WO2020235587A1

WO2020235587A1 - Tandospirone derivative

Info

Publication number: WO2020235587A1
Application number: PCT/JP2020/019911
Authority: WO
Inventors: 近藤　隆; 阿部　仁; 正佳倉知; 鈴木　道雄; 上原　隆
Original assignee: 国立大学法人富山大学; 学校法人金沢医科大学
Priority date: 2019-05-21
Filing date: 2020-05-20
Publication date: 2020-11-26
Also published as: JPWO2020235587A1

Abstract

A compound represented by formula (1) or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a drug for central nervous system diseases or as a candidate compound for a precursor of said active ingredient. In formula (1), R¹, R², and R³ each independently represent a substance selected from the group consisting of a hydrogen atom, a hydroxy group, and an alkoxy group having 1-6 carbon atoms, and at least one of R¹, R², and R³ is a hydroxy group.

Description

Tandospirone derivative

The present invention relates to tandospirone derivatives.

Central nervous system diseases are known as psychiatric and neurological diseases. Schizophrenia, bipolar disorder, depression, autism spectrum disorder, anxiety disorder, adjustment disorder, Alzheimer's disease, dementia, epilepsy, and Parkinson's disease are typical central nervous system diseases.

Schizophrenia is a mental dysfunction in which the ability to organize (integrate) mental functions such as thoughts, behaviors, and emotions declines over a long period of time, and hallucinations, delusions, abnormal behaviors, decreased motivation, and cognition during the course of the disorder. Various symptoms such as dysfunction appear. The prevalence of schizophrenia is about 1%, and it is a disease with a high incidence. It develops mainly in adolescence and progresses chronically.

The symptoms of schizophrenia are large and can be divided into positive symptoms, negative symptoms, and cognitive impairment. Positive symptoms include hallucinations, delusions, impaired self-consciousness that feels controlled by someone, impaired thinking that causes disorganized conversations and behaviors, and abnormal behaviors that are extremely agitated or behave strangely. I have symptoms of. Negative symptoms include flattening of emotions that cause poor expression of emotions, decreased motivation, decreased thinking ability, decreased relationships with people, and impaired interpersonal communication that leads to autism. As cognitive dysfunction, intellectual abilities such as memory, thinking, understanding, calculation, learning, language, and judgment appear.

Negative symptoms of schizophrenia and the cause of cognitive dysfunction are associated with volume loss in the patient's frontal cortex, and one of the major causes of volume loss in the frontal cortex is thought to be a decrease in parvalbumin-positive GABA neurons. ing. Parvalbumin-positive GABA neurons are cells that are present in the cerebral neocortex and express parvalbumin among inhibitory neurons (cerebral neocortical interneurons) that release GABA (γ-aminobutyric acid). Non-Patent Document 1 suggests that the decrease in parvalbumin-positive GABA neurons in an animal model of schizophrenia is mediated by oxidative stress.

In addition, according to the main hypothesis of schizophrenia, the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis and the oxidative stress / GABAergic origin hypothesis, NMDA acceptance on GABAergic neurons Decreased body function causes oxidative stress, resulting in a decrease in parvalbumin-positive GABA neurons, resulting in impaired synchronous firing on a number of pyramidal neurons that are innervated by parvalbumin-positive GABA neurons and cognitive Dysfunction and numerous psychological symptoms occur (Non-Patent Documents 2 and 3).

The pillars of treatment for central nervous system diseases such as schizophrenia are treatment by medication and psychiatric rehabilitation. Some central nervous system diseases, such as schizophrenia mentioned above, are caused by a decrease in nerve cells or damage to nerve cells, and for such diseases, , Neuroprotective drugs are effective.

On the other hand, it is difficult to create new drugs for central nervous system diseases such as schizophrenia because there are many diseases for which the cause of the disease and the underlying treatment have not yet been solved.

Under such circumstances, an object of the present invention is to provide a candidate compound for an active ingredient of a drug for central nervous system diseases or a novel compound that can be a precursor thereof.

That is, the present invention is as follows.
[1]
A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(In the formula (1), R ¹ , R ² and R ³ are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and an alkoxy group having 1 to 6 carbon atoms, and are R ¹ , R. at least one of the ² and R ³ one is a hydroxy group.)
[2]
In formula (1), R ¹ , R ² and R ³ are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and a methoxy group, respectively, and among R ¹ , R ² and R ³ . The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein at least one is a hydroxy group.
[3]
The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R ¹ is a methoxy group, R ² is a hydroxy group, and R ³ is a hydrogen atom in the formula (1). ..
[4]
In the formula (1), the compound according to [1] or [2], wherein R ¹ is a hydroxy group, R ² is a methoxy group, and R ³ is a hydrogen atom, or a pharmaceutically acceptable salt thereof. ..
[5]
The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are hydroxy groups and R ³ is a hydrogen atom, respectively, in the formula (1).
[6]
A pharmaceutical composition containing the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof as an active ingredient.
[7]
The pharmaceutical composition according to [6], which is a neuroprotective agent.
[8]
The pharmaceutical composition according to [6] or [7], which is a therapeutic agent for a central nervous system disease.
[9]
The pharmaceutical composition according to any one of [6] to [8], which is a therapeutic agent for schizophrenia.
[10]
A method for protecting nerves, wherein the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof is administered to a patient.
[11]
A method for treating a central nervous system disease, wherein the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof is administered to a patient.
[12]
A method for treating schizophrenia, wherein the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof is administered to a patient.
[13]
The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, which is used for nerve protection.
[14]
The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, which is used for the treatment of central nervous system diseases.
[15]
The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, which is used for the treatment of schizophrenia.
[16]
Use of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof for producing a neuroprotective drug.
[17]
Use of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for a central nervous system disease.
[18]
Use of the compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof for producing a therapeutic agent for schizophrenia.

The compound of the present invention is a novel compound that can be a candidate compound for an active ingredient of a drug for central nervous system diseases or a precursor thereof.

The ¹ H-NMR spectrum of compound A is shown. The spectrum of ¹³ C-NMR of compound A is shown. The ¹ H-NMR spectrum of compound B is shown. The spectrum of ¹³ C-NMR of compound B is shown. The ¹ H-NMR spectrum of Compound C is shown. The spectrum of ¹³ C-NMR of compound C is shown. The ¹ H-NMR spectrum of compound D is shown. The spectrum of ¹³ C-NMR of compound D is shown. 6 is a graph showing the results of measuring the antioxidant activity of compounds I, A, B, C, clozapine and olanzapine by the APF method. It is a graph which shows the antioxidant activity measurement result by the HPF method of compounds I, A, B, C, clozapine and olanzapine. 6 is a graph showing the results of measuring the antioxidant activity of compounds I, A, B, C, clozapine and olanzapine by the DCFH method. It is a graph which shows the result of the methamphetamine-induced transfer momentum measurement for compound A. It is a graph which shows the result of the methamphetamine-induced transfer momentum measurement for compound B. It is a graph which shows the result of the methamphetamine-induced transfer momentum measurement about clozapine. It is a graph which shows the result of the glutathione concentration measurement in the medial prefrontal cortex for compound A. It is a graph which shows the result of the glutathione concentration measurement in the medial prefrontal cortex for compound B. It is a graph which shows the result of the glutathione concentration measurement in the medial prefrontal cortex for compound C. It is a graph which shows the result of the glutathione concentration measurement in the medial prefrontal cortex about clozapine. It is a graph which shows the result of the glutathione concentration measurement in the medial prefrontal cortex about olanzapine. It is a graph which shows the oxidized glutathione / reduced glutathione ratio in the medial prefrontal cortex for compound A. It is a graph which shows the oxidized glutathione / reduced glutathione ratio in the medial prefrontal cortex for compound C. It is a graph which shows the measurement result of the parvalbumin positive GABA nerve number in the medial prefrontal cortex for compound A. It is a graph which shows the measurement result of the parvalbumin positive GABA nerve number in the medial prefrontal cortex for compound B. It is a graph which shows the measurement result of the parvalbumin-positive GABA nerve number in the medial prefrontal cortex for compound C. It is a graph which shows the measurement result of the parvalbumin positive GABA nerve count in the medial prefrontal cortex about clozapine. It is a graph which shows the measurement result of the parvalbumin-positive GABA nerve count in the medial prefrontal cortex about olanzapine.

[Compound of formula (1)]
The present invention provides a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(In the formula (1), R ¹ , R ² and R ³ are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and an alkoxy group having 1 to 6 carbon atoms, and are R ¹ , R. at least one of the ² and R ³ one is a hydroxy group.)

In formula (1), R ¹ , R ² and R ³ are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and a methoxy group, respectively, and among R ¹ , R ² and R ³ . It is preferable that at least one is a hydroxy group. Compounds in which at least one of R ¹ , R ² and R ³ is a hydroxy group and the remaining group is a hydrogen atom, a hydroxy group, or a methoxy group and a pharmaceutically acceptable salt thereof have antioxidant activity. It is expensive and can be easily manufactured by the manufacturing method described later.

In the formula (1), it is more preferable that R ¹ is a methoxy group, R ² is a hydroxy group, and R ³ is a hydrogen atom. Such compounds are (3aR ^* , 4S ^* , 7R ^* , 7aS ^* ) -2- (4- (4- (4-hydroxy-3-methoxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H- 4,7-Metanoisoindole-1,3 (2H) -dione. The compound and its pharmaceutically acceptable salt have high antioxidant activity. The compound is a compound represented by the following formula (2).

In the formula (1), it is more preferable that R ¹ is a hydroxy group, R ² is a methoxy group, and R ³ is a hydrogen atom. Such compounds are (3aR ^* , 4S ^* , 7R ^* , 7aS ^* ) -2- (4- (4- (3-hydroxy-4-methoxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H- 4,7-Metanoisoindole-1,3 (2H) -dione. The compound and its pharmaceutically acceptable salt also have high antioxidant activity. The compound is a compound represented by the following formula (3).

It is more preferable that R ¹ and R ² are hydroxy groups and R ³ is a hydrogen atom in the formula (1), respectively. Such compounds are (3aR ^* , 4S ^* , 7R ^* , 7aS ^* ) -2- (4- (4- (3,4-dihydroxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H-4, 7-Metanoisoindole-1,3 (2H) -dione. The compound and its pharmaceutically acceptable salt also have high antioxidant activity. The compound is a compound represented by the following formula (4).

The term "pharmaceutically acceptable salt" as used herein is not particularly limited as long as it forms a salt with the compound represented by the formula (1) and is pharmaceutically acceptable, and is, for example, inorganic. Examples thereof include acid salts, organic acid salts, inorganic base salts, organic base salts, acidic or basic amino acid salts and the like.

Examples of inorganic acid salts include hydrochlorides, hydrobromates, sulfates, nitrates, phosphates and the like, and examples of organic acid salts include acetates, succinates, fumarates and maleines. Carboates such as acid salts, tartrates, citrates, lactates, stearate, benzoates, mandelates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, benzenesulfonic acids Examples include sulfonates such as salts.

Examples of inorganic base salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salts, ammonium salts and the like. Examples of organic base salts include organic base salts. Examples thereof include diethylamine salt, diethanolamine salt, meglumin salt, N, N'-dibenzylethylenediamine salt and the like.

Examples of acidic amino acid salts include aspartate, glutamic acid and the like, and examples of basic amino acid salts include arginine salt, lysine salt, ornithine salt and the like.

Hereinafter, in the present specification, the term "compound according to the present invention" means a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.

The compound of the following formula (5) is tandospirone. Tandospirone is a 5- _HT1A receptor partial agonist and is used as a drug for improving anxiety / depressive symptoms of psychosomatic disorder and neurosis. In addition, tandospirone can prevent cognitive impairment in schizophrenia model animals (rats) (Horiguchi et al., Neuropathic psychiatry, 2012, Vol. 37, No. 10, p. 2175-2183), and schizophrenia. It has been reported to have neuroprotective effects such as improving the memory function of patients (Sumiyoshi et al., American Journal of Psychiatry, 2001, Vol. 158, p.1722-1725).

The compound of the following formula (6) is apocynin. Apocynin was isolated from Picrorhizakurroa, a plant of the genus Koouren from the Western Himalayas, which was used as a folk medicine for liver / heart disease, jaundice, and asthma. Apocynin inhibits NADPH oxidase activity and inhibits the production of reactive oxygen species. Therefore, it has antioxidant activity and exhibits a wide range of anti-inflammatory effects.

Therefore, it is considered that the compound according to the present invention having a part of each structure of tandospirone and apocynin has an antioxidant effect and a neuroprotective effect at the same time. Furthermore, since tandospirone and apocynin are compounds that have been used as pharmaceuticals for a long time or have been contained in folk medicine, it is considered that the compound according to the present invention is highly safe for the human body.

[Use of compounds]
Since the compound according to the present invention has high antioxidant activity, it may be used as an active ingredient of a pharmaceutical composition for preventing and treating various diseases. Reactive oxygen species that are overproduced in the body cause protein oxidation, lipid oxidation, nucleic acid decomposition, etc., damage cells, cause dysfunction, and affect the progression of pathological conditions. The target disease of the pharmaceutical composition containing the compound according to the present invention as an active ingredient is a disease induced or promoted by overproduction of active oxygen in the body. The antioxidant activity of the compounds according to the present invention may improve the symptoms of diseases caused by such oxidative stress. Examples of such diseases include central nervous system diseases, cardiovascular diseases, digestive system diseases, renal diseases, respiratory diseases, metabolic / endocrine diseases, allergic diseases, eye diseases, aging / senile diseases, and the like. Be done. Further, as described above, the compound according to the present invention is considered to have a neuroprotective effect, and may be used as an active ingredient of a neuroprotective drug. As used herein, the term "neuroprotective drug" refers to a drug that reduces the degree of disease caused by impaired nerve cell function.

Therefore, the compound according to the present invention exerts a particularly effective effect on central nervous system diseases due to its antioxidant activity and neuroprotective action, and may be used as an active ingredient of a therapeutic agent for central nervous system diseases. Diseases targeted by the therapeutic agent for central nervous system diseases containing the compound according to the present invention include schizophrenia and other neuropsychiatric diseases in which oxidative stress has been reported to be involved in the pathological condition, for example, Alzheimer's disease. , Parkinson's disease, bipolar disorder, depression, anxiety disorder, schizophrenia, epilepsy and the like. In addition, tandospirone, which is the parent substance of the present invention, is approved for insurance coverage for psychosomatic disorders. According to the Nanzando Medical Dictionary (2015), psychosomatic disorder is a condition in which psychosocial factors are closely involved in the onset and course of physical illness, and organic or functional disorders are recognized. However, physical symptoms associated with other psychosomatic disorders such as neuropathy and depression are excluded. ”, And digestive ulcers, bronchial asthma, migraine, and irritable bowel syndrome are mentioned. Therefore, the compound according to the present invention may be effective for these psychosomatic disorders as well as the parent substance.

For example, with respect to schizophrenia, as mentioned above, the causes of negative symptoms of schizophrenia and cognitive dysfunction are associated with volume loss in the patient's frontal cortex and are one of the major causes of volume loss in the frontal cortex. One is considered to be a decrease in parvalbumin-positive GABA neurons, and Non-Patent Document 1 suggests that the decrease in parvalbumin-positive GABA neurons in an animal model of schizophrenia is mediated by oxidative stress. There is. The main hypothesis of schizophrenia is that decreased function of NMDA receptors on GABAergic neurons causes oxidative stress, resulting in a decrease in parvalbumin-positive GABA neurons, resulting in a decrease in parvalbumin-positive GABA neurons. Synchronous firing on a large number of controlled pyramidal neurons is impaired, resulting in cognitive dysfunction and numerous psychological symptoms.

Therefore, the antioxidant action of the compound according to the present invention may reduce oxidative stress in the frontal cortex and improve negative symptoms of schizophrenia and cognitive dysfunction. That is, the compound according to the present invention may be suitably used as an active ingredient of a therapeutic agent for schizophrenia.

In addition, clozapine, which is used as a therapeutic agent for schizophrenia, has a serious side effect of agranulocytosis, but clozapine-induced agranulocytosis causes oxidative stress and apoptosis of granulocytes. (Fehsel et al., Journal of Clinical Psychopahrmacology, 2005, Vol. 25, p. 419-426) and clozapine-induced agranulocytosis of glutathione precursor N-acetylcysteine, which has antioxidant activity. Suppression of schizophrenia (Williams et al., Molecular Therapy, 2000, Vol. 58, p. 207-216) has been reported. On the other hand, since the compound according to the present invention has an antioxidant effect contrary to clozapine, it may be used as a therapeutic agent for schizophrenia without the side effect of agranulocytosis instead of clozapine.

The target patient of the pharmaceutical composition containing the compound according to the present invention as an active ingredient is preferably a human or a non-human mammal. In addition, as a form of the pharmaceutical composition, for example, oral administration with tablets, capsules, granules, powders, syrups, etc., or parenteral administration with injections, suppositories, inhalants, transdermal absorbents, external preparations, etc. Administration is mentioned. In addition, in order to prepare each preparation of such various dosage forms, the compound according to the present invention may be used alone or as another pharmaceutically acceptable excipient, binder, bulking agent, disintegrant, surfactant. Agents, lubricants, dispersants, buffers, preservatives, flavoring agents, odorants, fragrances, coatings, carriers, diluents, colorants and the like can be used in appropriate combinations.

Further, the compound according to the present invention may function as the active ingredient of the pharmaceutical composition itself, or may be a precursor of the active ingredient of the pharmaceutical composition. That is, the compound according to the present invention may be used as a precursor, and the final compound obtained by chemically changing the compound according to the present invention may function as an active ingredient of the pharmaceutical composition. Such chemical changes may be made in vitro or in vivo.

[Method for producing the compound of formula (1)]
The compound of the formula (1) can be produced, for example, by dehydrating and condensing the compound of the following formula (7) and the compound of the following formula (8).

In the formula ^(8), R 1, ^{R 2} and ^{R 3} are the same as ^R 1, ^{R 2} and ^{R 3} in the formula (1). However, as described later, it may be protected by R ^1, R ² and / or R ³ is protected if necessary group.

The compound of the formula (7) is N- (4-piperazinylbutyl) bicyclo [2.2.1] heptane-2,3-dicarboxyimide, and is, for example, Japanese Patent Application Laid-Open No. 62-1323179. (Or, it can be prepared by the method described in European Patent Application Publication No. 0196096 (A2)).

The compound of the formula (1) can be produced by dissolving the compound of the formula (7) and the formula (8) in a solvent and adding a dehydration condensing agent. When R ¹ , R ² and / or R ^{3 of} formula (1) are highly active groups, these groups may be protected with protecting groups, if necessary. As such a protecting group, a known protecting group can be used. For example, when R ¹ , R ² and / or R ³ are hydroxy groups, a benzyl group or the like can be used as the protecting group. In this case, the target compound can be obtained by removing the protecting group after the reaction, if necessary. The introduction and removal of these protecting groups can be carried out by known methods such as Peter G. et al. M. Wuts, "Greene's Protective Groups in Organic Synthesis, 5th Edition", 2014, may be carried out according to the method described in Wiley.

Examples of the dehydration condensing agent include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), N, N'-dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBT), and diphenylphosphoryl. Acid azide (DPPA), 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride n hydrate (DMT-MM), 2-methyl-6 -Known dehydration condensing agents such as nitrobenzoic acid anhydride (MNBA) can be used, and these can be used alone or in combination of two or more. Preferably, the dehydration condensing agent is EDC.

Examples of the solvent used for dehydration condensation include dichloromethane, tert-butanol, tetrahydrofuran, chloroform, diethyl ether, benzene, cyclohexane, n-hexane, acetonitrile, dimethylformamide, tert-butylmethyl ether and dimethylacetamide. Can be used alone or in combination of two or more. Preferably, the solvent is a mixed solvent of dichloromethane and tert-butanol or tetrahydrofuran.

The generated compound of formula (1) can be appropriately purified, washed and dried. Further, when the compound of the formula (1) is used, it can be appropriately dissolved in a solvent before use. The solvent used for the dehydration condensation described above can also be suitably used when the compound of the formula (1) is used.

Hereinafter, the present invention will be described based on examples. The present invention is not limited to the following examples.

[Composite synthesis]
(Synthesis of Compound A)
(3aR ^* , 4S ^* , 7R ^* , 7aS ^* ) -2- (4- (4- (4-hydroxy-3-methoxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H-4 by the following method , 7-Metanoisoindole-1,3 (2H) -dione (hereinafter referred to as "Compound A") was synthesized. Compound A is a compound having the structure of the above formula (2), and in the formula (1), R ¹ is a methoxy group, R ² is a hydroxy group, and R ³ is a hydrogen atom. Is.

N- (4-piperazinylbutyl) bicyclo [2.2.1] heptane-2,3-dicarboxyimide (compound of formula (7), hereinafter referred to as "compound I") 504 mg, 4-hydroxy- 358 mg of 3-methoxybenzoic acid and 701 mg of EDC were dissolved in a mixture of 12.5 mL of dichloromethane and 0.35 mL of tert-butanol. After stirring at room temperature for 1 hour, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and further with saturated brine. The obtained residue was purified by silica gel column chromatography to obtain white amorphous compound A (455 mg).

(Synthesis of compound B)
(3aR ^* , 4S ^* , 7R ^* , 7aS ^* )-2- (4- (4- (3-hydroxy-4-methoxybenzoyl) piperazin-1-yl) butyl) hexahydro-1H-4 by the following method , 7-Metanoisoindole-1,3 (2H) -dione (hereinafter referred to as "Compound B") was synthesized. Compound B is a compound having the structure of the above formula (3), and in the formula (1), R ¹ is a hydroxy group, R ² is a methoxy group, and R ³ is a hydrogen atom. Is.

Compound I was dissolved in a mixture of 508 mg, 3-hydroxy-4-methoxybenzoic acid (358 mg) and EDC (679 mg) in a mixture of 12.5 mL of dichloromethane and 0.35 mL of tert-butanol. After stirring at room temperature for 1 hour, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and further with saturated brine. The obtained residue was purified by silica gel column chromatography to obtain white amorphous compound B (555 mg).

(Synthesis of compound C)
(3aR ^* , 4S ^* , 7R ^* , 7aS ^* ) -2- (4- (4- (3,4-dihydroxybenzoyl) piperazine-1-yl) butyl) hexahydro-1H-4,7 by the following method -Metanoisoindole-1,3 (2H) -dione (hereinafter referred to as "Compound C") was synthesized. Compound C is a compound having the structure of the above formula (4), and in the formula (1), both R ¹ and R ² are hydroxy groups, and R ³ is a hydrogen atom.

1.00 g of Compound I, 1.43 g of 3,4-dibenzyloxybenzoic acid, 1.40 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), dichloromethane (25 mL) and tert. -Dissolved in a mixture of butanol (0.7 mL). After stirring at room temperature for 35 minutes, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and further with saturated brine. The obtained residue was purified by silica gel column chromatography to obtain 1.55 g of white amorphous compound D. Compound D is a compound in which R ¹ and R ² are benzyloxy groups (-OBn) and R ³ is a hydrogen atom in the formula (1). Under a hydrogen atmosphere, 1.26 g of compound D and 620 mg of 10% palladium-carbon were suspended in 65 mL of tetrahydrofuran (THF) and stirred vigorously for two days. The solid was filtered off using a filter paper, and the residue obtained by concentration was purified by silica gel column chromatography to obtain a pale red amorphous compound C (687 mg).

The structures of the obtained compounds A, B, C and D were confirmed by ¹ H-NMR and ¹³ C-NMR. 1 to 8 show the spectra of ¹ H-NMR and ¹³ C-NMR of compounds A to D. FIG. 1: ¹ H-NMR of compound A, FIG. 2: ¹³ C-NMR of compound A, FIG. 3: ¹ H-NMR of compound B, FIG. 4: ¹³ C-NMR of compound B, FIG. 5: of compound C. ^{1 1} H-NMR, FIG. 6: ¹³ C-NMR of compound C, 7: ^{1 1} H-NMR of compound D, FIG. 8: ¹³ C-NMR of compound D.

[Measurement of antioxidant activity of compounds (in vitro)]
The in vitro antioxidant activity of compounds I, A, B, C, clozapine and olanzapine was measured by the following methods. Clozapine and olanzapine are conventional therapeutic agents for schizophrenia.

(Materials and methods)
Human lymphoma cells U937 were used. One of compounds I, A, B, C, clozapine and olanzapine was added to the cell suspension as a drug so as to have a concentration of 100 μM, and a cell suspension to which different drugs were added was prepared. As a control, a cell suspension to which no drug was added was used. After culturing each cell suspension at 37 ° C. for 30 minutes, a fluorescent reagent was added. As a fluorescent reagent, one of three types, aminophenylfluorescein (APF method), hydroxyphenylfluorescein (HPF method), 2', 7'-dichlorodihydrofluorescein (DCFH method), has a fluorescent reagent concentration of 2.5 μM. It was added so as to become. In the DCFH method, the antioxidant activity of clozapine was measured by changing the concentration of clozapine to 25 μM and 50 μM in addition to the concentration of 100 μM. In the APF process, hydroxyl radicals as active oxygen species (· OH) and hypochlorite ion (OCl ^-) can be measured scavenging activity, the HPF process, scavenging activity of hydroxyl radicals as active oxygen species (· OH) In the DCFH method, the scavenging activity of hydrogen peroxide (H ₂ O ₂ ) as an active oxygen species can be measured. After adding each fluorescent reagent, the cells were further cultured for 15 minutes and then irradiated with X-rays (dose 10 Gy). Immediately after irradiation, the fluorescence intensity of each cell was measured by the flow cytometry method.

(result)
9 to 11 show the results of antioxidant activity measurement by the APF method, the HPF method, and the DCFH method, respectively. In each figure, the vertical axis represents the fluorescence intensity of each cell suspension when the fluorescence intensity when the control cell suspension is not irradiated with X-rays is 1, and "*" in the figure represents the fluorescence intensity of each cell suspension. , The t-test with the significance level set to 5% shows that there is a significant difference. 9 and 10 are graphs of control, compounds I, A, B, C, clozapine, and olanzapine from the left. The left figure of FIG. 11 is a graph of control, compounds I, A, B, C and clozapine from the left, and the right figure of FIG. 11 is a graph of control, 25 μM clozapine, 50 μM clozapine, 100 μM clozapine and 100 μM olanzapine from the left. Is.

From FIG. 9 (APF method), Compound A, B, C, the clozapine and olanzapine, intracellular hydroxyl radicals (· OH) or hypochlorite (OCl ^-) that there are scavenging activity was shown. No scavenging activity was observed in Compound I, which is a precursor of Compounds A to C.

From FIG. 10 (HPF method), it was shown that compounds A, B, C and olanzapine have intracellular hydroxyl radical (.OH) scavenging activity. No scavenging activity was observed in Compound I and clozapine.

From FIG. 11 (DCFH method), it was shown that compound C and olanzapine have the scavenging activity of intracellular hydrogen peroxide (H ₂ O ₂ ). On the contrary, clozapine was shown to have an effect of enhancing intracellular hydrogen peroxide.

[Measurement of effect of compounds using animal models (in vivo)]
Compounds A, B, C, clozapine and olanzapine were administered to model animals of schizophrenia by the following methods, and weight measurement, transfer exercise measurement, and glutathione measurement in the medial prefrontal cortex were performed.

(Materials and methods)
1. 1. Creation of schizophrenia model animals Uehara et al., Psychopharmacology, 2009, Vol. 206, p. 623-630 (“Reference 1”), Uehara et al., Brain Research, September 17, 2010, Vol. 1352, p. 223-230 (hereinafter, "Reference 2"), and Uehara et al., Journal of Psychiatry Research, May 2012, Vol. 46, No. 5, p. A schizophrenia model animal was prepared as follows according to the method described in 622-629 (hereinafter, “Reference 3”). Wistar rats were used in the experiment. A 14-day-old female rat (Japan Cesslercy Co., Ltd., Hamamatsu, Japan) was purchased. Male pups obtained by giving birth to female rats were randomly divided into two groups, and the following treatments were performed for 4 days 7 to 10 days after birth. Neonatal MK-801 Group: MK-801 (Sigma-Aldrich, St. Louis, Missouri, USA) 0.2 mg / kg body weight, an N-methyl-D-aspartate glutamate receptor (NMDA receptor) antagonist It was subcutaneously administered once a day. Neonatal saline group: Saline 0.2 mg / kg body weight was subcutaneously administered once a day. Weaned on the 21st day after birth, and then bred every 4 to 6 animals. According to Reference 1 above, rats administered with MK-801 at an early age exhibit schizophrenia-like symptoms at an early stage of maturity.

2. 2. Administration of compounds A, B, C, clozapine and olanzapine 1. The neonatal MK-801 group and the neonatal saline group obtained in the above were divided into 6 groups, respectively, and drug administration was performed. Compounds A, B, C prepared as described above, clozapine (Sigma Aldrich, St. Louis, Missouri, USA) and olanzapine (Fujifilm Wako Pure Chemical Industries, Ltd., Osaka, Japan) were used as drugs, and the same amount of physiology was used as a control. Saline was used. One of the above drugs or physiological saline was subcutaneously administered once a day for 14 days 43 to 56 days after birth. The doses were 2.5 mg / kg / day for compounds A, B and C, 5 mg / kg / day for clozapine and 0.2 mg / kg / day for olanzapine.

3. 3. Body weight measurement and measurement of methamphetamine-induced transfer momentum According to the method described in Reference 2, methamphetamine-induced transfer momentum was measured as follows. A transfer motion measuring device (AMB-2020, Ohara Medical Industry Co., Ltd., Tokyo, Japan) was used to measure the transfer momentum. The measurement of the transfer momentum is described in 2. above. Rats administered with Compounds A to C, clozapine or olanzapine were subjected to 57 days after birth (24 hours after the final administration of compounds A, B, C, clozapine or olanzapine). Each rat was weighed prior to the transfer momentum measurement. Thirty minutes after the rats were transferred to the device, methamphetamine 1.0 mg / kg (Dainippon Sumitomo Pharmaceutical Co., Ltd., Tokyo, Japan) was subcutaneously administered, and methamphetamine-induced transfer momentum was measured for 90 minutes. The increase in methamphetamine-induced transfer momentum can be used as a model for positive symptoms of schizophrenia.

4. Measurement of glutathione in the medial prefrontal cortex 3. Immediately after the measurement of methamphetamine-induced transfer momentum, the brain was removed, the left prefrontal cortex was carefully excised, and glutathione was measured. For the measurement of glutathione, total glutathione, reduced glutathione (Glutathione-SH; GSH) and oxidized glutathione (Glutathione-S-S-Glutathione; GSSG) were used to measure glutathione using a glutathione measurement kit (Japan Aging Control Laboratory, Shizuoka, Japan). ) Was measured. Each measured amount was the concentration per tissue weight.

5. Measurement of parvalbumin-positive GABA nerve count in the medial prefrontal cortex. Immediately after the measurement of methamphetamine-induced transfer momentum, the brain was removed, the right prefrontal cortex was carefully excised, and the parvalbumin-positive GABA nerve number was measured. A tissue specimen having a thickness of 30 μm was prepared from the excised tissue. Immunostaining was performed using an antibody against parvalbumin, and the number of parvalbumin-positive GABA nerves was measured.

6. For statistical body weight, a two-way ANOVA (post-hoc Bonferroni test) was performed. Methamphetamine-induced translocation momentum and glutathione- and parvalbumin-positive GABA nerve counts in the medial prefrontal cortex were analyzed by one-way ANOVA. The main effects were neonatal treatment (saline, MK-801) and drug administration (saline, compounds A, B, C, clozapine, olanzapine). If appropriate, after one-way ANOVA, each group was compared on a Bonferroni test.

(result)
1. 1. Effect of each drug on body weight Table 1 shows the body weight of rats in each group measured 57 days after birth. Administration of MK-801 during the neonatal period (7-10 days after birth) did not affect body weight (p = 0.055). On the other hand, in the drug administration before and after puberty (43-56 days after birth), the administration of compounds A, B, C and olanzapine did not affect the body weight, but the administration of clozapine reduced the body weight (p <0.01). ).

2. 2. Methamphetamine-induced transfer momentum FIGS. 12 to 14 are graphs showing the results of methamphetamine-induced transfer momentum measurement for compound A, compound B, and clozapine, respectively. In each figure, the vertical axis indicates the amount of transfer momentum per 90 minutes, and in the figure, “*” indicates that there is a significant difference in the Bonferroni test with the significance level of 5%. In addition, in each figure, from the left, the group in which the physiological saline was administered 57 days after birth in the neonatal physiological saline group, and the drug (Compounds A, B or Crozapine) -administered group, neonatal MK-801 group to which saline was administered 57 days after birth, neonatal MK-801 group to receive drug (compound A, B or clozapine) 57 days after birth The graph of the group to which was administered is shown.

Interactions (p <0.01 and p = 0.025, respectively) were observed in compound A administration and compound B administration, but no main effect was observed (FIGS. 12 and 13, respectively). With olanzapine administration, an interaction was observed (p = 0.036), but no main effect was observed. No interaction was observed with clozapine administration, and the main effects (p = 0.037 and p <0.01, respectively) were observed with neonatal MK-801 administration and drug administration, respectively (FIG. 14). These statistical results show the following. That is, compounds A, B, and olanzapine suppress the methamphetamine-induced momentum increased by administration of neonatal MK-801. Clozapine itself has the effect of enhancing methamphetamine-induced momentum.

3. 3. Total glutathione in the medial prefrontal cortex FIGS. 15-19 are graphs showing the results of glutathione concentration measurements in the medial prefrontal cortex for compounds A, B, C, clozapine, and olanzapine, respectively. In each figure, the vertical axis indicates the total glutathione concentration per tissue weight, and in the figure, “*” indicates that there is a significant difference in the Bonferroni test with the significance level of 5%. In addition, in each figure, from the left, the group in which the physiological saline was administered 57 days after birth in the neonatal physiological saline group, and the drug (Compounds A, B, C, clozapine or olanzapine) administered, neonatal MK-801 group administered physiological saline 57 days after birth, neonatal MK-801 group 57 days after birth drug (Compound A, A graph of the group to which B, C, clozapine or olanzapine) was administered is shown.

The total glutathione (GSH + GSH) concentration showed an interaction between compound A administration, compound B administration, and compound C administration (p = 0.011, p = 0.037, p <0.01), but compound A. No main effects of administration, compound B administration, and compound C administration were observed (FIGS. 15, 16, 16 and 17). Furthermore, in the administration of Compound A and the administration of Compound C, the total glutathione concentration decreased by the administration of MK-801 in the neonatal period was significantly improved by the administration of Compound A and the administration of Compound C even in the Bonferroni test. On the other hand, no interaction was observed with olanzapine administration, and only the main effect of neonatal MK-801 administration was observed (p <0.01) (FIG. 18). No interaction was observed with clozapine administration, but the main effects (p <0.01, p <0.01) were observed with neonatal MK-801 administration and clozapine administration, respectively (Fig. 19). These statistical results show the following. That is, compounds A, B and C ameliorate the reduction in glutathione caused by administration of neonatal MK-801. Olanzapine does not affect the glutathione reduction caused by neonatal MK-801 administration. Clozapine itself has the effect of lowering glutathione.

4. Oxidized glutathione / reduced glutathione ratio in the medial prefrontal cortex FIGS. 20 and 21 are graphs showing the oxidized glutathione / reduced glutathione ratio in the medial prefrontal cortex for compounds A and C, respectively. From the left, the neonatal saline group to which physiological saline was administered 57 days after birth, the neonatal saline group to which the drug (compound A or C) was administered 57 days after birth, and neoplasia. The graph of the group to which the physiological saline was administered 57 days after birth in the childhood MK-801 group, and the group to which the drug (compound A or C) was administered 57 days after birth in the neonatal MK-801 group is shown.

Oxidized glutathione / reduced glutathione ratio (GSSG / GSH ratio) did not show any interaction between compound A administration and compound C administration, but the main effect of drug administration (compound A or compound C) was observed, respectively ( p <0.01, p = 0.038) (FIGS. 20, 21). Administration of olanzapine and clozapine did not show any significant changes. These statistical results show the following. That is, compound A and compound C have the effect of lowering the oxidized glutathione / reduced glutathione ratio by themselves, but clozapine and olanzapine do not have such an effect.

5. Number of parvalbumin-positive GABA nerves in the medial prefrontal cortex FIGS. 22-26 are graphs showing the results of cell density of parvalbumin-positive GABA nerves in the medial prefrontal cortex for compounds A, B, C, clozapine, and olanzapine, respectively. Is. In each figure, the vertical axis indicates the cell density of parvalbumin-positive GABA nerve, and in the figure, “*” indicates that there is a significant difference in the Bonferroni test with the significance level of 5%. In addition, in each figure, from the left, the group in which the physiological saline was administered 57 days after birth in the neonatal physiological saline group, and the drug (compounds A, B, etc.) in the neonatal physiological saline group on 57 days after birth. C, clozapine or olanzapine) administered, neonatal MK-801 group administered physiological saline 57 days after birth, neonatal MK-801 group 57 days after birth drug (Compound A, A graph of the group to which B, C, clozapine or olanzapine) was administered is shown.

The parvalbumin-positive GABA nerve counts showed an interaction with compound A administration, compound B administration, and compound C administration, respectively (p = 0.012, p <0.001, p = 0.002). In the administration of Compound A and the administration of Compound B, the main effects were observed for each of the neonatal MK-801 treatment and the drug administration (Compound A: p <0.001, p = 0.012; Compound B: p = 0.002). , P = 0.042). In the administration of compound C, the main effect was observed in the treatment of neonatal MK-801 (p = 0.01). In the Bonferroni test, compound A administration, compound B administration, and compound C administration all improved the parvalbumin-positive GABA nerve count decreased by neonatal MK-801 treatment. No interaction was observed with clozapine and olanzapine administration, and only the main effect of neonatal MK-801 treatment was observed (p = 0.004, p <0.001). These results indicate that Compound A, Compound B and Compound C have the effect of improving the decrease in parvalbumin-positive GABA nerve count caused by administration of MK-801, but clozapine and olanzapine have no effect.

Claims

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

(In the formula (1), R 1 , R 2 and R 3 are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and an alkoxy group having 1 to 6 carbon atoms, and are R 1 , R. at least one of the 2 and R 3 one is a hydroxy group.)
In formula (1), R 1 , R 2 and R 3 are groups independently selected from the group consisting of a hydrogen atom, a hydroxy group and a methoxy group, respectively, and among R 1 , R 2 and R 3 . The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein at least one is a hydroxy group.
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is a methoxy group, R 2 is a hydroxy group, and R 3 is a hydrogen atom in the formula (1).
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydroxy group, R 2 is a methoxy group, and R 3 is a hydrogen atom in the formula (1).
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are hydroxy groups and R 3 is a hydrogen atom, respectively, in the formula (1).
A pharmaceutical composition containing the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
The pharmaceutical composition according to claim 6, which is a neuroprotective agent.
The pharmaceutical composition according to claim 6 or 7, which is a therapeutic agent for central nervous system diseases.
The pharmaceutical composition according to any one of claims 6 to 8, which is a therapeutic agent for schizophrenia.