JPWO2019044844A1 - New Sin3 modulator and its pharmaceutical use - Google Patents

Abstract

The present invention provides a Sin3 modulator, particularly a prophylactic and / or therapeutic agent for mental illness, which comprises the following compound or a pharmaceutically acceptable salt thereof as an active ingredient. The prophylactic and / or therapeutic agents for psychiatric disorders of the present invention are particularly useful for psychiatric disorders such as ASD, depression and epilepsy.

Description

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

Mental illness is thought to be caused by a complex interaction of many genetic and environmental factors, but the mechanism at the molecular level is still largely unknown, and the effects of drug treatment are not always sufficient. There is also.
For example, in autism spectrum disorder / autism spectrum disorder (hereinafter abbreviated as ASD), which is a type of developmental disorder, there is no effective drug for the prevention and treatment of its core symptoms, and effective preventive and therapeutic drugs are strongly desired. It is rare.
Depression is a type of mental illness called mood disorder, and existing antidepressants take a long time to develop their effects, and about 30% of patients are ineffective with antidepressants. There is a strong demand for antidepressants with a novel mechanism that are effective for patients who are ineffective with early antidepressants or conventional antidepressants (treatment-resistant depression).
In addition, epilepsy is a disease that causes repeated "epileptic seizures" such as sudden loss of consciousness and loss of reaction. Currently, there are various drugs as antiepileptic drugs, but there are 2 patients with intractable epilepsy who do not improve by them. There are ~ 30%. There is a strong demand for antiepileptic drugs with a novel mechanism that is also effective for patients with instinct epilepsy.

Therapeutic agents for various drug discovery targets have been developed, but the epigenetic mechanism may be involved in the onset of psychiatric disorders considered to be "complex genetic disorders", and they are innovative (conventional mechanism of action). The current situation is that the development of effective drugs (which is different from the introduction) has not yet been achieved.

Specific action targets include the nuclear protein NRSF (Neuron-Restrictive Silencer Factor, also known as REST (RE1-Silencing Transcription Factor)), which is responsible for transcriptional regulation of many nerve-specific genes, and transcription that specifically binds to NRSF. The Sin3 protein is known as a collipulator (Non-Patent Documents 1 and 2).
Although there is a report that the regulator of Sin3 is effective for fibromyalgia and analgesia (Patent Document 1), there is a report that it is effective for psychiatric disorders, especially ASD, depression and epilepsy. Not done.

WO2014 / 088106A1

Molecular and Cellular Biology, 2000, 20, 2147. The Journal of Biological Chemistry, 2000, 275, 9461.

An object of the present invention is to provide a prophylactic and / or therapeutic agent for psychiatric disorders, particularly psychiatric disorders such as ASD, depression and epilepsy, which are useful and have a new mechanism of action different from existing agents. And.

In view of the above problems, the present inventors first focused on the binding between NRSF and Sin3, searched for a compound that inhibits (controls) the binding, and further develops various psychiatric disorders of the compound using an animal model. The effect of the above was confirmed, and the present invention was completed.
That is, the gist of the present invention is as follows.
[1] A prophylactic and / or therapeutic agent for mental illness containing a Sin3 modulator as an active ingredient.
[2] The prophylactic and / or therapeutic agent according to the above [1], wherein the mental illness is autism spectrum disorder / autism spectrum disorder.
[3] The prophylactic and / or therapeutic agent according to the above [1], wherein the mental illness is depression.
[4] The prophylactic and / or therapeutic agent according to the above [1], wherein the mental illness is epilepsy.
[5] The prophylactic and / or therapeutic agent according to the above [1], wherein the Sin3 modulator is the following compound or a pharmaceutically acceptable salt thereof.

[6] A prophylactic and / or therapeutic agent for mental illness containing the following compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[7] The prophylactic and / or therapeutic agent according to [6] above, wherein the mental illness is autism spectrum disorder / autism spectrum disorder.
[8] The prophylactic and / or therapeutic agent according to the above [6], wherein the mental illness is depression.
[9] The prophylactic and / or therapeutic agent according to [6] above, wherein the mental illness is epilepsy.
[10] The following compounds or pharmaceutically acceptable salts thereof.

[11] A prophylactic and / or therapeutic agent for a psychiatric 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 prophylactic and / or therapeutic method according to [11] above, wherein the mental illness is autism spectrum disorder / autism spectrum disorder.
[13] The preventive and / or therapeutic method according to [11] above, wherein the mental illness is depression.
[14] The preventive and / or therapeutic method according to [11] above, wherein the mental illness is epilepsy.
[15] The following compounds or pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of mental illness.

[16] The compound according to the above [15] or a pharmaceutically acceptable salt thereof, wherein the mental illness is autism spectrum disorder / autism spectrum disorder.
[17] The compound according to the above [15] or a pharmaceutically acceptable salt thereof, wherein the mental illness is depression.
[18] The compound according to the above [15] or a pharmaceutically acceptable salt thereof, wherein the mental illness is epilepsy.

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

FIG. 1 is a graph showing the results of Test Example 1. The effects of Example 1 compound on social behavioral disorders (A) and cognitive dysfunction (B) of fetal valproic acid-administered mice are shown. FIG. 2 is a graph showing the results of Test Example 1. The action of Example 1 compound on hyperalgesia and allodynia of fetal valproic acid-administered mice is shown. (A) shows the result of the hot plate test, (B) shows the result of the Hongfly test, and (C) shows the result of the acetic acid rising test. FIG. 3 is a graph showing the results of Test Example 2. Example 1 in a forced swimming test using a corticosterone chronically administered mouse depression model shows the action of the compound. FIG. 4 is a graph showing the results of Test Example 2. The action of the Example 1 compound on anhedonia induced by chronic administration of corticosterone is shown. FIG. 5 is a chart showing the results of Test Example 3 (NMR experiment). It is shown that the NMR peak shape of Example 1 compound changes in the presence of mSin3B PAH1 and GST-fused mSin3B PAH1. The upper row shows the results of STD-NMR, the middle row shows the results of Waterlogsy measurement, and the lower row shows the results of 3919 Watergate measurement. FIG. 6 is a graph showing the results of Test Example 3 ( ¹ H- ¹⁵ N HSQC titration experiment). In the ¹ H- ¹⁵ N HSQC spectrum of mSin3B PAH1, it is shown that the chemical shift is changed by the presence of the compound of Example 1. FIG. 7A is a diagram showing a binding structure between the compound of Example 1 and mSin3B PAH1. FIG. 7B is a diagram showing a binding structure between NRSF and mSin3B PAH1.

The present invention provides a prophylactic and / or therapeutic agent for mental illness containing a Sin3 modulator as an active ingredient. The details will be described below.

(Sin3 modulator)
Sin3 is one of the scaffold proteins involved in the transcriptional regulation mechanism, has no tissue specificity, is widely expressed, and is highly conserved from yeast to humans. It has four PAH (paired amphipathic helix) domains and HDAC (Histone deacetylase) interaction domains with different binding partners, such as transcription factors, colipressors, and methylated CpG binding proteins. The PAH1 domain is the most N-terminal domain of the four PAH domains and interacts with the transcriptional repressor NRSF. In the present invention, the "Sin3 modulator" is not particularly limited in its origin as long as it is a substance capable of inhibiting (controlling) 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 1000, and examples thereof include organic compounds and derivatives thereof that can be usually used as pharmaceuticals, and compounds and derivatives thereof produced by making full use of an organic synthesis method and the like, and natural compounds. Derived compounds and derivatives thereof, preferably organic compounds and derivatives thereof that can be used as pharmaceuticals. In addition, examples of the polymer compound include compounds having a molecular weight of about 1000 or more, such as proteins, polynucleic acids, polysaccharides, and combinations thereof.

The Sin3 modulator may be a pharmaceutically acceptable salt thereof. Examples of the salt include 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, silicic acid and fumal. Acid addition salts with acids such as acids, phosphonic acids, hydrochloric acid, nitrates, hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid; metal salts such as sodium, potassium, magnesium, calcium; eg, trimethylamine, Examples thereof include salts with organic bases such as triethylamine, pyridine, picolin, N-methylpyrrolidin, N-methylpiperidin and N-methylmorpholin.

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

The Sin3 modulator may be crystalline or amorphous. When the Sin3 modulator is crystalline, it can be used as a Sin3 modulator in the present invention regardless of whether it has a single crystalline form or a crystalline mixture. Crystals can be produced by crystallization by applying a crystallization method known per se.

The Sin3 modulator may be a solvate (for example, hydrate or the like) or a non-solvate, and both can be used as the 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, the following formula is preferable.

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

The Sin3 modulator has a psychiatric disorder-improving effect on mammals (eg, humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, rabbits, etc.) by inhibiting the Sin3-NRSF interaction. Therefore, it is useful as a prophylactic and / or therapeutic agent for various psychiatric disorders (hereinafter, also referred to as an agent of the present invention).

(Mental illness)
In the present invention, psychiatric disorders are various diseases / symptoms defined in Chapter 5 "Mental and behavioral disorders" of the 10th edition (ICD-10) of "International Statistical Classification of Diseases and Related Health Problems" and American psychiatry. It means various diseases / symptoms defined in the 5th edition (DSM-5) of "Mental Disorders Diagnosis and Statistics Manual" published by the Society, and also Chapter 6 "Nervous System Diseases" of ICD-10. Includes epilepsy as defined by G40 and G41. The present invention is effective for diseases and pathological conditions caused by Sin3-NRSF interaction among psychiatric disorders, and can exert an excellent improving effect on ASD, depression and epilepsy in particular.
"Autism Spectrum Disorders / Autism Spectrum Disorders (ASD)" is classified as "Neurodevelopmental Disorders / Neurodevelopmental Disorders" in DSM-5, which is a diagnostic standard of the American Psychiatric Association, and in ICD-10. , F84 Pervasive developmental disorders (PDD), asperger syndrome, unspecified pervasive developmental disorder, childhood disintegrative disorder (CDD), fragile X syndrome, let syndrome, etc. It is a concept that includes. Its basic characteristics are behavioral syndromes that appear by about 3 years of age and are mainly characterized by the following core symptoms.
1. 1. Persistent flaws in social communication and social interaction 2. Limited, repetitive behavior, interest, or mode of activity "depression" means a disorder classified as F30-F39 "mood [emotion] disorder" in ICD-10, diagnosed by the American Psychiatric Association. According to the standard DSM-5, it is included in the category of "depressive disorder group". In a narrower sense, it means major depressive disorder, and if a major depressive episode can be confirmed in the medical history, a major depressive disorder can be diagnosed. Will be done. However, in general, the term depression may mean major depressive disorder and dysthymia, or may mean mood disorder in general, and is not always used in a fixed manner. Therefore, "depression" in the present invention includes all cases where a doctor diagnoses depression or depression. As used herein, the term "depression" is a concept that includes depression.
"Epilepsy" is a chronic brain disorder caused by various causes and is characterized by recurrent seizures (epileptic seizures) resulting from excessive firing of cerebral neurons, which are accompanied by various clinical symptoms and laboratory findings. Seizures are broadly divided into generalized seizures (tonic seizures, simple absence seizures, complex absence seizures, pointed seizures, weakness seizures) and partial seizures (simple partial seizures, complex partial seizures, secondary generalized seizures). However, any seizure may be the subject of the present invention.

The Sin3 modulator is blended with a pharmaceutically acceptable carrier to form a solid preparation such as tablets, capsules, granules, powders; a liquid preparation such as a syrup or an injection; a patch, an ointment, a plaster, etc. It can be appropriately formulated as a skin absorbent; an inhalant; a suppository. The content of the active ingredient Sin3 modulator in the formulation is generally about 0.01 to about 99.9% by weight, preferably about 0.1 to about 50% by weight, based on the entire formulation.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances commonly used as preparation materials can be used. Specifically, it contains excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents, etc. can do. Further, if necessary, formulation additives such as preservatives, antioxidants, colorants, and sweeteners can be used.

Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, citrus 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 methyl cellulose, polyvinylpyrrolidone and the like.

Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, sodium carboxymethyl starch and the like.

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

Preferable examples of the solubilizing agent 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 surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate; polyvinyl alcohol, polyvinylpyrrolidone, etc. Examples thereof include sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

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

Preferable examples of the buffer include, for example, a buffer solution such as phosphate, acetate, carbonate and citrate.
Preferable examples of the soothing agent include benzyl alcohol and the like.

Preferable examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Preferable examples of the antioxidant include sulfites, ascorbic acid and the like.
Preferable examples of the colorant include tar pigments, caramel, iron sesquioxide, titanium oxide, riboflavins and the like.
Preferable examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.

The dose of the preparation is age, body weight, general health condition, gender, diet, administration time, administration method, excretion rate, type of Sin3 modulator to be used, combination of drugs, and treatment at the time of the patient. It depends on the severity of the condition and takes into account those or other factors.
For example, when the Sin3 modulator is a compound of the present invention, the preparation has a daily dose of about 1 to 100 mg / kg (body weight), preferably about 2 to 60 mg / kg (body weight), as the amount of the active ingredient Sin3 modulator. It is more preferable to administer 5 to 40 mg / kg, more preferably about 10 to 30 mg / kg (body weight) in one dose or in two to three divided doses.

Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited thereto.
The measurement conditions for 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 condition: 0 to 5 min. 5 to 100% (v / v) Solution B, 5 to 6 min. 100% (v / v) Solution B
Flow velocity: 1 mL / min

Example 1
(1) Isopropyl (R) -1-((S) -1-((2,2-diethoxyethyl) (isopentyl) amino) -4- (methylthio) -1-oxobutane-2-ylamino) -1- Oxobutane-2-yloxycarbamate (S) -2-amino-N- (2,2-diethoxyethyl) -N-isopentyl-4- (methylthio) butanamide (Compound of Reference Example 3: 2.9 g, 8. 66 mmol) and (R) -2- (isopropyloxycarbonylaminooxy) butyric acid (compound of Reference Example 10: 1.78 g, 8.67 mmol) were dissolved in methanol (50 mL) and N-methylmorpholine (0.87 g, 0.87 g, 8.6 mmol) and 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium (DMT-MM, 3.6 g, 13.0 mmol) were added. The mixture was left overnight at room temperature. The reaction mixture was concentrated under reduced pressure and ethyl acetate (80 ml) was added. The organic phase was washed with brine, 10% citric acid and sodium bicarbonate, dried over Glauber's salt, 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 oily substance, 3.33 g, yield 74%). TLC (silica gel, developing solvent hexane: ethyl acetate = 1: 1), Rf = 0.52 (phosphormobudenic acid heating coloration)
(2) (3R, 6S, 9aS) -isopropyl3-ethyl-8-isopentyl-6- (2- (methylthio) ethyl) -4,7-dioxohexahydropyrazino [2,1-c] [1 , 2, 4] Oxaziazine-1 (6H) -carboxylate (Example 1 compound)
Isopropyl (R) -1-((S) -1-((2,2-diethoxyethyl) (isopentyl) amino) -4- (methylthio) -1-oxobutane-2-ylamino) -1-oxobutane-2 -Iloxycarbamate (3.33 g, 6.38 mmol) formic acid (35 ml) was added and left overnight at room temperature. The formic acid was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane-ethyl acetate mixed solvent, ethyl acetate concentration 20% to 50% gradient), and the title compound (colorless oily substance, 2.03 g, yield) was purified. 74%) was obtained. TLC (silica gel, developing solvent hexane: ethyl acetate = 1: 1), Rf = 0.63 (phosphomolybic acid heating coloration)
LC-MS: RT = 4.75 min. Obs MS m / z = 430 (M + 1) ⁺

Reference example 1
N- (2,2-diethoxyethyl) -3-methylbutane-1-amine 2-bromo-1,1-diethoxyethane (39.4 g, 0.2 mol) and 3-methylbutane-1-amine (52. Potash 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 oily substance, 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 coloration)

Reference example 2
(S)-(9H-Fluoren-9-yl) methyl 1-((2,2-diethoxyethyl) (isopentyl) amino) -4- (methylthio) -1-oxobutane-2-ylcarbamate N- (2) , 2-Diethoxyethyl) -3-methylbutane-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), diisopropylethylamine (5.68 g, 44 mmol) and (1- [bis (dimethylaminodimethylamino)) 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 the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The organic phase was washed with saline, 10% citrate solution, and sodium bicarbonate solution, dried with sardine, and concentrated under reduced pressure. The residue was silica gel chromatography (hexane). Purification with a mixed solvent of ethyl acetate (ethyl acetate concentration 10% to 35% gradient) gave the title compound (colorless oily substance, 10.9 g, yield 98%). TLC (silica, 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-fluorene-9-yl) methyl 1-((2,2) 2-Diethoxyethyl) (isopentyl) amino) -4- (methylthio) -1-oxobutane-2-ylcarbamate (Compound of Reference Example 2: 10.9 g, 19.6 mmol) was dissolved in dichloromethane (100 mL). Piperidine (8.51 g, 100 mmol) was added and left overnight at room temperature. The reaction mixture is concentrated and the residue is purified by silica gel chromatography (first hexane-ethyl acetate mixed solvent, ethyl acetate concentration 20% -30% gradient, then chloroform-methanol mixed solvent, methanol concentration 0% -20% gradient). The title compound (colorless oily substance, 3.60 g, yield 55%) was obtained. TLC (silica gel, developing solvent chloroform: methanol = 10: 1) Rf = 0.46 (ninhydrin heating coloring)

Reference example 4
(S) -2-acetoxybutyric acid (S) -2-hydroxybutyric acid (35 g, 340 mmol) was added with acetyl chloride under ice-cooling, and then refluxed by heating at 60 ° C. for 4 hours. Excess acetyl chloride was distilled off under reduced pressure, and diethyl ether was added. The organic phase was dried over Glauber's salt and concentrated under reduced pressure to give the title compound (colorless oily substance, 42 g, yield 85%). TLC (silica gel, developing solvent petroleum ether: ethyl acetate: acetic acid = 10: 1: 0.1) Rf = 0.8 (phosphomolybdic acid heating coloration)

Reference example 5
(S) tert-Butyl -2-acetoxybutyric acid (S) -2-acetoxybutyric acid (compound of Reference Example 4: 42 g, 288 mmol) and tert-butyl alcohol in a solution of 4-dimethylaminopyridine (DMAP, DMAP, 400 mL) in dichloromethane (400 mL). 17 g, 140 mmol) was added. A solution of dicyclohexylcarbodiimide (DCC, 85 g, 438 mmol) in dichloromethane (250 mL) was then added under ice cooling. The reaction mixture was stirred at room temperature overnight. The urea compound produced was filtered off, the organic phase was 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 oily substance, 46 g, yield 80%). TLC (silica gel, developing solvent petroleum ether: ethyl acetate = 10: 1), Rf = 0.8 (phosphomolybic acid heating coloration)

Reference example 6
(S) tert-butyl -2-hydroxybutyrate Potashium carbonate (20.1 g, 146 mmol) was dissolved in methanol (56 mL) and water (80 mL), and tert-butyl (S) -2-acetoxybutyrate (reference example 5). Compound: 10 g, 49 mmol) was added. The solution was vigorously stirred at room temperature overnight. Methanol was distilled off under reduced pressure and extracted twice with dichloromethane to obtain the title compound (white solid, 5 g, yield 64%). TLC (silica gel, developing solvent petroleum ether: ethyl acetate = 10: 1), Rf = 0.6 (phosphomolybic acid heating coloration)

Reference example 7
(R) -2- (1,3-Dioxoisoindoline-2-yloxy) butyrate tert-butyl (S) -2-hydroxybutyrate 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) in anhydrous tetrahydrofuran (30 mL) and diethyl azodicarboxylate (2 mL, 12) under 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 the mixture was stirred. The organic phase was dried over Glauber's salt 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 (phosphomolybic acid heating coloration)

Reference example 8
(R) -2- (Aminooxy) butyrate tert-butyl (R) -2- (1,3-dioxoisoindoline-2-yl) butyrate tert-butyl (Compound of Reference Example 7: 2.5 g, 8) .2 mmol) was dissolved in methanol (20 mL), hydrous hydrazine (1.7 mL, 25 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 3% aqueous sodium hydrogen carbonate (10 mL) and ether were added, and the mixture was stirred. The organic phase was dried over Glauber's salt and concentrated. The residue was purified by silica gel chromatography (hexane-dichloromethane mixed solvent, dichloromethane concentration 30%) to give the title compound (colorless oily substance, 1 g, yield 70%). TLC (silica gel, developing solvent petroleum ether: dichloromethane = 1: 2), Rf = 0.3 (phosphomolybic acid heating coloration)

Reference example 9
(R) -2- (Isopropyloxycarbonylaminooxy) butyrate tert-butyl (R) -2- (aminooxy) butyrate tert-butyl (Compound of Reference Example 8: 7.0 g, 40 mmol) in acetonitrile (20 mL) Pyridine (6.3 g, 80 mmol) was added to the mixture, and isopropylchlorostate (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% citric acid water and sodium bicarbonate water, dried over Glauber's salt, 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 oily substance, 10.4 g, quantitative yield). TLC (silica gel, developing solvent hexane: ethyl acetate = 4: 1), Rf = 0.58 (phosphomolybic acid heating coloration)

Reference example 10
(R) -2- (Isopropoxycarbonylaminooxy) Butyric Acid (R) -2- (Isopropoxycarbonylaminooxy) Butyric Acid tert-Butyl (Compound of Reference Example 9: 10.45 g, 40 mmol) Formic acid (50 ml) Was added and left overnight. Formic acid was distilled off under reduced pressure to give the title compound (white solid, 8.45 g, quantitative yield).

Test Example 1 Evaluation of pharmacological action using fetal valproic acid-administered ASD model mice Mice exposed to valproic acid at 12.5 days of fetal period are widely recognized as a highly relevant ASD (Autistic Spectrum Disorder) model. There is. In this mouse, social behavioral disorders, novel object recognition disorders, abnormal pain sensitivity, etc. are observed. Therefore, using this mouse, the improvement effect of the administration of the compound of the present invention on social behavioral disorders, novel object recognition disorders, and abnormal pain sensitivities (hot plate test, Hongfly test, acetate rising test) was evaluated.

(1) Preparation of fetal valproic acid-administered ASD model mice ICR-based 8-week-old male and female mice were subjected to conditions of room temperature of 22 ± 1 ° C. and illumination time of 12 hours a day (8: 00-20: 00). In an environment where food and water could be freely ingested in each cage made of polycarbonate resin (24 cm × 17 cm × 12 cm), 5-6 animals were bred in groups per cage. After acclimatization to the breeding environment, vaginal dirt was collected daily from 9-12 week old female mice and the sexual cycle was confirmed by Giemsa staining. Pre-estrus or estrus female mice were cohabited and mated with male mice aged 9-20 weeks only overnight. The next day was defined as the 0th day of gestation, and male offspring derived from the mice were used in the experiment. Mice on day 12.5 of gestation were intraperitoneally administered 500 mg / kg of sodium valproate (Kataoka et al., 2013; Takuma et al., 2014; Hara et al., 2016) (Figs. 1 and 2). , VPA). The control group (Saline in FIGS. 1 and 2) was intraperitoneally administered with physiological saline used as a solvent. Mother and child were separated at 3 weeks of age and subjected to experiments after 8 weeks of age. The test compound was prepared by dissolving a drug solution in physiological saline so that the final concentration of DMSO was 8%, the final concentration of Soltor HS15 was 2%, and the concentration of the test compound was 3 mg / mL, and the drug solution was intraperitoneally administered once a day from 8 weeks of age. After administration (30 mg / kg), a social behavior test and a novel object recognition test were performed at 10 weeks of age, and a pain sensitivity test was performed at 11 weeks of age. As a comparative control, the same amount of the drug solution containing no test compound was administered (Vehicle in FIGS. 1 and 2).

(2) Social behavior test
According to the method of Hara et al. (2016), it was carried out in the light period (8: 00-20: 00). In a soundproof laboratory set to an illuminance of 350 lux, the test mouse was placed in a polysalphon test cage (38 cm x 22 cm x 20 cm) containing a wooden sterilized soft chip (Sankyo Lab Service Co., Ltd.) for 60 minutes. I got used to it. Then, a male invading mouse of the same strain and the same weight that had never been encountered with the test mouse was inserted, and a video recording of the state for 20 minutes was performed. The olfactory behavior (face sniff and ano-genital sniff) exhibited by the test mouse 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 in the light period (8: 00-20: 00) according to the method of Hara et al. (2016). First, in a soundproof laboratory set to an illuminance of 30 lux, one day in a test cage (30 cm x 30 cm x 35 cm) made of acrylic-modified polyvinyl chloride with only wooden sterilized soft chips (Sankyo Lab Service Co., Ltd.) laid. The test mice were acclimatized for 10 minutes for 3 consecutive days. On the 4th day, two different objects (object a and b were randomly selected from a golf ball, a Lego block, a plastic cylinder and an outlet) were placed 8 cm away from the wall and allowed to explore freely for 10 minutes. (Training trial). Twenty-four hours later, the object b was freely searched for 5 minutes in a test cage replaced with the novel object c (test trial). Animal behavior in training and test trials was video-recorded 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 the identification index.

(4) Evaluation results of social behavior test and novel object recognition test Social behavior disorder and novel object recognition dysfunction after maturity due to administration of valproic acid during the fetal period were improved by chronic administration of the test compound (compound of Example 1). (Fig. 1). From the above results, it was clarified that the compound of Example 1 was effective against ASD-like behavioral abnormalities exhibited by fetal valproic acid-administered mice. In each group n = 12, the data was expressed as mean ± standard error. ** P <0.01 (Tukey-Kramer test was performed after two-way ANOVA.)

(5) Hot plate test The hot plate test was carried out in the light period (8: 00-20: 00) according to the method of Horiguchi et al. (2013a). The hot plate temperature of the device (HOT / COLD PLATE; Model 35100; Ugo Basile, Italy) was set to 49 ± 0.5 ° C., and the test mice were gently introduced. The behavior of the mouse licking or jumping on the hind limbs was regarded as a pain reaction, and the time until one of the reactions first occurred (escape reaction time) was measured. The cut-off value of the escape reaction time was set to 30 seconds in order to prevent tissue damage due to heat stimulation.

(6) Honfly test The Honfly test was performed in the light period (8: 00-20: 00) according to the method of Horiguchi et al. (2013b). Place the mouse on a stainless steel mesh, cover it with an acrylic resin box (3.5 cm x 8.5 cm x 8.0 cm), and after confirming that the spontaneous movement has been reduced, make a phone perpendicular to the center of the toes of the foot. The fly filament (Touch-Test® Sensory Evaluators; North Coast Medical, CA, USA) was pressed until it bent. Stimulus was applied sequentially from the one with a large filament diameter to the one with a small filament diameter, and the minimum mechanical stimulation value of the filament that caused the escape behavior was set as the escape reaction threshold.

(7) Acetic acid rising test The acetic acid rising test was carried out according to the method of Horiguchi et al. (2013a). The test mouse was placed in an acrylic resin cylinder (diameter 17 cm, height 24 cm), acclimatized for 30 minutes, and then 0.9% acetic acid (Wako Pure Chemical Industries, Ltd., Osaka) was added to the abdominal cavity at a volume of 10 mL / kg. It was administered internally. The number of occurrences of rising behavior (behavior of contracting the abdomen or behavior of twisting the body to extend the hind limbs) was measured 15 minutes after administration.

(8) Hot plate test, Hongfry test, Acetic acid rising test Evaluation results Post-maturation hyperalgesia and allodynia (hot plate test, Hongfly test, acetate rising test) due to administration of valproic acid during the fetal period are the test compounds (Example 1). It was improved by chronic administration of the compound) (Fig. 2). From the above results, it was clarified that the compound of Example 1 is effective against the ASD-like abnormal pain sensitivity shown by the fetal valproic acid-administered mice. In each group n = 12, the data was expressed as mean ± 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 a model mouse for chronic administration of corticosterone Chronic administration of corticosterone mimics the increase in corticosterone secretion due to stress loading, and the HPA axis (hypothalamic-pituitary-adrenal axis) It is a model animal of depression showing functional failure, and is considered to be a model animal of treatment-resistant depression because it is not improved by existing antidepressants (tricyclic and SSRI (Selective Serotonin Reuptake Inhibitors)). ..
As a depression-like behavior, a forced swimming test, which is widely used as a behavior model imitating despair, was conducted, and a female selectivity test was conducted as a behavior model imitating anhedonia (anhedonia). Depression caused by administration of the compound of the present invention. The improvement of symptoms was evaluated.

(1) Preparation of a model mouse for chronic administration of corticosterone depression
C57BL6 / J 5-week-old male mice were placed in a polycarbonate resin cage (24 cm x 17 cm x 12 cm) under the conditions of room temperature 22 ± 1 ° C. and illumination time 12 hours a day (8: 00-20: 00). In an environment where food and water can be freely ingested, 5-6 animals per cage were bred in groups. From the age of 6 weeks, 20 mg / kg of corticosterone (CRT in FIGS. 3 and 4) was subcutaneously administered once a day for 3 consecutive weeks. A 0.5% (W / V) carboxymethyl cellulose solution (Vehicle in FIGS. 3 and 4) used as a solvent was subcutaneously administered to the control group.
The test compound was prepared by dissolving a drug solution in physiological saline so that the final concentration of DMSO was 8%, the final concentration of Soltor HS15 was 2%, and the concentration of the test compound was 3 mg / mL, starting 1 week after chronic administration of corticosterone. It was intraperitoneally administered (10, 30 mg / kg) for 2 weeks 30 minutes before the administration of corticosterone, and a behavioral test was conducted 24 hours after the final administration.

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

(3) Results of evaluation of forced swimming test The depression-like symptoms induced by chronic administration of corticosterone and evaluated by the forced swimming test were improved by chronic administration of the test compound (compound of Example 1) (Fig. 3). From the above results, it was clarified that the compound of Example 1 is effective for the depression-like symptoms exhibited by the mice chronically administered corticosterone. In each group n = 12, the data was expressed as mean ± 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 in the light period (8: 00-20: 00) according to the method of Ago et al. (2015). In a soundproof laboratory set to an illuminance of 400 lux, a wooden sterilized soft chip (experiment) was placed in a test cage (42 cm x 50 cm x 30 cm) made of acrylic-modified polyvinyl chloride divided into three sections by two transparent partitions. A bedding for animals; Sankyo Lab Service Co., Ltd.) was placed, and a test male mouse was introduced into the central section of the device. After acclimation for 90 minutes, female and male mice of the same age and strain that had never encountered the test mouse were introduced as invading mice into wire mesh boxes (10 cm x 6.5 cm x 20 cm) installed in the left and right compartments, respectively. did. Then, the test mice were allowed to freely explore the test cage for 10 minutes. The situation was videotaped, and the time that the test mice stayed in each section was analyzed using ANY-maze (registered trademark) video tracking software (Stoelting Co., IL, USA). The ratio of the time spent in the female mouse compartment to the total time spent in the female and male mouse compartments was calculated as the female selectivity (%).

(5) Results of evaluation of female selectivity test The 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 (compound of Example 1) (Fig. 4). ). From the above results, it was clarified that the compound of Example 1 is effective for the depression-like symptoms exhibited by the mice chronically administered corticosterone. In each group n = 12, the data was expressed as mean ± 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 the 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 The GST-fused mSin3B PAH1 protein was subcloned with a recombinant pGX-6P-1 vector (GE Healthcare) of the mSin3B PAH1 coding region and expressed in Escherichia coli strain BL21 (DE3).

(3) NMR experiment The NMR experiment was performed at 298K on a Bruker AVANCE 700 equipped with a cryoprobe. The spectrum was 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) were measured by mSin3B PAH1 ( 10 μM) and the 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.
In the NMR of the test compound, the peak shape changed 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)). 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) uses mSin3B (100 μM) and the test compound (Example 1) using a phosphate buffer (100 mM, pH 7.2) containing 5% dimethyl sulfoxide. Compound, 1 mM) was carried out at a mixing ratio of 1: 1 or 1:10.
In the ¹ H- ¹⁵ N HSQC spectrum of mSin3B PAH1, a chemical shift change was observed due to the presence of the test compound, indicating a strong interaction between the compound of the present invention and Sin3 (FIG. 6, 1: 0 and 1: 1 overlap). Writing).

Test Example 4 Binding analysis calculation The binding analysis calculation of mSin3B and the compound of the present invention (compound of Example 1) based on NMR data is based on the HADDOCK / CNS protocol (Dominguez et al., 2003; de Vries et al., 2010; Wassenaar et. It was carried out using al., 2012). An NMR analysis structure (2CR7) was used as the initial structure of mSin3B, and an energy minimization structure using a UFF force field (Rappe et al., 1992) was used as the initial structure of the compound of the present invention. In the HSQC spectrum, the signals of the amino acid residues of Phe58, Glu85, Ile90, Val91 and Leu97 have disappeared, and it is considered that these amino acid residues are in contact with the compound of Example 1, and these are bound as active residues. Analytical calculations were performed. 1000 structures were generated, and the optimum 200 structures among them were optimized by molecular dynamics calculation. The binding structure between the compound of the present invention and mSin3B PAH1 is shown in FIG. The compounds of the present invention have been shown to occupy the binding site of NRSF.

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

This application is based on Japanese Patent Application No. 2017-163741 filed in Japan (filed on August 28, 2017), the contents of which are incorporated herein by reference.

Claims (14)

A prophylactic and / or therapeutic agent for psychiatric disorders containing a Sin3 modulator as an active ingredient. The prophylactic and / or therapeutic agent according to claim 1, wherein the psychiatric disorder is autism spectrum disorder / autism spectrum disorder. The prophylactic and / or therapeutic agent according to claim 1, wherein the mental illness is depression. The prophylactic and / or therapeutic agent according to claim 1, wherein the mental illness is epilepsy. The prophylactic and / or therapeutic agent according to claim 1, wherein the Sin3 modulator is the following compound or a pharmaceutically acceptable salt thereof.
A prophylactic and / or therapeutic agent for mental illness containing the following compound or a pharmaceutically acceptable salt thereof as an active ingredient.
The prophylactic and / or therapeutic agent according to claim 6, wherein the mental illness is autism spectrum disorder / autism spectrum disorder. The prophylactic and / or therapeutic agent according to claim 6, wherein the mental illness is depression. The prophylactic and / or therapeutic agent according to claim 6, wherein the mental illness is epilepsy. The following compounds or pharmaceutically acceptable salts thereof.
A prophylactic and / or therapeutic agent for a psychiatric disorder, comprising administering to a patient in need of the following compound or an effective amount of a pharmaceutically acceptable salt thereof.
11. The prophylactic and / or therapeutic method of claim 11, wherein the psychiatric disorder is at least one selected from the group consisting of autism spectrum disorders / autism spectrum disorders, depression and epilepsy. The following compounds or pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of psychiatric disorders.
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.