model mice administered with the RR-, SS-, SR- or RS-form of clemastine. (Example 3) is a diagram showing the EAE score of EAE model mice administered with YK-321. (Example 4) is a diagram showing a schematic diagram (A) and measurement results (B) of the measurement of the expression level of MBP in primary cultured mouse oligodendrocyte precursor cells to which the RR-, SS-, SR- or RS-form of clemastine has been added. (Example 5) is a diagram showing the results of evaluating histamine H1 receptor (Histamine Receptor H1: HRH1) antagonist activity. (Example 6)

[0012] The present invention provides a compound (hereinafter, sometimes referred to as "the compound of the present invention") that is useful as an active ingredient of an agent for treating myelination-related diseases.

[0013] In this specification, the term "clemastine" refers to the clemastine RR form (sometimes simply referred to as the "RR form") and is used to include (R)-2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine and its salts. In this specification, the term "clemastine optical isomers" is used to include the SS form ((S)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine and its salts), the SR form ((R)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine and its salts), and the RS form ((S)-2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine and its salts).

[0014] As used herein, the term "salt" of a compound refers to any salt formed with the compound of the present invention, including, for example, salts with inorganic acids, organic acids, inorganic bases, organic bases, and basic or acidic amino acids. As used herein, the term "pharmacologically acceptable salt" of a compound refers to a salt that is pharmacologically acceptable and has the desired activity of the compound of the present invention (e.g., myelination-promoting activity), including, for example, salts with inorganic acids, organic acids, inorganic bases, organic bases, and basic or acidic amino acids. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of salts with organic acids include salts with fumaric acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzoic acid, toluenesulfonic acid, and the like, with fumarates and oxalates being particularly preferred. Examples of salts with inorganic bases include salts with sodium, potassium, calcium, magnesium, ammonium, and the like. Examples of salts with organic bases include salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, etc. Examples of salts with basic amino acids include salts with lysine, arginine, histidine, etc. Examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0015] As used herein, the term "dysmyelination-related disease" refers to a disease caused by myelination. Myelin is formed by oligodendrocytes to cover axons and promote axonal conduction velocity through saltatory conduction. Therefore, myelination by oligodendrocytes is involved in higher brain functions such as sociality and emotional behavior. Furthermore, failure to differentiate oligodendrocyte precursor cells into mature oligodendrocytes results in failure of myelination, resulting in brain dysfunction. The therapeutic agent for myelination-related disease of the present invention can improve, alleviate, alleviate, and / or suppress symptoms caused by myelination by promoting myelination. The myelination-promoting effect can be confirmed, for example, by promoting the expression (increased expression level) of oligodendrocyte markers in a subject or cells derived from a subject (e.g., oligodendrocytes), or by suppressing symptoms caused by myelination (e.g., suppression of EAE score, etc.) in a subject (e.g., an experimental autoimmune encephalomyelitis (EAE) model animal). Examples of myelination disorder-related diseases include demyelinating diseases and psychiatric disorders. Experimental autoimmune encephalomyelitis (EAE) is an animal model of demyelinating diseases, shares many pathologies with multiple sclerosis, and can be produced, for example, according to the method described in J Vis Exp. 2014 Apr 15;(86):51275. As used herein, unless otherwise specified, the term "subject" refers to a human or other mammal, including, for example, humans, mice, rabbits, cats, dogs, horses, cows, monkeys, chimpanzees, baboons, and other apes.

[0016] As used herein, examples of "demyelinating disease" include multiple sclerosis, Charcot-Marie-Tooth disease, diffuse sclerosis, generalized sclerosis, encephalitis, acute disseminated encephalomyelitis, acute cerebellitis, transverse myelitis, acute polyradiculitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Marchifava-Bignami disease, central pontine myelinolysis, central corpus callosum demyelination, neuromyelitis optica, Devic's disease, Barrow's disease, HIV myelopathy, HTLV myelopathy, progressive multifocal leukoencephalopathy, secondary demyelinating disease, subacute necrotizing myelitis, and adrenoleukodystrophy.

[0017] As used herein, "multiple sclerosis" refers to a demyelinating disease of the central nervous system characterized by destruction of the myelin sheaths that cover nerve fibers in the brain, spinal cord, optic nerves, etc., and is a disease in which the disorder progresses with repeated relapses and remissions. Symptoms vary depending on the site of the lesion, and include a variety of neurological symptoms such as visual impairment, limb paralysis, sensory impairment, gait disturbance, dysesthesias, sensory paralysis, eye pain, and numbness. Examples of multiple sclerosis include relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis.

[0018] As used herein, the term "mental disorder" refers to a condition accompanied by functional impairment due to the presence of specific mental or behavioral symptoms, as listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Such conditions include substance-related disorders such as drug addiction (e.g., alcohol use disorder), anxiety disorders (e.g., schizophrenia, depression, bipolar disorder, and panic disorder), and conditions exhibiting various symptoms, such as sexual dysfunction. Therefore, "mental disorder" includes dementia, schizophrenia, alcohol use disorder, depression, manic-depressive illness, bipolar disorder, anxiety disorder, impulsive disorder, bulimia, panic disorder, social anxiety disorder, insomnia, attention deficit hyperactivity disorder (ADHD), personality disorder, dissociative disorder, sleep apnea syndrome, and fibromyalgia, with depression, schizophrenia, dementia, and / or alcohol use disorder being particularly preferred. Many psychiatric disorders have been reported to be associated with myelination abnormalities, including morphological changes in the myelin sheath and decreased myelination, and it has been reported that clemastine promotes myelination and alleviates depressive-like behavior in depression model animals (Sci Rep. 2017 May 19;7(1):2200; Neuroscience. 2020 Sep 1;443:218-232; J Neurosci. 2016 Jan 20;36(3):957-62). The myelination-promoting effect of the therapeutic agent for myelination abnormalities of the present invention is extremely useful for treating psychiatric disorders, as well as demyelinating diseases.

[0019] As used herein, "depression" refers to symptoms including persistently depressed mood or loss of interest or pleasure, present nearly every day for a two-week period. Criteria for diagnosing depression include the DSM-5.

[0020] As used herein, "schizophrenia" refers to a condition in which the ability to organize thoughts, actions, and emotions in accordance with a single purpose, i.e., the ability to integrate, declines over a long period of time, during which certain hallucinations, delusions, etc. occur. Criteria for diagnosing schizophrenia include DSM-5 and ICD-10.

[0021] As used herein, "dementia" refers to a state in which cognitive function that was once normal is persistently impaired due to an acquired brain disorder. Dementia is generally diagnosed when functional impairment is observed to the extent that it interferes with daily or social life. Examples of dementia include Alzheimer's disease, vascular dementia, dementia with Lewy bodies, normal pressure hydrocephalus, frontotemporal lobar degeneration, neurofibrillary tangle-type senile dementia, dementia caused by other diseases (e.g., infectious diseases), alcoholic dementia, and vitamin deficiency dementia, with Alzheimer's disease being particularly preferred. Furthermore, "dementia" in the present invention also includes dementia that is a mixture of any of these disease types. Furthermore, dementia of unknown or unspecified disease type is also included in "dementia" in the present invention.

[0022] As used herein, "alcohol use disorder" refers to a condition in which some mental or physical disorder is caused by alcohol consumption, and preferably alcohol-related brain dysfunction (e.g., alcoholic dementia) and / or myelination abnormalities. As used herein, "alcohol use disorder" includes, for example, alcoholism, a condition in which some mental or physical disorder is caused by alcohol consumption but does not reach the level of alcohol dependence (harmful alcohol use), a condition in which social or family problems are caused by alcohol consumption (alcohol abuse), and a condition in which some alcohol-related problems are caused without experiencing withdrawal symptoms or continuous alcohol consumption (prealcoholism). The condition in which some mental or physical disorder is caused by alcohol consumption may occur during alcohol consumption or abstinence. As used herein, "abstinence" refers to a state in which alcohol consumption is abstained after alcohol consumption. As used herein, "alcohol" is the main component of alcoholic beverages such as so-called "sake" (alcoholic drinks), and is a general term for substances in which the hydrogen atoms of hydrocarbons are replaced with OH groups, specifically ethanol (EtOH). In this specification, "mental disorders" include brain dysfunction, myelin abnormalities, auditory hallucinations, sleep disorders, etc., and "physical disorders" include hypertension, arrhythmia, alcoholic liver disease, etc.

[0023] One way to diagnose alcohol use disorder is the DSM-5. In the DSM-5, alcohol use disorder is diagnosed when two or more of the following occur within a 12-month period: - Use in greater amounts or for longer periods than intended - Unsuccessful attempts to reduce or limit use - Spending a lot of time obtaining, using, or recovering from alcohol - Craving - Recurrent use that prevents one from fulfilling responsibilities at work, school, or home - Continuing use despite causing or worsening social or interpersonal problems - Abandoning or curtailing social, occupational, or recreational activities for personal reasons - Recurrent use despite physically unsafe situations - Continuing use despite perceptions that physical or mental problems are getting worse - Tolerance - Withdrawal symptoms - Craving for substance use

[0024] As used herein, "alcoholism" refers to a state in which excessive alcohol consumption results in mental or physical dependence on alcohol, resulting in mental or physical disorders. One method for diagnosing alcoholism is the International Statistical Classification of Diseases and Related Health Problems-10 (ICD-10), 10th edition. According to ICD-10, alcoholism is diagnosed when a person experiences three or more of the following six symptoms simultaneously for one month or more in the past year, or experiences them repeatedly: - Intense craving for alcohol - Loss of control over drinking - Withdrawal symptoms - Evidence of tolerance - Lifestyle centered around drinking - Time consuming drinking behavior - Drinking despite problems

[0025] In this specification, "psychological dependence" refers to an intense desire to drink alcohol, an inability to control drinking and cut down, spending most of the day drinking or recovering from it and ignoring other forms of entertainment, and not abstaining from alcohol despite worsening mental and physical problems, etc., and "physical dependence" refers to withdrawal symptoms such as trembling hands and sweating as the alcohol wears off the body, and needing to drink more alcohol than before to become intoxicated, etc.

[0026] As used herein, "symptoms caused by myelination abnormalities" are not particularly limited as long as they are symptoms that differ from a normal state in which there is no myelin abnormality, and examples include visual impairment, paralysis and / or weakness of the limbs and / or tail, sensory impairment, gait disturbance, dysesthesias, sensory paralysis, spinal curvature, combinations of these, etc. Improvement, alleviation, mitigation, and / or suppression of symptoms caused by myelination abnormalities may be determined by determining a symptom score that indicates the degree of progression of symptoms caused by myelination abnormalities in a subject, and comparing the symptom scores between subjects administered with a test compound and subjects not administered with the compound.

[0027] As used herein, the "symptom score" may use a known scoring standard, or a new scoring standard may be established. Examples of known scoring standards include those described in the literature (Journal of Neurochemistry, 2019, 148.3: 413-425), and these standards may be used with appropriate modifications. For example, when experimental autoimmune encephalomyelitis (EAE) model mice are used as subjects, the following standard may be used. According to this standard, a higher score indicates more progression of symptoms, and a lower score indicates improvement, alleviation, mitigation, and / or suppression of symptoms.

[0028] (EAE score criteria) 0, normal; 0.5, partial tail droop; 1, complete tail droop; 1.5, abnormal gait; 2, abnormal gait with hind limb weakness; 2.5, paralysis and weakness of one hind limb; 3, paralysis of both hind limbs; 3.5, paralysis of both hind limbs with hunched posture; 4, paralysis of both forelimbs and hind limbs; 5, moribund or dead.

[0029] The compound of the present invention may be a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof, excluding clemastine: １ is independently selected from the list comprising: an aliphatic heterocycle, an aromatic heterocycle; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R configuration).

[0030]

[0031] In one embodiment, Z １ is an aliphatic heterocycle optionally substituted with an alkyl group as defined below: １ is the following formula (A1):

[0032]

[0033] In the formula, - R １ is alkyl; X １is carbon or a heteroatom, where the heteroatom is preferably oxygen, nitrogen, or sulfur. When the heteroatom is nitrogen, it is preferred that one hydrogen on the nitrogen is replaced with an alkyl group; each R ２ is independently selected from the list including H, alkyl, ═O; １ is 0 or 1.

[0034] A preferred example of formula (A1) is:

[0035]

[0036] In one embodiment, Z １ is an aromatic heterocycle defined as follows: １ is the following formula (B):

[0037]

[0038] In the formula, - R ３ is alkyl; X ２ and X ３ are respectively nitrogen or carbon; ２ is 0.

[0039] A preferred example of formula (B) is:

[0040]

[0041] The compound of the present invention may be a compound represented by the following formula (2) or a pharmacologically acceptable salt thereof, excluding clemastine: ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; - Z ２ The portion excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R configuration).

[0042]

[0043] In one embodiment, Z ２ is an aliphatic heterocycle defined as: ２ is the following formula (C):

[0044]

[0045] In the formula, - n ３ is 0, 1 or 2; m １ is 1 or 2; R ４ is an alkyl group.

[0046] A preferred example of formula (C) is:

[0047]

[0048] The compound of the present invention may be a compound represented by the following formula (3) or a pharmacologically acceptable salt thereof, excluding clemastine: ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; - Z ３ The portion excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R configuration).

[0049]

[0050] In one embodiment, Z ３ is an aliphatic heterocycle defined as: ３ is the following formula (D):

[0051]

[0052] -n ４ is 0, 1 or 2; m ２ is 0 or 1; １ is 1 or 2; R ５ is an alkyl group.

[0053] A preferred example of formula (D) is:

[0054]

[0055] The compound of the present invention may be a compound represented by the following formula (4) or a pharmacologically acceptable salt thereof, excluding clemastine: ４ is independently selected from the list comprising -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; ５ is 1, 2 or 3; Z ４The portion excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R configuration).

[0056]

[0057] In one embodiment, Z ４ is an aliphatic heterocycle defined as: ４ is the following formula (E): ６ is 1 to 4; each R ６ is independently selected from the list including H, alkyl groups.

[0058]

[0059] In one embodiment, Z ４ is an aliphatic heterocycle defined as: ４ is the following formula (F) or (G); ４ is a heteroatom, where the heteroatom is preferably oxygen, nitrogen, or sulfur. When the heteroatom is nitrogen, it is preferred that one hydrogen on the nitrogen is replaced with an alkyl group. - R ７ and R ８ are each H or an alkyl group.

[0060]

[0061] Preferred examples of formulae (E), (F) and (G) are:

[0062]

[0063] The term “alkyl,” by itself or as part of another substituent, refers to a group of the formula C x H 2x+1 where x is a number equal to or greater than 1. Generally, alkyl groups of the present invention contain 1 to 20, preferably 1 to 10, more preferably 1 to 5, and most preferably 1 to 3 carbon atoms. Alkyl groups may be straight or branched, and may be substituted as indicated herein. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms the designated group may contain. Thus, for example, C 1-4Alkyl means alkyl of 1 to 4 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers; and decyl and its isomers. C1-C6 alkyl includes all linear, branched, or cyclic alkyl groups having 1 to 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g., n-butyl, i-butyl, and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopentyl, 2-, 3-, or 4-methylcyclopentyl, cyclopentylmethylene, and cyclohexyl. The term "optionally substituted alkyl" refers to an alkyl group that is optionally substituted at any available point of attachment with one or more substituents (e.g., 1 to 4 substituents, e.g., 1, 2, 3, or 4 substituents, or 1 to 2 substituents). Non-limiting examples of such substituents include halo, hydroxyl, carbonyl, nitro, amino, oxime, imino, azido, hydrazino, cyano, aryl, heteroaryl, cycloalkyl, acyl, alkylamino, alkoxy, thiol, alkylthio, carboxylic acid, acylamino, alkyl ester, carbamate, thioamide, urea, sulfonamide, and the like.

[0064] The present invention provides a therapeutic agent for myelination-related diseases (hereinafter, sometimes referred to as "the therapeutic agent of the present invention"), which comprises, as an active ingredient, a compound represented by the above formula (1), (2), (3), or (4) or the following formula (5), (6), (7), or (8), or a pharmacologically acceptable salt thereof.

[0065] (In the formula, (R) represents an asymmetric carbon atom in the R configuration.)

[0066] (In formulas (6) to (8), (R) represents an asymmetric carbon atom in the R configuration.)

[0067] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to an amount capable of achieving a therapeutically effective effect in a subject. The effective amount varies depending on the characteristics of the subject and can be appropriately determined by one skilled in the art. The dosage of the therapeutic agent of the present invention is a therapeutically effective amount and can be appropriately determined depending on the age, sex, body weight, symptoms, dosage form, route of administration, number of doses, frequency of doses, timing of doses, and the judgment of a physician or veterinarian. For example, when administered orally to an adult, the daily dose may be 0.001 to 0.5 mg / kg body weight, preferably 0.01 to 0.1 mg / kg body weight, calculated as the active ingredient, the compound of the present invention or a pharmacologically acceptable salt thereof. The route of administration of the therapeutic agent of the present invention is not particularly limited, and can be administered orally or parenterally, although oral administration is preferred. Examples of formulations suitable for oral administration include tablets, granules, fine granules, powders, syrups, solutions, capsules, and suspensions. The therapeutic agent of the present invention can be manufactured by known or future-developed manufacturing methods. Liquid preparations for oral administration can be produced using additives for formulations such as water, sugars such as sucrose, sorbitol, fructose, etc., glycols such as polyethylene glycol, propylene glycol, etc., oils such as sesame oil, olive oil, soybean oil, etc., and preservatives such as p-hydroxybenzoic acid esters, etc. Furthermore, solid preparations such as capsules, tablets, powders, or granules can be produced using excipients such as lactose, glucose, sucrose, mannitol, etc., disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as methylcellulose, polyvinyl alcohol, hydroxypropyl cellulose, gelatin, etc., surfactants such as fatty acid esters, etc., and plasticizers such as glycerin, etc.

[0068] If necessary, the therapeutic agent of the present invention can be prepared by encapsulating the compound of the present invention or a pharmacologically acceptable salt thereof, which is the active ingredient, in microcapsules (microcapsules made of hydroxymethylcellulose, gelatin, poly[methyl methacrylic acid], etc.), or by using a colloid drug delivery system (liposomes, albumin microspheres, microemulsions, nanoparticles, nanocapsules, etc.) (see, for example, Remington's Pharmaceutical Science 16th edition, Osol, A. Ed. (1980)). Furthermore, methods for converting drugs into sustained-release drugs are also known, and these methods can be applied to the therapeutic agent of the present invention.

[0069] The present invention relates to a method for producing a compound represented by the above formula (1), (2), (3), (4), (5), (6), (7) or (8) or a pharmacologically acceptable salt thereof.

[0070] The compounds represented by the above formula (1), (2), (3), (4), (5), (6), (7), or (8) or pharmacologically acceptable salts thereof can be produced using (R)-1-(4-chlorophenyl)-1-phenylethane-1-ol and / or chemically modified forms thereof as starting materials, for example, in accordance with the procedures described in the Examples. In the present invention, the chemical modification of (R)-1-(4-chlorophenyl)-1-phenylethane-1-ol to produce the chemically modified form is not particularly limited. For example, functional groups may be added to, substituted for, and / or removed from (R)-1-(4-chlorophenyl)-1-phenylethane-1-ol, and any combination of chemical modifications may be used.

[0071] The present invention relates to a method for screening active ingredients of therapeutic agents for myelinating disorders.

[0072] The present invention provides a screening method for active ingredients of therapeutic agents for myelination-related diseases, characterized in that the R-isomer 1-(4-chlorophenyl)-1-phenylethane-1-ol is used as a lead compound, and in which candidate compounds are selected based on one or more functions selected from the following 1) to 3): 1) increasing the expression level of an oligodendrocyte marker in oligodendrocytes cultured with the addition of the candidate compound, compared to oligodendrocytes to which the candidate compound is not added; 2) increasing the expression level of an oligodendrocyte marker in a subject, excluding humans, to which the candidate compound is administered, compared to subjects to which the candidate compound is not administered; 3) improving, alleviating, mitigating, and / or suppressing symptoms caused by myelination-related diseases in a subject, excluding humans, to which the candidate compound is administered, compared to subjects to which the candidate compound is not administered.

[0073] The present inventors prepared optical isomers of clemastine, namely, the RR, SS, SR, and RS isomers, with the benzyl carbon atom and the 2-position carbon atom of pyrrolidine as asymmetric atoms, as disclosed in the Examples. They then examined their myelination-promoting activity. Compared with the SS isomer, the RR and RS isomers exhibited greater suppressive effects on EAE scores, while the SR isomer did not exhibit significant suppressive effects on EAE scores. Additionally, the RS isomer significantly suppressed weight loss compared to controls. Based on these findings, the inventors discovered that the R-isomer of the benzyl carbon atom of clemastine is the primary structural component responsible for the activity. They then developed a screening method for active ingredients for the treatment of myelination-related diseases, which is characterized by using the R-isomer, 1-(4-chlorophenyl)-1-phenylethan-1-ol (hereinafter sometimes referred to as "(R)-1-(4-chlorophenyl)-1-phenylethan-1-ol"), as a lead compound.

[0074] The screening method of the present invention uses (R)-1-(4-chlorophenyl)-1-phenylethane-1-ol as a lead compound. In the screening method of the present invention, it is sufficient for the test compound synthesized and / or designed from the lead compound to have a structure in which the asymmetric carbon atom at the benzyl position in the clemastine structure is in the R configuration. Chemically modifying the pyrrolidine structure in the clemastine structure can be expected to improve pharmacological activity, stability, and / or safety. The pyrrolidine structure in the clemastine structure can be varied in various ways and is not limited, as described below. Test compounds in the screening method of the present invention are prepared by varying the pyrrolidine structure in the clemastine structure in various ways, as described in the Examples, and then reacting the resulting compound with (R)-1-(4-chlorophenyl)-1-phenylethan-1-ol.

[0075] In one aspect, the screening method of the present invention is characterized by adding a test compound to oligodendrocytes, culturing them, measuring the expression level of an oligodendrocyte marker in the cultured oligodendrocytes, and selecting a compound that increases the expression level of the oligodendrocyte marker compared to oligodendrocytes to which the test compound has not been added. The expression level of the oligodendrocyte marker in oligodendrocytes to which the test compound has not been added may be a reference value previously determined from past data. Oligodendrocytes can be cultured using known or future culture methods. The origin of oligodendrocytes is not particularly limited, and oligodendrocytes derived from mammals such as humans, mice, monkeys, chimpanzees, dogs, cows, pigs, rabbits, and rats can be used.

[0076] In one embodiment, the screening method of the present invention comprises collecting a test sample from a subject (excluding humans) to whom a test compound has been administered in vivo, measuring the expression level of an oligodendrocyte marker in the test sample, and selecting a compound that increases the expression level of the oligodendrocyte marker compared to a subject not administered the test compound. The expression level of the oligodendrocyte marker in a subject not administered the test compound may be a reference value previously determined from past data.

[0077] In one aspect, the screening method of the present invention is characterized by selecting a compound that improves, alleviates, alleviates, and / or suppresses symptoms caused by myelination abnormalities in a subject (excluding humans) administered with the test compound in vivo, compared to a subject not administered with the test compound. Examples of the "subject" in the screening method of the present invention include mammals, including mice, rabbits, cats, dogs, horses, cows, monkeys, chimpanzees, baboons, and other apes.

[0078] The test compound in the screening method of the present invention is not particularly limited as long as it can be synthesized using (R)-1-(4-chlorophenyl)-1-phenylethane-1-ol as a lead compound, and can include, for example, compounds obtained by combinatorial chemistry techniques or conventional synthesis techniques, various known compounds, etc. Examples of such test compounds include compounds represented by formula (1), (2), (3), or (4) described below (excluding clemastine) or pharmacologically acceptable salts thereof.

[0079] As used herein, the term "oligodendrocyte" is used to refer to a concept that includes oligodendrocyte precursor cells and mature oligodendrocytes. As used herein, the term "oligodendrocyte marker" may be an oligodendrocyte precursor cell marker that indicates differentiation from neural stem cells to oligodendrocyte precursor cells, or may be a mature oligodendrocyte marker or myelin marker that indicates differentiation from neural stem cells or oligodendrocyte precursor cells to mature oligodendrocytes. Examples include myelin markers such as MAG (Myelin-associated glycoprotein), CNPase (2',3'-Cyclic Nucleotide 3'-Phosphodiesterase), and MBP (Myelin basic protein); mature oligodendrocyte markers such as CC1 (APC; Adenomatous polyposis coli) and Olig2 (Oligodendrocyte transcription factor 2); and oligodendrocyte precursor cell markers such as PDGFRα (Platelet-derived growth factor receptor α) and NG2 (Neuron-glial Antigen 2). MBP, MAG, CNPase, CC1, or PDGFRα is particularly preferred. In the screening method of the present invention, the expression level of an oligodendrocyte marker can be measured by known or future developed methods, for example, by immunological techniques such as Western blotting using antibodies, immunohistochemical staining, ELISA, and flow cytometry for test samples obtained in vitro or in vivo, protein quantification methods such as mass spectrometry and amino acid sequence analysis, and nucleic acid quantification methods such as quantitative PCR (qPCR), PCR, microarray, sequencing, and chromatography.

[0080] As used herein, the term "test sample" may be a specimen collected from a subject, or may be a sample prepared from a specimen, and examples thereof include brain tissues and slices such as the frontal cortex and hippocampus, urine, feces, exudates such as pus, sputum, lymph nodes, tonsils, skin, lymph, blood, mucous membranes, etc. In the screening method of the present invention, the subject can be changed as appropriate, and for example, a subject in which experimental autoimmune encephalomyelitis (EAE) has been induced can be used.

[0081] To aid in understanding the present invention, the present invention will be specifically described below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

[0082] Example 1 Synthesis of Clemastine Optical Isomers In this example, (S)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine fumarate (SS isomer), (S)-2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine fumarate (RS isomer), and (R)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine fumarate (SR isomer), which are optical isomers of clemastine RR isomer ((R)-2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine), were synthesized.

[0083] Synthesis of (R)-1-(4-chlorophenyl)-1-phenylethan-1-ol: 1-(4-chlorophenyl)ethane-1-one (1 g, 6.47 mmol), 2,4,6-triphenylboroxin (4.02 g, 12.89 mmol), CsF (3.93 g, 25.9 mmol), (2S,2'S,3S,3'S)-WingPhos (0.17 g, 0.232 mmol), magnesium bromide (0.42 g, 2.257 mmol), dichlorotetraethylene dirhodium(I) (0.04 g, 0.098 mmol), and MTBE (32 mL) were placed in an argon-purged 100 mL autoclave. The reaction mixture was heated in an oil bath and stirred at a bath temperature of 110-120 °C for 20 hours. After cooling to room temperature, H2O (200 ml) and DCM (200 ml) were added, and the organic layer was separated. The obtained organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (heptane / ethyl acetate = 100 / 0 to 90 / 10) to obtain (R)-1-(4-chlorophenyl)-1-phenylethan-1-ol (hereinafter sometimes referred to as "compound (R)-1") as a colorless oil (0.96 g, yield 64%). The spectral data of the product ( 1 H-NMR and 13 The results of CNMR and chiral HPLC analysis are shown below.

[0084] 1 H NMR (400MHz, CDCL3) δ7.41-7.24(m, 9H), 2.15 (s, 1H),1.94 (s, 3H); 13 C NMR (100MHz, CDCL3)δ147.4, 146.5,132.7, 128.3, 128.2, 127.3, 127.2, 125.7, 75.9, 30.8; MS m / z215(M-OH +);Chiral HPLC analysis (Analysis conditions column:AD-3, 3μ, 4.6x250mm, oven:40℃, flow rate: 1mL / min, solvent: n-hexane / IPA=97 / 3) RT12.47 min ((R)-1).

[0085] (Synthesis of (S)-1-(4-chlorophenyl)-1-phenylethan-1-ol) Using the chiral ligand (2R,2'R,3R,3'R)-WingPhos in the same manner as for compound (R)-1, (S)-1-(4-chlorophenyl)-1-phenylethan-1-ol (hereinafter sometimes referred to as "compound (S)-1") was obtained as a colorless oil (1.04 g, yield 69%). The results of chiral HPLC analysis are shown below.

[0086] Chiral HPLC analysis (Analysis conditions column: AD-3, 3μ, 4.6x250mm, oven:40℃, flow rate: 1mL / min, solvent:n-hexane / IPA=97 / 3) RT 13.41min ((S)-1).

[0087] (Synthesis of (S)-2-(2-chloroethyl)-1-methylpyrrolidine) A 30 ml flask purged with argon was charged with (S)-2-(1-methylpyrrolidin-2-yl)ethan-1-ol ((S)-2-OH) (0.35 g, 2.71 mmol, 99% ee) and chloroform (5 ml). The mixture was cooled in an ice bath, and a solution of thionyl chloride (0.534 ml, 7.31 mmol) in chloroform (2 ml) was added dropwise. The reaction mixture was heated in an oil bath and refluxed overnight. The reaction mixture was concentrated under reduced pressure to give (S)-2-(2-chloroethyl)-1-methylpyrrolidine (hereinafter sometimes referred to as "compound (S)-2-Cl") as a brown solid (486 mg, 97% yield). Compound (S)-2-Cl was added with DCM (20 ml) and 1M aqueous KOH (20 ml), and the organic layer was separated. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give compound (S)-2-Cl (free form) as a brown oil. The synthesis of compound (S)-2-Cl is outlined below. Because it was an unstable compound, it was used immediately in the next step.

[0088]

[0089] (Synthesis of (R)-2-(2-chloroethyl)-1-methylpyrrolidine) (R)-2-(1-methylpyrrolidin-2-yl)ethan-1-ol ((R)-2-OH) (0.25 g, 1.935 mmol, 99% ee) was used in the same manner to obtain (R)-2-(2-chloroethyl)-1-methylpyrrolidine (hereinafter sometimes referred to as "(R)-2-Cl (free form)") as a brown oil.

[0090] (Synthesis of (S)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidinefumarate (SS form)) Compound (S)-1 (0.47 g, 2.032 mmol) and toluene (13 ml) were placed in an argon-purged 50 ml flask, and 60% NaH (0.11 g, 2.71 mmol) was added. The reaction solution was heated under reflux for 3 hours. After cooling to room temperature, a toluene (6 ml) solution of (S)-2-Cl (free form) (0.20 g, 1.36 mmol) obtained in the previous step was added, and the mixture was heated under reflux for 20 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) and HO (30 ml) were added, and the organic layer was separated. The organic layer was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel chromatography (heptane / ethyl acetate = 100 / 0 to 95 / 5) to obtain (S)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine (hereinafter sometimes referred to as "compound 3-B (free form)") as a slightly yellow oil (252 mg, yield 54%). To a solution of the obtained compound 3-B (free form) in ethanol (2.5 ml), fumaric acid (0.09 g, 0.733 mmol) was added and heated to 50 °C to dissolve. The mixture was cooled to room temperature, and the precipitated solid was collected by filtration. After drying under reduced pressure at 40°C for 2 days, (S)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine fumarate (hereinafter sometimes referred to as "compound 3-B fumarate") was obtained as a white solid (287 mg, yield 85%, LC 99%). The spectral data of the obtained product ( 1 H-NMR and 13 The C NMR and specific rotation were consistent with those reported in the literature (Helv. Chim. Acta 1976, 59, 2462.). The outline of the synthesis of compound 3-B fumarate and the spectral data of the product are shown below.

[0091]

[0092] [α] D 20 -16.8°(c=0.5 MeOH); 1 H NMR (400MHz, CD3OD)δ7.36-7.23 (m, 9H), 6.68 (s, 2H), 3.72-3.60 (m, 1H), 3.50-3.41 (m, 2H),3.33-3.30(m, 1H), 3.17-3.10 (m, 1H), 2.91 (s, 3H), 2.26 (m, 2H), 2.12-1.98 (m,2H), 1.87(s, 3H), 1.81-1.71 (m, 2H); 13 C NMR (100MHz, CD3OD)δ 171.5,147.1, 146.8, 136.2, 133.7, 129.5, 129.2, 129.1, 128.3, 127.8, 81.8,60.2, 57.1,32.1, 30.6, 25.8, 22.4; MS m / z 344, 346 [(M+1)-fumaric acid,(M+3)-fumaricacid].

[0093] (Synthesis of (S)-2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidinefumarate (RS form)) Compound (R)-1 (0.51 g, 2.20 mmol) and toluene (20 ml) were placed in an argon-purged 50 ml flask, and 60% NaH (0.12 g, 2.96 mmol) was added. The reaction solution was heated under reflux for 3 hours. After cooling to room temperature, a toluene (6 ml) solution of (S)-2-Cl (free form) (0.22 g, 1.491 mmol) obtained in the previous step was added, and the mixture was heated under reflux for 20 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) and HO (30 ml) were added, and the organic layer was separated. The organic layer was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel chromatography (heptane / ethyl acetate = 100 / 0 to 95 / 5) to give (S)-2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine (hereinafter sometimes referred to as "Compound 3-D (free form)") as a slightly yellow oil (246 mg, 48% yield). To a solution of the obtained Compound 3-D (free form) in ethanol (2.5 mL), fumaric acid (0.09 g, 0.733 mmol) was added and heated to 50 °C to dissolve. The mixture was cooled to room temperature, and the precipitated solid was collected by filtration. After drying under reduced pressure at 40°C for 2 days, (S)-2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine fumarate (hereinafter sometimes referred to as "compound 3-D fumarate") was obtained as a white solid (265 mg, yield 81%, LC 99%). The spectral data of the obtained product ( 1 H-NMR and 13 The C NMR and specific rotation were consistent with those reported in the literature (Helv. Chim. Acta 1976, 59, 2462.). The outline of the synthesis of compound 3-D fumarate and the spectral data of the product are shown below.

[0094]

[0095] [α] D 20 -33.9°(c=0.5MeOH); 1 H NMR (400MHz, CD3OD)δ7.36-7.24(m, 9H), 6.68 (s,2H), 3.69-3.60 (m, 1H), 3.49-3.45 (m, 2H), 3.29-3.27 (m, 1H),3.20-3.15 (m, 1H),2.92 (s, 3H), 2.30-2.15 (m, 2H), 2.10-1.99 (m, 2H), 1.87 (s,3H), 1.79-1.65 (m,2H); 13 C NMR (100MHz, CD3OD) δ171.4,147.1, 146.8, 136.2,133.7, 129.3, 129.2, 129.1, 128.4, 128.0, 81.8, 60.2, 57.1,32.1, 30.6, 25.7,22.4; MS m / z 344, 346 [(M+1)-fumaric acid, (M+3)-fumaricacid].

[0096] (Synthesis of (R)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidinefumarate (SR form)) Compound (S)-1 (0.54 g, 2.37 mmol) and toluene (20 ml) were placed in an argon-purged 50 ml flask, and 60% NaH (0.12 g, 2.96 mmol) was added. The reaction solution was heated under reflux for 3 hours. After cooling to room temperature, a toluene (6 ml) solution of (R)-2-Cl (free form) (0.215 g, 1.461 mmol) obtained in the previous step was added, and the mixture was heated under reflux for 20 hours. The reaction solution was cooled to room temperature, and ethyl acetate (30 ml) and HO (30 ml) were added, and the organic layer was separated. The organic layer was dried over NaSO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel chromatography (heptane / ethyl acetate = 100 / 0 to 95 / 5) to give (R)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine (hereinafter sometimes referred to as "Compound 3-C (free form)") as a slightly yellow oil (251 mg, 50% yield). To a solution of the obtained Compound 3-C (free form) in ethanol (2.5 ml), fumaric acid (0.09 g, 0.733 mmol) was added and heated to 50 °C to dissolve. The mixture was cooled to room temperature, and the precipitated solid was collected by filtration. After drying under reduced pressure at 40°C for 2 days, (R)-2-(2-((S)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1-methylpyrrolidine fumarate (hereinafter sometimes referred to as "compound 3-C fumarate") was obtained as a white solid (195 mg, yield 58%, LC 99%). The spectral data of the obtained product ( 1 H-NMR and 13 The C NMR and specific rotation were consistent with those reported in the literature (Helv. Chim. Acta 1976, 59, 2462.). The outline of the synthesis of compound 3-C fumarate and the spectral data of the product are shown below.

[0097]

[0098] [α] D 20 +33.1°(c=0.4 MeOH); 1 HNMR (400MHz,CD3OD)δ7.36-7.24 (m, 9H), 6.68 (s, 2H), 3.65-3.61 (m, 1H), 3.49-3.44(m, 2H),3.30-3.27 (m, 1H), 3.18-3.10 (m, 1H), 2.92 (s, 3H), 2.91-2.18 (m, 2H),2.05-2.02(m, 2H), 1.87 (s, 3H), 1.76-1.73 (m, 2H); 13 C NMR (100MHz,CD3OD)δ171.4, 147.1, 146.8, 136.2, 133.7, 129.3, 129.2, 129.1,128.4, 128.0, 81.8,60.2, 57.1, 32.1, 30.6, 25.7, 22.4; MS m / z 344, 346[(M+1)-fumaric acid,(M+3)-fumaric acid].

[0099] Example 2 Evaluation of the Effects of Drug Administration on Experimental Autoimmune Encephalomyelitis (EAE) Model Mice In this example, EAE model mice were prepared and the symptoms of drug administration were evaluated.

[0100] Eight- to ten-week-old female C57BL / 6 mice were purchased from Japan SLC Co., Ltd. and used to generate EAE model mice. All mice were housed in plastic cages under a 12-hour light-dark cycle with free access to food and water. EAE, a model of demyelination (demyelination model), was induced according to the method described previously (Bittner, S., Afzali, A. M., Wiendl, H. & Meuth, S. G. Myelin oligodendrocyte glycoprotein (MOG35-55) induced experimental autoimmune encephalomyelitis (EAE) in C57BL / 6 mice. J Vis Exp (2014). https: / / doi.org:10.3791 / 51275). Myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide (MEVGWYRSPFSRVHLYRNGK, 200 μg; Cat# S-PEP, Scrum) emulsified with complete Freund's adjuvant (CFA; Cat# D614-0050, RCK) was administered subcutaneously to mice at two sites on the dorsal flank on days 0 and 2. Simultaneously with MOG immunization, pertussis toxin (600 ng; Cat# 516560-50UGCN, Merck) was administered intraperitoneally.

[0101] The drugs (RR, SS, RS, and SR) were dissolved in a solvent (3% dimethyl sulfoxide (DMSO)) at 5 mg / kg and orally administered daily from day 10 after EAE induction (immunization). EAE symptoms were evaluated by clinical score (EAE score) and weight loss. Mice were weighed every 3 days, and the EAE score was evaluated daily for 28 days. The EAE score was evaluated based on the following criteria:

[0102] (EAE score criteria) 0, normal; 0.5, partial tail droop; 1, complete tail droop; 1.5, abnormal gait; 2, abnormal gait with hind limb weakness; 2.5, paralysis and weakness of one hind limb; 3, paralysis of both hind limbs; 3.5, paralysis of both hind limbs with hunched posture; 4, paralysis of both forelimbs and hind limbs; 5, moribund or dead.

[0103] The results of the EAE symptom evaluation are shown in Figure 1, and the results of body weight measurements are shown in Figure 2. In Figures 1 and 2, "dpi" refers to days post-immunization. Administration of the SS, RR, or RS isomer significantly suppressed EAE scores compared to the control (vehicle) (two-way ANOVA, ****P < 0.0001, **P < 0.01). The suppressive effect of administration of the RR or RS isomer on EAE scores was greater than that of the SS isomer. Administration of the SR isomer did not significantly suppress EAE scores compared to the control. Furthermore, administration of the RS isomer significantly suppressed weight loss compared to the control (vehicle) (two-way ANOVA, ***P < 0.001). The EAE score results indicated that, among the optical isomers of clemastine, administration of the RR or RS isomer was more effective in suppressing EAE symptoms. The suppression (improvement) of EAE symptoms indicates the suppression (improvement) of myelin breakdown in the demyelination model due to the myelination-promoting effect of the administered drug. These results confirmed that the RS and RR enantiomers of clemastine have promyelination-promoting effects. This indicates that the R-isomer, 1-(4-chlorophenyl)-1-phenylethane-1-ol, which shares the same skeleton as the RS and RR isomers, is important for promoting myelination. Furthermore, weight loss is known to occur as EAE symptoms progress. Since weight loss was suppressed only when the RS isomer was administered, the RS isomer is considered to have a particularly strong promyelination effect.

[0104] Example 3 Synthesis of Novel Compounds Using 1-(4-chlorophenyl)-1-phenylethane-1-ol as a Lead Compound In this example, 2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1,4-dimethylpiperazine oxalate (YK-314), 2-(((R)-1-(4-chlorophenyl)-1-phenylethoxy)methyl)-1-methylpyrrolidine oxalate (YK-321), and 2-(3-((R)-1-(4-chlorophenyl)-1-phenylethoxy)propyl)-1-methylpyrrolidine (YK-325) were synthesized.

[0105] (Synthesis of 2-(2-chloroethyl)-1,4-dimethylpiperazine) The outline of the synthesis is shown below.

[0106]

[0107] Compound 4 (200 mg, 1.26 mmol) and thionyl chloride (2 mL, 27.4 mmol) were placed in an argon-purged 10 mL vessel. The reaction solution was heated using a heat block and refluxed overnight. The reaction solution, from which a solid precipitated, was concentrated under reduced pressure to give 2-(2-chloroethyl)-1,4-dimethylpiperazine (hereinafter sometimes referred to as "compound 4-Cl") as a white solid (228 mg, 102% yield). This was used in the next step without further purification.

[0108] (Synthesis of 2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1,4-dimethylpiperazine oxalate (YK-314)) The outline of the synthesis is shown below.

[0109]

[0110] The synthesis is described in detail below. A 10-ml vessel purged with argon was charged with compound (R)-1 (100 mg, 0.430 mmol), compound 4-Cl (145 mg, 0.581 mmol) obtained in the previous step, and toluene (2 ml), and 90% NaNH (70 mg, 1.590 mmol) was added. The reaction mixture was heated under reflux for 4 hours. After cooling to room temperature, ethyl acetate (10 ml) and H O (10 ml) were added, and the organic layer was separated. The organic layer was dried over Na SO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel chromatography (heptane / ethyl acetate = 100 / 0 to 95 / 5) to give 2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1,4-dimethylpiperazine (hereinafter sometimes referred to as "compound 5") as a colorless oil (111 mg, 69% yield). The MTBE (1 Oxalic acid (27 mg, 0.295 mmol) was added to a solution of 1 ml of hexane and stirred for a while. The precipitated solid was collected by filtration. After drying under reduced pressure at room temperature overnight, 2-(2-((R)-1-(4-chlorophenyl)-1-phenylethoxy)ethyl)-1,4-dimethylpiperazineoxalate (sometimes referred to as "compound YK-314") was obtained as a white solid (87 mg, yield 53%, compound purity measured by HPLC 95%). The spectral data and HPLC analysis results of the product are shown below.

[0111] MS m / z 373,375[(M+1)-oxalic acid, (M+3)-oxalic acid]; HPLC purity measurement (Analysis conditions LC-2040C: column: YMC-Triart C18, 3μm, 4.6× 75mm, oven: 40℃, Flow rate: 1.5 mL / min, solvent A: 10mM K2HPO4 aq. (pH7.0)+5% MeCN, solvent B : MeCN, 0 min (B:0), 0-28.0min (B: 79), 28.0-34.0min(B: 79), 34.0-34.1min (B: 0), 34.1-37.0min (B: 0)) RT 21.18min_96.1% (YK-314).

[0112] (Synthesis of 2-(((R)-1-(4-chlorophenyl)-1-phenylethoxy)methyl)-1-methylpyrrolidine oxalate (YK-321)) The outline of the synthesis is shown below.

[0113]

[0114] The synthesis is described in detail below. A 10 ml vessel purged with argon was charged with compound (R)-1 (100 mg, 0.430 mmol), compound 6-Cl (90 mg, 0.516 mmol) shown in the schematic diagram above, and toluene (2 ml), followed by the addition of 90% NaNH2 (40 mg, 0.988 mmol). The reaction mixture was heated under reflux for 4 hours. After cooling to room temperature, ethyl acetate (10 ml) and H2O (10 ml) were added, and the organic layer was separated. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel chromatography (heptane / ethyl acetate = 100 / 0 to 95 / 5). The oil obtained after concentration was repurified by silica gel chromatography (chloroform / methanol = 100 / 0 to 95 / 5) to give 2-(((R)-1-(4-chlorophenyl)-1-phenylethoxy)methyl)-1-methylpyrrolidine (hereinafter sometimes referred to as "Compound 7") as a colorless oil (78 mg, 55% yield). Oxalic acid (20 mg, 0.233 mmol) was added to a solution of the obtained Compound 7 in EtO (1 mL) and stirred for a while. The mixture was concentrated under reduced pressure, and the precipitated solid was dried under reduced pressure at room temperature overnight to give 2-(((R)-1-(4-chlorophenyl)-1-phenylethoxy)methyl)-1-methylpyrrolidineoxalate (hereinafter sometimes referred to as "Compound YK-321") as a white solid (77 mg, 81% yield, compound purity measured by HPLC: 95%). The spectral data and HPLC analysis results of the product are shown below.

[0115] MS m / z 330, 332[(M+1)-oxalicacid, (M+3)-oxalic acid];HPLC purity measurement (Analysis conditions LC-2040C column: YMC-Triart C18, 3μm, 4.6 × 75mm, oven: 40℃, Flowrate: 1.5 mL / min, solvent A: 10mM K2HPO4 aq. (pH 7.0)+5% MeCN, solvent B :MeCN, 0 min (B:0), 0-28.0min (B: 79), 28.0-34.0min (B: 79), 34.0-34.1min (B:0), 34.1-37.0min (B: 0)) RT 21.78 min_95.7% (YK-321).

[0116] (Synthesis of 2-(3-((R)-1-(4-chlorophenyl)-1-phenylethoxy)propyl)-1-methylpyrrolidine (YK-325)) The outline of the synthesis is shown below.

[0117]

[0118] The synthesis is described in detail below. A 10 ml vessel purged with argon was charged with compound (R)-1 (210 mg, 0.908 mmol), compound 8-Cl (90 mg, 0.454 mmol) shown in the schematic diagram above, and toluene (2 ml), followed by the addition of 90% NaNH2 (70 mg, 1.590 mmol). The reaction mixture was heated under reflux for 48 hours. After cooling to room temperature, ethyl acetate (10 ml) and H2O (10 ml) were added, and the organic layer was separated. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by NH silica gel chromatography (heptane / ethyl acetate = 100 / 0 to 80 / 20). The oil obtained after concentration was repurified by silica gel chromatography (chloroform / methanol = 100 / 0 to 90 / 10) to give 2-(3-((R)-1-(4-chlorophenyl)-1-phenylethoxy)propyl)-1-methylpyrrolidine (free form) (sometimes referred to as "compound YK-325") as a colorless oil (18 mg, 10% yield, 95% purity measured by HPLC). The spectral data and HPLC analysis results of the product are shown below.

[0119] MS m / z 358,360[(M+1), (M+3)]; HPLC purity measurement (HPLC conditions LC-2040C, column: YMC-Triart C18, 3μm, 4.6 × 75mm, oven: 40℃, Flow rate: 1.5 mL / min, solvent A: 10mM K2HPO4 aq. (pH 7.0)+5% MeCN, solvent B : MeCN, 0min (B:0), 0-28.0min (B: 79), 28.0-34.0min (B: 79), 34.0-34.1min (B: 0),34.1-37.0min (B: 0)) RT 21.92 min_95.2% (YK-325).

[0120] Example 4 Evaluation of the Effects of Drug Administration on Experimental Autoimmune Encephalomyelitis (EAE) Model Mice (2) In this example, symptoms of drug administration were evaluated using EAE model mice.

[0121] EAE model mice were prepared using the same procedure as in Example 2. The drug (YK-321) was dissolved in a solvent (3% dimethyl sulfoxide (DMSO)) at 5 mg / kg and orally administered daily from day 10 after EAE induction (immunization). EAE symptoms were evaluated using a clinical score (EAE score). The EAE score was evaluated daily for 22 days. The EAE score was evaluated based on the same criteria as in Example 2.

[0122] The results of the evaluation of EAE symptoms are shown in Figure 3. When YK-321 was administered, the EAE score was suppressed compared to the control (vehicle) group. These results confirmed that YK-321 has the effect of promoting myelination.

[0123] Example 5: Evaluation of myelination-promoting activity In this example, the myelination-promoting activity of drugs (RR, SS, RS, and SR) was evaluated in vitro using primary cultures of mouse oligodendrocyte precursor cells (OPCs). The outline of the evaluation method is shown in Figure 4(A).

[0124] Mouse primary OPCs were isolated as follows. First, whole brains were removed from anesthetized 1-day-old mice. The cortex was isolated, the meninges were removed, and the cortex was minced to prepare a cell suspension. The suspension was digested with 0.25% trypsin-EDTA (ThermoFisher) for 15 minutes and then suspended in high-glucose DMEM medium (Nacalai Tesque, Inc.) supplemented with L-glutamine and sodium pyruvate, 10% fetal bovine serum (FBS, Nichirei Biosciences, Inc.), and 0.1% penicillin-streptomycin (Nacalai Tesque, Inc.). The cells were gently dissociated with a Pasteur pipette. The resulting cell suspension was filtered through a 70 μm cell strainer and centrifuged at 800 × g for 5 minutes at room temperature. The resulting pellet was resuspended in DMEM containing 10% FBS and transferred to a 75 cm plate coated with ε-poly-L-lysine (Fujifilm Corporation). 2The cells were seeded into a flask (DIV 0; hereafter, DIV refers to the number of days after the start of culture). They were then cultured statically in a 37°C CO2 incubator, with medium changes every three days. On DIV 7, the flask was pre-shaked at 220 rpm at 37°C for 1 hour to remove microglia. After shaking, the medium was replaced with a new one and the flask was placed in a 5% CO2 incubator for 5 hours. To recover OPCs, the flask was then shaken at 260 rpm at 37°C for 12 hours, and the floating cells in the resulting supernatant were collected. The collected cell suspension was seeded into a Petri dish and placed in a 5% CO2 incubator for 3 hours. After the incubation, the supernatant was filtered through a 70 μm filter and centrifuged at 1000 × g at room temperature. The resulting pellet was suspended in DMEM / F12 medium supplemented with 2 mM GlutaMAX (Thermo Fisher), 1% N-2 Supplement (Thermo Fisher), 2% B27 (Thermo Fisher), 20 ng / mL FGF (Fujifilm), and 20 ng / mL PDGF (Sigma) and plated onto ε-poly-L-lysine-treated dishes (Day 8). Cells were then cultured statically in a CO2 incubator at 37°C, with half of the medium replaced every 2–3 days. On Day 14, various drugs (RR, SS, RS, and SR) were added at 1 μM in 10 nM DMSO, and the cells were harvested 72 hours later. Expression levels of the myelin marker myelin basic protein (MBP) and control β-actin were measured by qPCR.

[0125] As a result, the expression level of MBP increased when the RR and RS forms were added, whereas the expression level of MBP did not increase when the SS and SR forms were added (Fig. 4B). More specifically, when the RR or RS form was administered, the expression level of MBP (ratio to β-actin) was approximately two-fold higher than that of the control (vehicle) ( ＊ p<0.05).

[0126] Example 6 Evaluation of Histamine H1 Receptor (HRH1) Antagonist Activity In this example, the in vitro HRH1 antagonist activity of drugs (RR, SS, RS, and SR forms) was evaluated.

[0127] A reporter assay was performed using the human HRH1 antagonist activity evaluation system from Tanso Biosciences' GPCR contract testing (Cosmo Bio Co., Ltd.) employing the measurement principle described in WO 2020 / 026979. Reporter cells prepared by Tanso Biosciences were cultured in high-glucose DMEM medium (containing L-glutamine and sodium pyruvate, Nacalai Tesque) supplemented with 10% fetal bovine serum (FBS, Nichirei Biosciences) and 1% penicillin-streptomycin (Nacalai Tesque). Cells were released using trypsin-EDTA and suspended in DMEM containing 10% dialyzed FBS. The suspended cells were seeded at 24,000 cells per well into a 96-well clear microplate (Greiner Bio-One). The cells were incubated overnight at 37°C under 5% CO2 conditions to allow them to adhere to the microplate bottom. After incubation, cells were transiently transfected with a plasmid encoding HRH1 and a luciferase reporter (100 ng / well total) constructed by Tanso Biosciences using FuGENE 6 transfection reagent (Promega). After transfection, cells were again cultured overnight at 37°C under 5% CO2 conditions before treatment with test compounds (RR, SS, RS, and SR). To evaluate antagonist activity (n=2), test compound solutions were added to each well at the desired final test concentrations (10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 100 pM, and 10 pM). Following test compound addition, standard agonist solutions were immediately added to each well at a final concentration of EC80, and cells were stimulated for 6 hours in a 37°C, 5% CO2 incubator. After stimulation, the medium was aspirated, and luciferase quantification reagent (Steady-Glo, Promega) was added to each well. Luciferase luminescence (RLU) was measured using a plate reader (Victor Nivo, PerkinElmer Japan). Data analysis was performed using the Python scientific calculation library Scipy. The concentration-dependent measurement results were approximated to the Hill equation using the nonlinear least-squares method, and parameter estimation was performed according to the following equation:Reporter activity = {(Curve top - Curve bottom) x Conc. Hill / (Conc Hill +IC50 Hill ) + Curve bottom

[0128] A concentration-response curve showing the relationship between reporter activity and test compound concentration was constructed based on the luciferase luminescence units (RLU) measured for each concentration of test compound and the solvent control in the presence of a standard agonist (Figure 5). In Figure 5, "●" indicates the measured activity of each concentration of test compound, and "◆" indicates the measured activity of the solvent control. The results of parameter estimation using nonlinear least squares are shown in Table 1. As shown in Table 1, the RS isomer had a higher IC50 and lower HRH1 antagonist activity than the RR isomer. This suggests that the RS isomer is expected to have fewer side effects, such as drowsiness and fatigue, than the RR isomer.

[0129]

[0130] The present invention can provide compounds useful as active ingredients for therapeutic agents for myelination-related diseases, and therapeutic agents for myelination-related diseases. Furthermore, the screening method of the present invention can screen for active ingredients for therapeutic agents for myelination-related diseases.

Claims

1. A compound represented by the following formula (1), (2), (3) or (4) (excluding clemastine and its optical isomers) or a pharmacologically acceptable salt thereof. (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form).

2. Z １ is the following formula (A1) or (B), and Z ２ is the following formula (C), and Z ３ is the following formula (D), and Z ４ The compound according to claim 1, or a pharmacologically acceptable salt thereof, wherein: (In the formula, R １ is alkyl; X １ is carbon or a heteroatom; each R ２ are independently selected from the list including H, alkyl, =O; n １ is either 0 or 1.) (In the formula, R ３ is alkyl; X ２ and X ３ are each nitrogen or carbon; n ２ is 0.) (where n ３ is 0, 1 or 2; m １ is 1 or 2; R ４ is an alkyl group. (where n ４ is 0, 1 or 2; m ２ is 0 or 1; １ is 1 or 2; R ５ is an alkyl group. (where n ６ is 1 to 4; each R ６ are independently selected from the list including H, alkyl groups. (In formula (F), X ４ is a complex number. In formula (G), R ７ and R ８ are each H or an alkyl group.

3. Formula (A1) is selected from the following list: Formula (B) is selected from the list below: Formula (C) is selected from the list below: Formula (D) is selected from the list below; and Formula (E), (F) or (G) is selected from the following list: The compound according to claim 2 or a pharmacologically acceptable salt thereof.

4. A compound represented by any one of the following formulas (6) to (8) or a pharmacologically acceptable salt thereof: (In formulas (6) to (8), (R) represents an asymmetric carbon atom in the R configuration.) 5. A therapeutic agent for myelination-related diseases, comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.

6. A therapeutic agent for myelination-related diseases, comprising, as an active ingredient, a compound represented by the following formula (5) or a pharmacologically acceptable salt thereof: (In the formula, (R) represents an asymmetric carbon atom in the R configuration.) 7. The therapeutic agent according to claim 5, wherein the myelination disorder-related disease is one or more selected from the group consisting of demyelinating diseases and psychiatric disorders.

8. The therapeutic agent according to claim 7, wherein the demyelinating disease is any one or more selected from the group consisting of multiple sclerosis, Charcot-Marie-Tooth disease, diffuse sclerosis, generalized sclerosis, encephalitis, acute disseminated encephalomyelitis, acute cerebellitis, transverse myelitis, acute polyradiculitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Marchifava-Bignami disease, central pontine myelinolysis, central corpus callosum demyelination, neuromyelitis optica, Devic's disease, Barrow's disease, HIV myelopathy, HTLV myelopathy, progressive multifocal leukoencephalopathy, secondary demyelinating disease, subacute necrotizing myelitis, and adrenoleukodystrophy.

9. The therapeutic agent according to claim 7, wherein the mental disorder is one or more selected from the group consisting of dementia, schizophrenia, alcohol use disorder, depression, bipolar disorder, anxiety disorder, impulsive disorder, bulimia, panic disorder, social anxiety disorder, insomnia, attention deficit hyperactivity disorder (ADHD), personality disorder, dissociative disorder, sleep apnea syndrome, and fibromyalgia.

10. A method for producing a compound represented by the following formula (1), (2), (3) or (4) or a pharmacologically acceptable salt thereof, characterized in that (R)-1-(4-chlorophenyl)-1-phenylethane-1-ol and / or its chemically modified form is used as a starting material. (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form).

11. A method for screening for active ingredients of therapeutic agents for myelination-related diseases, comprising using a test compound synthesized and / or designed using the R-isomer 1-(4-chlorophenyl)-1-phenylethane-1-ol as a lead compound and selecting compounds by one or more methods selected from the following 1) to 3): 1) adding the test compound to oligodendrocytes and culturing them, measuring the expression level of an oligodendrocyte marker in the cultured oligodendrocytes, and selecting a compound that increases the expression level of the oligodendrocyte marker compared to oligodendrocytes to which the test compound is not added; 2) collecting test samples from subjects, excluding humans, to which the test compound has been administered, measuring the expression level of an oligodendrocyte marker in the test samples, and selecting a compound that increases the expression level of the oligodendrocyte marker compared to subjects to which the test compound has not been administered; 3) selecting a compound that shows improvement, alleviation, mitigation, and / or suppression of symptoms caused by myelination in subjects, excluding humans, to which the test compound has been administered, compared to subjects to which the test compound has not been administered.

12. The screening method according to claim 11, wherein the test compound is a compound represented by the following formula (1), (2), (3) or (4) (excluding clemastine) or a pharmacologically acceptable salt thereof: (In the formula, Z １ are independently selected from the list including aliphatic heterocycles, aromatic heterocycles; Z １ The moiety excluding the above has an R configuration at least at the asymmetric carbon atom (optical isomer R form). (In the formula, Z ２ is independently selected from the list including an aliphatic heterocycle attached to the right moiety through an oxygen and having an alkyl side chain leading to said oxygen; Z ２ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ３ is independently selected from the list comprising an aliphatic heterocycle attached to oxygen through an alkyl side chain; Z ３ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form). (In the formula, Z ４ is independently selected from the list consisting of -N(CH3)2 and an aliphatic heterocycle bonded via a nitrogen in the aliphatic heterocycle; n ５ is 1, 2 or 3; Z ４ The configuration at at least the asymmetric carbon atom is the R configuration (optical isomer R form).

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