WO2019044844A1 - NOVEL Sin3 MODULATOR AND MEDICAL APPLICATION THEREOF - Google Patents

Abstract

The present invention provides a drug for the prevention and/or treatment of mental illness, the drug including as an active ingredient a Sin3 modulator, in particular the following compound or a pharmacologically acceptable salt thereof. This drug for the prevention and/or treatment of mental illness is especially useful in mental illnesses such as ASD, depression, and epilepsy.

Description

Novel Sin3 Modulator and Its Pharmaceutical Use

The present invention relates to agents useful for the prevention and / or treatment of mental disorders.

Mental illness is thought to be caused by the complex interaction of many genetic factors and environmental factors, but its molecular level mechanism is still largely unknown, and the effect of drug treatment is not necessarily sufficient. There is also.
For example, in autistic spectrum disorder / autism spectrum disorder (hereinafter abbreviated as ASD), which is a type of developmental disorder, there is no drug effective for the prevention and treatment of its core symptoms, and effective prevention and treatment drugs are strongly desired It is rare.
Depression is a type of psychiatric disorder referred to as mood disorder, and the existing antidepressants have a long time to onset of action, and about 30% of patients who are ineffective for antidepressants have There is a strong demand for novel antidepressants that are effective in patients with early antidepressants and conventional antidepressants (treatment resistant depression).
In addition, epilepsy is a disease that causes “epileptic seizures” repeatedly, such as sudden loss of consciousness and loss of response, and there are currently various drugs as anti-epileptic drugs, but patients with intractable epilepsy do not improve There is ~ 30%. There is a strong demand for novel antiepileptic drugs that are effective for patients with intractable epilepsy.

Although therapeutic agents for various drug discovery targets have been developed, epigenetic mechanisms may be considered to be involved in the onset of psychiatric disorders considered to be “complex genetic disorders”, and thus innovative (conventional mechanisms The present situation is that development of an effective drug has not been achieved).

Specific action targets include the nuclear protein NRSF (Neuron-Restrictive Silencer Factor, aka REST (RE1-Silencing Transcription Factor)) responsible for transcriptional regulation of many nerve-specific genes, and transcription that specifically binds to NRSF Sin3 proteins are known as corepressors (Non-patent Documents 1 and 2).
Although there have been reports that Sin 3 regulators (modulators) are effective for fibromyalgia and analgesia (Patent Document 1), reports that it is effective for psychiatric disorders, particularly ASD, depression and epilepsy It has not been done.

WO2014 / 088106A1

The present invention aims to provide a preventive and / or therapeutic drug for mental diseases, particularly useful for mental diseases such as ASD, depression and epilepsy and having a new mechanism of action different from existing drugs. I assume.

In view of the above problems, the present inventors firstly focus on the binding between NRSF and Sin3, search for compounds that inhibit (control) the binding, and further use animal models for various mental diseases of the compounds. The effect of the present invention was confirmed to complete the present invention.
That is, the gist of the present invention is as follows.
[1] A preventive and / or therapeutic agent for a mental disease, which comprises a Sin3 modulator as an active ingredient.
[2] The prophylactic and / or therapeutic drug according to the above-mentioned [1], wherein the psychiatric disorder is autism spectrum disorder / autism spectrum disorder.
[3] The preventive and / or therapeutic agent according to the above-mentioned [1], wherein the psychiatric disorder is depression.
[4] The preventive and / or therapeutic agent according to the above-mentioned [1], wherein the psychiatric disorder is epilepsy.
[5] The prophylactic and / or therapeutic agent of the above-mentioned [1], wherein the Sin3 modulator is the following compound or a pharmaceutically acceptable salt thereof:

[6] An agent for the prophylaxis and / or treatment of a mental disorder comprising the following compound or a pharmaceutically acceptable salt thereof as an active ingredient:

[7] The prophylactic and / or therapeutic agent of the above-mentioned [6], wherein the psychiatric disorder is autism spectrum disorder / autism spectrum disorder.
[8] The preventive and / or therapeutic agent according to the above-mentioned [6], wherein the psychiatric disorder is depression.
[9] The preventive and / or therapeutic agent according to the above-mentioned [6], wherein the psychiatric disorder is epilepsy.
[10] The following compound or a pharmaceutically acceptable salt thereof.

[11] A preventive and / or therapeutic agent for a mental disease, which comprises administering an effective amount of the following compound or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[12] The method for prophylaxis and / or treatment according to the above-mentioned [11], wherein the psychiatric disorder is autism spectrum disorder / autism spectrum disorder.
[13] The method for prevention and / or treatment of the above-mentioned [11], wherein the psychiatric disorder is depression.
[14] The method for prevention and / or treatment of the above-mentioned [11], wherein the psychiatric disorder is epilepsy.
[15] The following compound or a pharmaceutically acceptable salt thereof for use in the prophylaxis and / or treatment of a mental disorder.

[16] The compound of the above-mentioned [15] or a pharmaceutically acceptable salt thereof, wherein the psychiatric disorder is autism spectrum disorder / autism spectrum disorder.
[17] The compound of the above-mentioned [15] or a pharmaceutically acceptable salt thereof, wherein the mental disease is depression.
[18] The compound of the above-mentioned [15] or a pharmaceutically acceptable salt thereof, wherein the psychiatric disorder is epilepsy.

Since the compound of the present invention and the drug containing the compound are effective for various psychiatric disorders (ASD, depression, epilepsy, etc.) by an action mechanism different from that of the existing therapeutic agents, the effect which can not be obtained with the existing therapeutic agents It can be expected, and it will be possible to eliminate the side effects that have been problematic with existing therapeutic agents.

FIG. 1 is a graph showing the results of Test Example 1. The effect of the compound of Example 1 on social behavioral disorder (A) and cognitive dysfunction (B) of fetal valproic acid-administered mice is shown. FIG. 2 is a graph showing the results of Test Example 1. The effect of the compound of Example 1 on hyperalgesia and allodynia (allodynia) of fetal valproic acid-administered mice is shown. (A) shows the result of the hot plate test, (B) shows the result of the Hong-Fly test, and (C) shows the result of the acetic acid writhing test. FIG. 3 is a graph showing the results of Test Example 2. Fig. 16 shows the effect of Example 1 compound in a forced swimming test using a corticosterone chronic administration mouse depression model. FIG. 4 is a graph showing the results of Test Example 2. FIG. 10 shows the effect of Example 1 compound on chronicia induced by corticosterone administration. FIG. 5 is a chart showing the results of Test Example 3 (NMR experiment). It is shown that the NMR peak shape of the compound of Example 1 changes in the presence of mSin3B PAH1 and GST fused mSin3B PAH1. The upper part shows the result of STD-NMR, the middle part shows the result of Waterlogsy measurement, and the lower part shows the result of 3919 Watergate measurement. FIG. 6 is a graph showing the results of Test Example 3 ( ¹ H- ¹⁵ N HSQC titration experiment). The ¹ H- ¹⁵ N HSQC spectrum of mSin 3 B PAH ¹ shows that the presence of the compound of Example 1 changes the chemical shift. FIG. 7A is a view showing the bonding structure of Example 1 compound and mSin3B PAH1. FIG. 7B is a view showing the combined structure of NRSF and mSin3B PAH1.

The present invention provides a preventive and / or therapeutic agent for a mental disease, which comprises a Sin3 modulator as an active ingredient. The details will be described below.

(Sin 3 modulator)
Sin3 is one of the scaffold proteins involved in the transcriptional regulatory mechanism, has no tissue specificity, is widely expressed, and is highly conserved from yeast to human. It has four PAH (paired amphipathic helix) domains and HDAC (Histone deacetylase) interaction domains that are different in binding partners, such as transcription factors, corepressors, and methylated CpG binding proteins. The PAH1 domain interacts with the transcriptional repressor NRSF at the most N-terminal of the four PAH domains. In the present invention, the “Sin3 modulator” is not particularly limited as long as it is a substance that can inhibit (control) this Sin3-NRSF interaction, and may be a low molecular weight compound or a high molecular weight compound. . Here, the low molecular weight compound is a compound having a molecular weight of less than about 1000, and includes, for example, organic compounds and derivatives thereof which can usually be used as pharmaceuticals, and compounds produced by utilizing organic synthesis methods etc. and derivatives thereof, natural A compound derived from it or its derivative, etc., desirably refers to an organic compound and its derivative that can be used as a medicine. The high molecular weight compound is a compound having a molecular weight of about 1000 or more, and includes proteins, polynucleic acids, polysaccharides, and combinations thereof.

The Sin3 modulator may be a pharmaceutically acceptable salt thereof. Such salts include, for example, trifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid Acid addition salts with acids such as acid, phosphonic acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid; eg, metal salts such as sodium, potassium, magnesium, calcium etc .; eg, trimethylamine, Examples thereof include salts with organic bases such as triethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine and the like.

When the Sin3 modulator has an isomer such as an optical isomer, stereoisomer, regioisomer, rotamer, etc., any one isomer or a mixture of isomers can be used as a Sin3 modulator in the present invention . For example, when an optical isomer is present in a Sin3 modulator, an optical isomer resolved from a racemate can also be used as a Sin3 modulator. Each of these isomers can be obtained as a single product by a synthesis method known per se, a separation method (concentration, solvent extraction, column chromatography, recrystallization etc.).

Sin3 modulators may be crystalline or amorphous. When the Sin3 modulator is a crystal, a single crystal or a mixture of crystal forms can be used as a Sin3 modulator in the present invention. The crystals can be produced by crystallization using a crystallization method known per se.

The Sin3 modulator may be a solvate (eg, hydrate etc.) or non-solvate, and both can be used as a Sin3 modulator of the present invention.

The Sin3 modulator may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) and the like.

As the Sin3 modulator used in the present invention, preferably the following formula

(Hereinafter, also referred to as a compound of the present invention).
The compounds of the present invention are novel compounds and can be produced, for example, by the method described in Example 1.

Sin3 modulators have an effect of improving mental diseases on mammals (eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.) by inhibiting Sin3-NRSF interaction. It is useful as an agent for preventing and / or treating various mental diseases (hereinafter also referred to as the agent of the present invention).

(Mental illness)
In the present invention, psychiatric disorders are defined as various diseases / symptoms as defined in Chapter 5, "Psychiatric and behavioral disorders" of "International Statistical Classification of Diseases and Related Health Problems" 10th Edition (ICD-10) and American Psychiatric Means the various diseases / symptoms defined in the “Diagnostic and Statistical Manual of Mental Disorders” 5th Edition (DSM-5) published by the Institute, and, further, Chapter 6 “Diseases of Nervous System” of ICD-10 It includes epilepsy defined by G40 and G41. The present invention is effective for diseases and conditions caused by Sin3-NRSF interaction among psychiatric diseases, and in particular, can exhibit excellent improving effects on ASD, depression and epilepsy.
"Autism spectrum disorder / autism spectrum disorder (ASD)" is classified into "neural developmental disorder group / neurodevelopmental disorder group" in DSM-5 which is a diagnostic standard of the American Psychiatric Association, and in ICD-10 F84, a disease that has been linked to pervasive developmental disorders (PDD), such as Asperger's syndrome, unspecific diffuse developmental disorders, childhood disintegration disorder (CDD), fragile X syndrome, Rett syndrome etc. It is an included concept. Its basic feature is a behavioral syndrome that appears by age 3 and is characterized mainly by the following core symptoms:
1. Persistent defects in social communication and social interaction Mode of limited, repetitive behavior, interest, or activity "Depression" means, in ICD-10, a disorder classified as F30-F39 "Mood [Emotional] disorder" and diagnosed by the American Psychiatric Association According to the standard DSM-5, it is included in the "depression disorder group" category. More narrowly means major depressive disorder, and if a major depressive episode can be confirmed in the medical history, a major depressive disorder is diagnosed, and if there is a mania episode, hypomania episode, or mixed episode, it is diagnosed as bipolar disorder Be done. However, in general, the term depression may mean major depressive disorder and dysthymic disorder, or it may mean mood disorder in general, and it is not always used in a defined manner. Thus, "depression" in the present invention includes all cases where a physician has diagnosed depression or depression. As used herein, the term "depression" is a concept that includes depression.
"Epileptic" is a chronic brain disease caused by various causes, characterized by repetitive seizures (epileptic seizures) derived from excessive firing of cerebral neurons, accompanied by various clinical symptoms and laboratory findings. Seizures are broadly divided into general seizures (tonic-clonic seizures, simple absence seizures, complex absence seizures, circumcision seizures, circumcision seizures, cataplexy seizures) and partial seizures (simple partial seizures, complicated partial seizures, secondary generalized seizures) However, any seizure can be the subject of the present invention.

The Sin 3 modulator is mixed with a pharmaceutically acceptable carrier, and is a solid preparation such as tablet, capsule, granule, powder, etc .; liquid preparation such as syrup, injection, etc .; patch, ointment, plaster, etc. It can be formulated suitably as a skin absorbent; an inhalation; a suppository. The content of the active ingredient Sin3 modulator in the preparation is usually about 0.01 to about 99.9% by weight, preferably about 0.1 to about 50% by weight, based on the whole preparation.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials can be used. Specifically, it includes an excipient in a solid preparation, a lubricant, a binder, a disintegrant, a solvent in a liquid preparation, a solubilizing agent, a suspending agent, a tonicity agent, a buffer, a soothing agent, etc. can do. Moreover, formulation additives such as preservatives, antioxidants, coloring agents, and sweeteners can also be used, if necessary.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate and the like.

Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, purified talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, sucrose, mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone and the like.

Examples of disintegrants include starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like.

Preferred examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like.

Preferred examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Examples of suspending agents include, for example, surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, etc .; polyvinyl alcohol, polyvinyl pyrrolidone, Carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like can be mentioned.

Preferred examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like.

Preferred examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.
Preferred examples of the soothing agent include benzyl alcohol and the like.

Preferred examples of preservatives include, for example, p-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferred examples of the antioxidant include sulfites, ascorbic acid and the like.
Preferred examples of the colorant include, for example, tar dyes, caramel, ferric oxide, titanium oxide, riboflavins and the like.
Preferred examples of sweetening agents include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.

The dosage of the preparation is age, body weight, general health condition, sex, diet, time of administration, method of administration, rate of excretion, type of Sin3 modulator used, combination of drugs, treatment of the patient at that time Depending on the degree of medical condition, it is decided in consideration of those or other factors.
For example, when the Sin3 modulator is the compound of the present invention, the preparation comprises about 1 to 100 mg / kg of body weight, preferably about 2 to 60 mg / kg of body weight, as a dose of the active ingredient Sin3 modulator, More preferably, it is preferable to administer about 5 to 40 mg / kg, more preferably about 10 to 30 mg / kg (body weight) in one or two to three divided doses.

EXAMPLES The present invention will be more specifically described below by Examples, Reference Examples and Test Examples, but the present invention is not limited thereto.
The measurement conditions of LC-MS are shown below.
Analyzer: Waters 2795
Column: Develosil C30-UG-5 (50 x 4.6 mm, Nomura Kagaku Co., Ltd.)
Solvent: Solution A = distilled water [containing 0.1% (v / v) formic acid]
Solution B = acetonitrile [containing 0.1% (v / v) formic acid]
Gradient conditions: 0 to 5 min. 5 to 100% (v / v) Solution B, 5 to 6 min. 100% (v / v) Solution B
Flow rate: 1 mL / min

Example 1
(1) Isopropyl (R) -1-((S) -1-((2,2-diethoxyethyl) (isopentyl) amino) -4- (methylthio) -1-oxobutan-2-ylamino) -1- Oxobutane-2-yloxycarbamate (S) -2-amino-N- (2,2-diethoxyethyl) -N-isopentyl-4- (methylthio) butanamide (the compound of Reference Example 3: 2.9 g, 8. 66 mmol) and (R) -2- (isopropyloxycarbonylaminooxy) butyric acid (the compound of Reference Example 10: 1.78 g, 8.67 mmol) were dissolved in methanol (50 mL), N-methylmorpholine (0.87 g, 8.6 mmol) and 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) chloride 4-methylmorpholinium chloride (DMT-MM, 3.6 g, 1 3.0 mmol) was added and the mixture was left at room temperature overnight. The reaction mixture was concentrated under reduced pressure and ethyl acetate (80 ml) was added. The organic phase was washed with brine, 10% aqueous citric acid and aqueous sodium bicarbonate, dried over sodium sulfate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate mixed solvent, ethyl acetate concentration 20% to 50% gradient) to give the title compound (colorless oil, 3.33 g, yield 74%). TLC (silica gel, developing solvent hexane: ethyl acetate = 1: 1), Rf = 0.52 (phosphormodenic acid heated color)
(2) (3R, 6S, 9aS) -isopropyl 3-ethyl-8-isopentyl-6- (2- (methylthio) ethyl) -4,7-dioxohexahydropyrazino [2,1-c] [1 , 2,4] Oxadiazine-1 (6H) -carboxylate (Example 1 compound)
Isopropyl (R) -1-((S) -1-((2,2-diethoxyethyl) (isopentyl) amino) -4- (methylthio) -1-oxobutan-2-ylamino) -1-oxobutane-2 -Formic acid (35 ml) was added to yloxycarbamate (3.33 g, 6.38 mmol) and left at room temperature overnight. The formic acid is distilled off under reduced pressure, and the residue is purified by silica gel chromatography (hexane-ethyl acetate mixed solvent, ethyl acetate concentration 20% to 50% gradient) to give the title compound (colorless oil, 2.03 g, yield) 74%). TLC (silica gel, developing solvent hexane: ethyl acetate = 1: 1), Rf = 0.63 (phosphomolybdic acid heated color)
LC-MS: RT = 4.75 min. Obs MS m / z = 430 (M + 1) ⁺

Reference Example 1
N- (2,2-diethoxyethyl) -3-methylbutan-1-amine 2-bromo-1,1-diethoxyethane (39.4 g, 0.2 mol) and 3-methylbutan-1-amine (52. Potassium carbonate (55.3 g, 0.4 mol) was added to a solution of 2 g (0.6 mol) in acetonitrile (300 mL), and the mixture was heated in an oil bath at 80 ° C. for 30 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to vacuum distillation to give the title compound (colorless oil, 34.4 g, yield 84%) as a fraction having a boiling point of 100-102 ° C. (1200 Pa). TLC (silica gel, developing solvent chloroform: methanol = 10: 1) Rf = 0.68 (iodine color)

Reference Example 2
(S)-(9H-fluoren-9-yl) methyl 1-((2,2-diethoxyethyl) (isopentyl) amino) -4- (methylthio) -1-oxobutan-2-ylcarbamate N- (2 , 2-Diethoxyethyl) -3-methylbutan-1-amine (Compound of Reference Example 1: 4.28 g, 21.0 mmol) and (S) -2-((((9H-fluoren-9-yl) methoxy) Dissolve carbonylamino) -4- (methylthio) butyric acid (7.43 g, 20.0 mmol) in dichloromethane (50 mL), add diisopropylethylamine (5.68 g, 44 mmol) and (1- [bis (dimethylamino) under ice-cooling ) Methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium-3-oxide hexafluorophosphate (HATU, 9.1 g 24 mmol) was added and stirred overnight at room temperature The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue The organic phase was washed with brine, 10% aqueous citric acid, aqueous sodium bicarbonate and dried over sodium sulfate The residue was purified by silica gel chromatography (hexane-ethyl acetate mixed solvent, ethyl acetate concentration: 10% to 35% gradient) to give the title compound (colorless oil, 10.9 g, yield 98%). TLC (silica gel, developing solvent hexane: ethyl acetate = 2: 1) Rf = 0.51 (ultraviolet light color development)

Reference Example 3
(S) -2-Amino-N- (2,2-diethoxyethyl) -N-isopentyl-4- (methylthio) butanamide (S)-(9H-fluoren-9-yl) methyl 1-((2,2, Dissolving 2-diethoxyethyl) (isopentyl) amino) -4- (methylthio) -1-oxobutan-2-ylcarbamate (the compound of Reference Example 1: 10.9 g, 19.6 mmol) in dichloromethane (100 mL), Piperidine (8.51 g, 100 mmol) was added and left at room temperature overnight. The reaction mixture is concentrated, and the residue is purified by silica gel chromatography (first, hexane / ethyl acetate mixed solvent, ethyl acetate concentration 20% to 30% gradient, then chloroform / methanol mixed solvent, methanol concentration 0% to 20% gradient) The title compound (colorless oil, 3.60 g, yield 55%) was obtained. TLC (silica gel, developing solvent chloroform: methanol = 10: 1) Rf = 0.46 (ninhydrin heated color)

Reference Example 4
(S) -2-Acetoxybutyric acid Acetyl chloride was added to (S) -2-hydroxybutyric acid (35 g, 340 mmol) under ice-cooling, and the mixture was then heated to reflux at 60 ° C. for 4 hours. The excess acetyl chloride was distilled off under reduced pressure and diethyl ether was added. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (colorless oil, 42 g, yield 85%). TLC (silica gel, developing solvent petroleum ether: ethyl acetate: acetic acid = 10: 1: 0.1) Rf = 0.8 (phosphomolybdic acid heated color)

Reference Example 5
(S) 2-Acetoxybutyric acid tert-butyl (S) 2-acetoxybutyric acid (the compound of Reference Example 4: 42 g, 288 mmol) in solution of tert-butyl alcohol in dichloromethane (400 mL) 4-dimethylaminopyridine (DMAP, 17 g, 140 mmol) were added. Next, a solution of dicyclohexylcarbodiimide (DCC, 85 g, 438 mmol) in dichloromethane (250 mL) was added under ice cooling. The reaction mixture was stirred at room temperature overnight. The urea compound formed is filtered off and the organic phase is washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether-ethyl acetate mixed solvent, ethyl acetate concentration 4%) to give the title compound (yellow oil, 46 g, yield 80%). TLC (silica gel, developing solvent petroleum ether: ethyl acetate = 10: 1), Rf = 0.8 (phosphomolybdic acid heated color)

Reference Example 6
(S) 2-hydroxybutyric acid tert-butyl potassium carbonate (20.1 g, 146 mmol) is dissolved in methanol (56 mL) and water (80 mL), and (S) 2-acetoxybutyric acid tert-butyl (Reference Example 5) Compound: 10 g, 49 mmol) was added. The solution was vigorously stirred at room temperature overnight. The methanol was evaporated under reduced pressure and extracted twice with dichloromethane to give the title compound (white solid, 5 g, yield 64%). TLC (silica gel, developing solvent petroleum ether: ethyl acetate = 10: 1), Rf = 0.6 (phosphomolybdic acid heated color)

Reference Example 7
(R) -2- (1,3-dioxoisoindoline-2-yloxy) butyric acid tert-butyl (S) -2-hydroxybutyric acid tert-butyl (compound of Reference Example 6: 1.86 g, 11.6 mmol) , N-hydroxyphthalimide (1.89 g, 11.6 mmol) and triphenylphosphine (3.04 g, 11.6 mmol) were dissolved in anhydrous tetrahydrofuran (30 mL), and diethyl azodicarboxylate (2 mL, 12) was cooled with ice cooling. .7 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was concentrated under reduced pressure. Dichloromethane and water were added to the reaction mixture and stirred, and the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate mixed solvent, ethyl acetate concentration 3%) to give the title compound (white solid, 2.5 g, yield 72%). TLC (silica gel, developing solvent petroleum ether: ethyl acetate = 10: 1), Rf = 0.4 (phosphomolybdic acid heated coloring)

Reference Example 8
(R) -2- (Aminooxy) butyric acid tert-butyl (R) -2- (1,3-dioxoisoindolin-2-yl) butyric acid tert-butyl (the compound of Reference Example 7: 2.5 g, 8 2 mmol) was dissolved in methanol (20 mL), hydrazine hydrate (1.7 mL, 25 mmol) was added, and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 3% aqueous sodium bicarbonate solution (10 mL) and ether were added and stirred. The organic phase is dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane-dichloromethane mixed solvent, dichloromethane concentration 30%) to give the title compound (colorless oil, 1 g, yield 70%). TLC (silica gel, developing solvent petroleum ether: dichloromethane = 1: 2), Rf = 0.3 (phosphomolybdic acid heated color)

Reference Example 9
(R) -2- (Isopropyloxycarbonylaminooxy) butyric acid tert-butyl (R) -2- (aminooxy) butyric acid tert-butyl (a compound of Reference Example 8: 7.0 g, 40 mmol) in acetonitrile (20 mL) Pyridine (6.3 g, 80 mmol) was added to the solution, and isopropyl chloroformate (5.88 g, 48 mmol) was further added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and ethyl acetate (80 ml) was added. The organic phase was washed with 10% aqueous citric acid and aqueous sodium bicarbonate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate mixed solvent, ethyl acetate concentration: 0% to 30% gradient) to give the title compound (colorless oil, 10.4 g, quantitative yield). TLC (silica gel, developing solvent hexane: ethyl acetate = 4: 1), Rf = 0.58 (phosphomolybdic acid heated color)

Reference Example 10
(R) -2- (isopropoxycarbonylaminooxy) butyric acid (R) -2- (isopropoxycarbonylaminooxy) butyric acid tert-butyl (compound of Reference Example 10: 10.45 g, 40 mmol) in formic acid (50 ml) Was left overnight. The formic acid was evaporated under reduced pressure to give the title compound (white solid, 8.45 g, quantitative yield).

Test Example 1 Evaluation of pharmacological actions using fetal valproic acid-administered ASD model mice Mice exposed to valproic acid at 12.5 days of gestational age are widely recognized as highly relevant ASD (Autistic Spectrum Disorder) models There is. In this mouse, social behavioral disorder, novel object recognition disorder, abnormal pain sensitivity, etc. are observed. Therefore, using the present mouse, the improving effect on social behavior disorder, novel object recognition disorder, pain sensitivity disorder (hot plate test, Hong fly test, acetic acid writhing test) by administration of the compound of the present invention was evaluated.

(1) Preparation of fetal valproic acid-administered ASD model mice: ICR 8-week-old male and female mice were treated under conditions of room temperature 22 ± 1 ° C. and illumination time 12 hours a day (8: 00-20: 00) Each group was fed with 5-6 animals per cage under an environment where food and water could be freely consumed in polycarbonate resin cages (24 cm × 17 cm × 12 cm). After acclimation to the breeding environment, vaginal fistulas were collected daily from 9-12 week-old female mice, and the sexual cycle was confirmed by Giemsa staining. The pre-estrus or estrus female mice were allowed to live together with 9-20 week old male mice only for one night, and were allowed to cross. The next day was defined as pregnancy day 0, and male offspring from the mouse were used for the experiment. To mice at 12.5 days of gestation, 500 mg / kg of sodium valproate was intraperitoneally administered (Kataoka et al., 2013; Takuma et al., 2014; Hara et al., 2016) (FIGS. 1 and 2) , VPA). Saline used as a solvent was intraperitoneally administered to the control group (Saline in FIGS. 1 and 2). Mother-infant separation was performed at 3 weeks of age, and was used for experiments after 8 weeks of age. The test compound was prepared by dissolving a drug solution dissolved in physiological saline so that the final concentration of DMSO is 8%, the final concentration of Soltol HS15 is 2%, and the concentration of test compound is 3 mg / mL. They were administered (30 mg / kg), and social activity tests and novel object recognition tests were performed at 10 weeks of age, and pain sensitivity tests were performed at 11 weeks of age. As a control for comparison, the same amount of a drug solution not containing the test compound was administered (in FIG. 1 and FIG. 2, Vehicle).

(2) Sociality behavior test It went to the light period (8: 00-20: 00) according to the method (2016) of Hara et al. In a soundproofing laboratory set to an illumination of 350 lux, place the test mouse in a polysulphone test cage (38 cm x 22 cm x 20 cm) containing a sterile wooden soft chip (Sankyo Lab Service Co., Ltd.) for 60 minutes. I got used to it. Then, male intrusive mice of the same strain and body weight that had not been encountered with the test mice were put in and videotaped for 20 minutes. The olfactory behavior (face sniff and ano-genital sniff) which the test mouse showed to the invading mouse was used as an index of social behavior, and the total time was measured.

(3) Novel Object Recognition Test The novel object recognition test was conducted at the light period (8: 00-20: 00) according to the method of Hara et al. (2016). First, in a soundproofing laboratory set to an illuminance of 30 lux, a test cage (30 cm x 30 cm x 35 cm) made of acrylic-modified polyvinyl chloride on which only a wooden sterile soft tip (Sankyo Lab Service Co., Ltd.) is laid The test mice were allowed to acclimate for 10 minutes for 3 consecutive days. Two different objects (objects a and b randomly select two from golf balls, Lego blocks, plastic cylinders and outlets) were placed at a distance of 8 cm from the wall on the fourth day and allowed to freely explore for 10 minutes (Training trial). Twenty-four hours later, the object b was freely searched for 5 minutes in a test cage in which the object c was replaced with the novel object, object c (test trial). The animal's behavior in training and testing trials was videotaped and the search time for each of the two objects was measured. The ratio (%) of the search time difference between the object c and the object a to the total search time in the test trial was calculated as a discrimination index.

(4) Social behavior test, novel object recognition test evaluation result Social behavior disorder and novel object cognitive dysfunction after maturation by valproic acid administration during fetal period are improved by chronic administration of a test compound (the compound of Example 1) Was done (Figure 1). From the above results, it is clear that the compound of Example 1 is effective against ASD-like behavioral abnormalities exhibited by fetal valproic acid-administered mice. In each group n = 12, data are expressed as mean value ± standard error. ** P <0.01 (Tukey-Kramer test was performed after two-way ANOVA)

(5) Hot plate test The hot plate test was performed in the light period (8: 00-20: 00) according to the method of Horiguchi et al. (2013a). The hot plate temperature of the apparatus (HOT / COLD PLATE; Model 35100; Ugo Basile, Italy) was set to 49 ± 0.5 ° C., and the test mouse was introduced gently. The pain response was the mouse's behavior of licking or jumping the hind limbs, and the time until the first response to any of the responses (evacuation response time) was measured. In order to prevent tissue damage due to heat stimulation, the cutoff value of the escape reaction time was set to 30 seconds.

(6) Hong Fly Test The Hong Fly test was conducted at the light period (8: 00-20: 00) according to the method of Horiguchi et al. (2013b). Place the mouse on a stainless steel mesh and cover it with an acrylic resin box (3.5 cm x 8.5 cm x 8.0 cm). After confirming that the locomotor activity has been alleviated, place the mouse vertically in the center of the foot of the footpad. Fly filaments (Touch-Test® Sensory Evaluators; North Coast Medical, CA, USA) were pressed until bent. Stimulation was sequentially applied from thick to thin filaments, and the minimum mechanical stimulation value of the filament causing the escape behavior was defined as the escape response threshold.

(7) Acetic Acid Rising Test The acetic acid rising test was conducted according to the method of Horiguchi et al. (2013a). The test mouse is placed in an acrylic resin cylinder (diameter 17 cm, height 24 cm), and after 30 minutes acclimation, peritoneal cavity with a volume of 10 mL / kg of 0.9% acetic acid (Wako Pure Chemical Industries, Ltd., Osaka) It was administered internally. The number of occurrences of writhing behavior (behind action of the abdomen, or action of twisting the body to extend the hind limbs) in 15 minutes after administration was measured.

(8) Hot plate test, Hong fly test, Acetic acid writhing test evaluation result Hyperalgesia and allodynia (hot plate test, Hong fly test, acetic acid writhing test) after maturation by administration of valproic acid in fetal period, the test compound (Example 1) Chronic administration of the compound (Figure 2). From the above results, it has become clear that the compound of Example 1 is effective against ASD-like abnormal pain sensitivity shown by fetal valproic acid-administered mice. In each group n = 12, data are expressed as mean value ± standard error. * P <0.05, ** P <0.01 (Tukey-Kramer test was performed after two-way ANOVA)

Test Example 2 Evaluation of pharmacological action using chronic administration of corticosterone depression model mice Chronic administration of corticosterone mimics increase in corticosterone secretion due to stress load and has HPA axis (hypothalamic-pituitary-adrenal axis) Depression model animals showing functional failure and considered to be treatment resistant depression model animals because they do not improve with existing antidepressants (tricyclic and SSRI (Selective Serotonin Reuptake Inhibitors)) .
As depression-like behavior, a forced swimming test widely used as a behavioral model that simulates despair is performed, and a female selectivity test is performed as a behavioral model that simulates annoyance (Anhedonia), and depression caused by administration of the compound of the present invention The improvement of symptoms was evaluated.

(1) Preparation of corticosterone chronic administration depression model mouse C57BL6 / J strain 5-week-old male mouse under conditions of room temperature 22 ± 1 ° C., illumination time 12 hours a day (8: 00-20: 00) The groups were reared in groups of 5-6 per cage under an environment where food and water could be freely consumed in a polycarbonate resin cage (24 cm × 17 cm × 12 cm). From 6 weeks of age, 20 mg / kg of corticosterone (in FIG. 3, in FIG. 4, CORT) was subcutaneously administered once daily for 3 weeks. The control group was subcutaneously administered a 0.5% (W / V) carboxymethylcellulose solution (vehicle in FIG. 3, 4) used as a solvent.
The test compound was prepared one week after chronic corticosterone administration of a drug solution dissolved in physiological saline so that the final concentration of DMSO is 8%, the final concentration of Soltol HS15 is 2%, and the concentration of test compound is 3 mg / mL. Thirty minutes prior to administration of costerone, it was intraperitoneally administered (10, 30 mg / kg) for 2 weeks, and behavioral tests were conducted 24 hours after the final administration.

(2) Forced swimming test The forced swimming test was conducted in the light period (8:00 to 20:00) according to the method of Ago et al. (2013). Water (25 ± 1 ° C.) was placed to a depth of 13 cm in an acrylic resin cylinder (diameter 19 cm, height 25 cm), test mice were allowed to swim one by one for 6 minutes, and the situation was video-recorded. After the test, the mouse was quickly pulled out of the water and wiped with a paper towel. The condition of "floating on the water surface without moving hands and feet" was regarded as immobility, and immobility time was measured during the test for 6 minutes.

(3) Forced swimming test evaluation results Depression-like symptoms induced by chronic administration of corticosterone and evaluated by the forced swimming test were ameliorated by chronic administration of the test compound (the compound of Example 1) (FIG. 3). From the above results, it has become clear that the compound of Example 1 is effective against depression-like symptoms exhibited by chronic administration of corticosterone mice. In each group n = 12, data are expressed as mean value ± standard error. * P <0.05, ** P <0.01 (Tukey-Kramer test was performed after two-way ANOVA)

(4) Female selectivity test The female selectivity test was conducted at the light period (8:00 to 20:00) according to the method of Ago et al. (2015). Sterile soft tip of wood in a test cage (42 cm x 50 cm x 30 cm) made of acrylic modified polyvinyl chloride divided into three compartments by two transparent partitions in a soundproof laboratory set at an illumination of 400 lux (experiment The animal bedding (Sankyo Lab Service Co., Ltd.) was inserted, and a test male mouse was introduced into the central section of the device. After 90 minutes of acclimation, the same age, female and male mice of the same strain without encountering the test mice were introduced as invading mice into wire mesh boxes (10 cm x 6.5 cm x 20 cm) placed in the left and right compartments respectively did. Thereafter, the test mice were allowed to freely explore the test cage for 10 minutes. The appearance was videotaped, and the time when the test mouse stayed in each section was analyzed using ANY-maze (registered trademark) video tracking software (Stoelting Co., IL, USA). The ratio of the residence time in the female mouse compartment to the total residence time in the female and male mouse compartment was calculated as the female selectivity (%).

(5) Female selectivity test evaluation result Depression-like symptoms induced by chronic administration of corticosterone and evaluated by the female selectivity test were improved by chronic administration of the test compound (the compound of Example 1) (FIG. 4) ). From the above results, it has become clear that the compound of Example 1 is effective against the depression-like symptoms of chronically administered corticosterone mice. In each group n = 12, data are expressed as mean value ± standard error. * P <0.05, ** P <0.01 (Tukey-Kramer test was performed after two-way ANOVA)

Test Example 3 Interaction Analysis with Sin3 by NMR The interaction between the compound of the present invention and Sin3 was analyzed using STD (Saturation Transfer Difference) -NMR and Waterlogsy method.

(1) Preparation of mSin3B PAH1 Protein The PAH1 domain (mSin3B PAH1) of mouse Sin3B was prepared by the method previously reported (Naruse et al., 1999; Nomura et al., 2005).

(2) Preparation of GST-Fused mSin3B PAH1 Protein GST-fused mSin3B PAH1 protein was subcloned in the pGX-6P-1 vector (GE Healthcare) in which the mSin3B PAH1 coding region was recombined and expressed in E. coli strain BL21 (DE3).

(3) NMR Experiment NMR experiment was performed at 298 K with Bruker AVANCE 700 equipped with a cryoprobe. The spectra were processed with TOPSPIN 3.2 software.
¹ H STD-NMR (Mayer et al., 2001; Meyer et al., 2003) and Waterlogsy (Dalvit et al., 2000; Dalvit et al., 2001; Antanasijevic et al., 2014) measurements are mSin3B PAH1 It was carried out with 10 μM) and a test compound (compound of Example 1, 100 μM). As a measurement sample, 500 μl of phosphate buffer (100 mM, pH 7.2) containing 5% dimethyl sulfoxide was prepared.
The NMR of the test compound changes its peak shape due to the presence of mSin3B PAH1 and GST-fused mSin3B PAH1 (FIG. 5, upper: STD NMR, middle: Waterlogsy, lower: 3919 Watergate (Sklenar et al., 1993)), the present invention A strong interaction between the compound and Sin3 was shown.

(4) ¹ H- ¹⁵ N HSQC titration ¹ H- ¹⁵ N HSQC titration experiment (Davis et al., 1992) used mSin 3 B (100 mM, pH 7.2) containing 5% dimethyl sulfoxide. 100 μM) and the test compound (compound of Example 1, 1 mM) were carried out in a mixing ratio of 1: 1 or 1:10.
In the ¹ H- ¹⁵ N HSQC spectrum of mSin 3 B PAH ^1, chemical shift changes were observed due to the presence of the test compound, and a strong interaction between the compound of the present invention and Sin 3 was shown (FIG. Writing).

Test Example 4 Binding Analysis Calculation Based on NMR data, binding analysis between mSin3B and the compound of the present invention (the compound of Example 1) was calculated using the HADDOCK / CNS protocol (Dominguez et al., 2003; de Vries et al., 2010; Wassenaar et al. al., 2012). An NMR analysis structure (2CR7) was used as the initial structure of mSin3B, and an energy minimized structure using the UFF force field (Rappe et al., 1992) as the initial structure of the compound of the present invention. The signals of the amino acid residues of Phe58, Glu85, Ile90, Val91 and Leu97 have disappeared in the HSQC spectrum, and these amino acid residues are considered to be in contact with the compound of Example 1, and these are combined as active residues. Analysis calculation was performed. One thousand structures were generated, and structure optimization was carried out by molecular dynamics calculation for the optimum 200 structures among them. The bonding structure of the compound of the present invention and mSin3B PAH1 is shown in FIG. The compounds of the present invention were shown to occupy the binding site of NRSF.

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Since the compound of the present invention and the drug containing the compound are effective for various psychiatric disorders (ASD, depression, epilepsy, etc.) by an action mechanism different from that of the existing therapeutic agents, the effect which can not be obtained with the existing therapeutic agents It can be expected, and it will be possible to eliminate the side effects that have been problematic with existing therapeutic agents.

This application is based on patent application No. 2017-163741 filed in Japan (filing date August 28, 2017), the contents of which are incorporated in full herein.

Claims (14)

1. A preventive and / or therapeutic agent for a mental disease, which comprises a Sin3 modulator as an active ingredient.
2. The prophylactic and / or therapeutic agent according to claim 1, wherein the psychiatric disorder is autism spectrum disorder / autism spectrum disorder.
3. The prophylactic and / or therapeutic agent according to claim 1, wherein the psychiatric disorder is depression.
4. The prophylactic and / or therapeutic agent according to claim 1, wherein the psychiatric disorder is epilepsy.
5. The prophylactic and / or therapeutic agent according to claim 1, wherein the Sin3 modulator is the following compound or a pharmaceutically acceptable salt thereof.
   

   
6. A preventive and / or therapeutic agent for a mental disease, which comprises the following compound or a pharmaceutically acceptable salt thereof as an active ingredient.
   

   
7. The prophylactic and / or therapeutic agent according to claim 6, wherein the psychiatric disorder is autism spectrum disorder / autism spectrum disorder.
8. The prophylactic and / or therapeutic agent according to claim 6, wherein the mental disease is depression.
9. The prophylactic and / or therapeutic agent according to claim 6, wherein the psychiatric disorder is epilepsy.
10. The following compound or a pharmaceutically acceptable salt thereof.
    

    
11. A preventive and / or therapeutic agent for a mental disorder, which comprises administering an effective amount of the following compound or a pharmaceutically acceptable salt thereof to a patient in need thereof.
    

    
12. The method for prevention and / or treatment according to claim 11, wherein the psychiatric disorder is at least one selected from the group consisting of autism spectrum disorder / autism spectrum disorder, depression and epilepsy.
13. The following compound or a pharmaceutically acceptable salt thereof for use in the prevention and / or treatment of a mental disease.
    

    
14. 14. The compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein the psychiatric disorder is at least one selected from the group consisting of autism spectrum disorder / autism spectrum disorder, depression and epilepsy.

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