KR20220055802A - Composition for antioxidant, anti-inflammatory, and dementia prevention or improvement comprising protein expression inhibitor and use thereof - Google Patents

Abstract

The present invention relates to a composition for preventing or improving antioxidant, anti-inflammatory, and dementia including a protein expression inhibitor and uses thereof. The present invention suppresses nerve cell death induced by a dementia-inducing toxic substance in nerve cells; has an excellent nerve cell protecting effect; provides preventing, improving, and treating effects of nerve cell damage; has an excellent anti-inflammatory effect by effectively inhibiting an inflammatory factor induced in activated microglial cells; and prevents or treats a nerve inflammation related disease. In addition, the present invention shows a protective effect for the nerve cell death in the nerve cells; confirms suppressing of nerve inflammation in activated microglial cells; and shows an effect as a pharmaceutical composition for establishing a new treating target in a brain nerve disease accompanied with nerve cell death and the nerve inflammation.

Description

Antioxidant, anti-inflammatory, and dementia prevention or improvement composition comprising a protein expression inhibitor, and use thereof

The present invention relates to a composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor, and uses thereof. More specifically, it provides a composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor. Through this, it can be used as a material in various food or pharmaceutical fields.

Aging is a functional, structural, and biochemical process that continues from birth to death. It occurs throughout the cells and tissues of the human body. It is a phenomenon that leads to the death of cells and the entire body. Theories explaining the aging process and causes are largely genetic (Chung.H.Y. et al., Kor. J. Gerontol., 2:1, 1992) and wasting theory (Chung.H.Y. et al., Kor. J. Gerontol. , 2:1, 1992). The double depletion theory explains that the function of the constituent cells of an organism deteriorates over time (wear & tear theory) or that it is caused by the accumulation of toxic substances. And free radicals generated through air pollution form toxic substances, thereby promoting aging and causing various diseases related to aging. The free radical theory is accepted as the most influential theory.

A free radical is a generic term for a material having one unpaired electron in its outermost electron orbit. In particular, free radicals derived from oxygen are called reactive oxygen species, and they react with proteins, lipids, carbohydrates, etc. to cause lipid peroxidation, DNA damage, and protein oxidation, thereby causing damage to intracellular structures and, consequently, cell death. In particular, it is involved in the inflammatory process as a cause of vascular aging, increasing arteriosclerosis, Alzheimer's disease, and homocysteine in the blood.

Toxic substances in the human body related to oxygen are called reactive oxygen species (ROS). These ROS types include superoxide, hydroxyl, peroxyl, alkoxyl, Free radicals such as hydroperoxyl, hydrogenperoxide, hypochlorous acid, ozone, singlet oxygen, peroxynitride There are non-free radicals (non free radial) such as peroxinitrite and the like. Among them, the most studied and important role among oxygen toxicity is superoxide free radicals, which are known as free radicals (Fridovich L., Science, 201:175,1978).

During aging, ROS generated in the mitochondria of cells becomes a target indicative of oxidative damage (Lesnefsky, E.J. & Hoppel, C.L. Arch. Biochem.Biophys.420, 287, 2003) This free radical theory, which is an intracellular oxygen radical has been reported that there are many correlations between aging-related oxidative stress and aging-related diseases (Finkel, T. & Holbrook, N.J., Science 408;239, 2000), and these oxidative stresses induce senescence. It has been reported to play an important role (Chen Q. et al., Proc. Natl. Acad. Sci. U. S. A. May 9;92(10):4337, 1995; Packer L. & Fuehr K., Nature, 267(5610) ):423, 1977).

This oxidative stress is a term used to describe the damage affecting cells by the oxidation of macromolecules due to increased levels of reactive oxygen species and decreased antioxidant reserve (Thomas C. & Squier, Experimental Gerontology, 36; 1539, 2001).

All aerobic organisms, including humans, fundamentally have a self-defense mechanism against the damage of active oxygen that always occurs in the process of energy metabolism using oxygen. It is the cause of several diseases such as arthritis, circulatory disorders, as well as dementia (Halliwell et al., Drugs, 42:569, 1991; Fukuzawa et al., J. Act. oxyg. Free Rad., 1:55, 1990).

For this reason, research on the development of antioxidants has been actively conducted, and antioxidant enzymes such as superoxide dismutase, catalase, and glutathioneperoxidase, which are enzyme-based prophylactic antioxidants, and vitamins that are natural antioxidants E, vitamin C, carotenoid, glutathione and synthetic antioxidant t-Butyl-4-hydroxyanisole (BHA) dibutylhydroxytoluene (3,5-(tButyl)-4- Although many antioxidants such as hydroxytoluene (BHT) are known, antioxidant enzymes decrease in their ability to defend against free radicals with age, and in the case of synthetic antioxidants, their mutagenicity and toxicity are pointed out, making them safer and stronger natural antioxidants. There is an urgent need for the development of the proposal.

On the other hand, inflammation (inflammation) is a local response to the wound site to initiate the invasion of pathogens or damaged tissue removal. Despite the positive role of inflammation, it has become one of the most common pathogenesis mechanisms for human diseases. The production of nitric oxide (NO) by activated monocytes and macrophages initiates a strong inflammatory response and is the most important part of the initial immune response to bacterial pathogens (Bogdan C., Nat. Immunol., 2 :907, 2001).

Inflammatory reaction is caused by tissue (cell) damage or infection with external infectious agents (bacteria, fungi, viruses, and various types of allergens). It exhibits a series of complex physiological reactions such as substance secretion, body fluid infiltration, cell migration, and tissue destruction and external symptoms such as erythema, edema, fever, and pain. In a normal case, the inflammatory response removes external infectious agents and regenerates damaged tissues to restore the function of the living organism, but if the inflammatory response is excessive or continuous because the antigen is not removed or an internal substance is the cause, it rather promotes mucosal damage, as a result. In some cases, it leads to diseases such as cancer.

Therefore, the development of a natural anti-inflammatory agent capable of preventing an excessive and persistent inflammatory reaction without side effects was also required.

KR 10-0510253 B1

It is an object of the present invention to provide a composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor, and uses thereof.

Another object of the present invention is to provide a composition capable of inhibiting neuronal cell death induced by dementia-inducing toxic substances in nerve cells and having an excellent neuroprotective effect, thereby preventing, improving and treating nerve cell damage will do

Another object of the present invention is to provide a composition useful for preventing or treating neuroinflammation-related diseases, which has an excellent anti-inflammatory effect by effectively inhibiting inflammation-inducing factors induced in activated microglia.

Another object of the present invention is to confirm that it exhibits a protective action against apoptosis in nerve cells and suppresses neuroinflammation in activated microglia cells, which is a cranial nerve disease accompanied by neuronal cell death and neuroinflammation. It may be provided as a pharmaceutical composition in which a new therapeutic target has been established.

In order to achieve the above object, the composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor according to an embodiment of the present invention contains a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient can contain:

[Formula 1]

[Formula 2]

here,

A is a substituent represented by Formula 2 or Formula 3,

* means the part to be joined,

L ₁ and L ₂ are the same or different from each other, and each independently represents a single bond, a substituted or unsubstituted C 1 to C 10 alkylene group and a substituted or unsubstituted C 6 to C 10 arylene group,

X ₁ is selected from the group consisting of O, S and N(R ₇ ),

Y ₁ And Y ₂ Are the same as or different from each other, each independently N or C (R ₈ ),

R ₁ to R ₈ are the same as or different from each other, and each independently hydrogen, deuterium, a cyano group, a nitro group, a halogen group, a hydroxy group, an alkylthio group having 1 to 4 carbon atoms, an alkyl group having 1 to 30 carbon atoms, 1 to 20 carbon atoms of a cycloalkyl group, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 5 to 60 nuclear atoms, 6 to carbon atoms 30 heteroarylalkyl group, C1-C30 alkoxy group, C1-C30 alkylamino group, C6-C30 arylamino group, C6-C30 aralkylamino group, C2-C24 hetero arylamino group, C1 to 30 alkylsilyl group, an arylsilyl group having 6 to 30 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms, and can form a substituted or unsubstituted ring by combining adjacent groups with each other,

When R ₁ to R ₈ are substituted, hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, alkyl group having 1 to 30 carbon atoms, alkenyl group having 2 to 30 carbon atoms, alkynyl group having 2 to 24 carbon atoms, carbon number A heteroalkyl group having 2 to 30 carbon atoms, an aralkyl group having 6 to 30 carbon atoms, a cycloalkyl group having 3 to 20 carbon atoms, a heterocycloalkyl group having 3 to 20 carbon atoms, an aryl group having 5 to 30 carbon atoms, a heteroaryl group having 2 to 30 carbon atoms, a carbon number Substituted with a substituent selected from the group consisting of a 3 to 30 heteroarylalkyl group, an alkoxy group having 1 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, an arylsilyl group having 6 to 30 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms And, when substituted with a plurality of substituents, they are the same or different from each other.

L ₁ and L2 may be the same as or different from each other, and each independently may be a single bond or an alkylene group having 1 to 10 carbon atoms.

The Y ₁ and Y ₂ are N.

Wherein X ₁ is O or S.

The composition may include the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as one or more active ingredients.

The compound represented by Formula 1 may be selected from the group consisting of the following compounds:

A pharmaceutical composition for preventing or improving antioxidant, anti-inflammatory and dementia including a protein expression inhibitor according to another embodiment of the present invention includes the compound in a pharmaceutically effective amount.

The pharmaceutical composition suppresses neuroinflammation in activated microglial cells, and thus has excellent therapeutic effect on cranial nerve diseases accompanied by neuronal cell death and neuroinflammation.

As used herein, the “halogen group” is fluorine, chlorine, bromine or iodine.

In the present invention, “alkyl” refers to a monovalent substituent derived from a saturated hydrocarbon having 1 to 40 carbon atoms in a straight or branched chain. Examples thereof include, but are not limited to, methyl, ethyl, propyl, isobutyl, sec-butyl, pentyl, iso-amyl, hexyl, and the like.

In the present invention, “alkenyl” refers to a monovalent substituent derived from a straight or branched unsaturated hydrocarbon having 2 to 40 carbon atoms and having one or more carbon-carbon double bonds. Examples thereof include, but are not limited to, vinyl, allyl, isopropenyl, 2-butenyl, and the like.

In the present invention, “alkynyl” refers to a monovalent substituent derived from a linear or branched unsaturated hydrocarbon having 2 to 40 carbon atoms and having one or more carbon-carbon triple bonds. Examples thereof include, but are not limited to, ethynyl, 2-propynyl, and the like.

In the present invention, “aryl” refers to a monovalent substituent derived from an aromatic hydrocarbon having 6 to 60 carbon atoms in which a single ring or two or more rings are combined. In addition, two or more rings may be simply attached to each other (pendant) or condensed form may be included. Examples of such aryl include, but are not limited to, phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, dimethylfluorenyl, and the like.

In the present invention, “heteroaryl” refers to a monovalent substituent derived from a monoheterocyclic or polyheterocyclic aromatic hydrocarbon having 6 to 30 carbon atoms. In this case, one or more carbons in the ring, preferably 1 to 3 carbons, are substituted with a heteroatom such as N, O, S or Se. In addition, a form in which two or more rings are simply attached to each other or condensed may be included, and further, a form condensed with an aryl group may be included. Examples of such heteroaryl include 6-membered monocyclic rings such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, phenoxathienyl, indolizinyl, indolyl ( polycyclic rings such as indolyl), purinyl, quinolyl, benzothiazole, and carbazolyl, and 2-furanyl, N-imidazolyl, 2-isoxazolyl , 2-pyridinyl, 2-pyrimidinyl, and the like, but is not limited thereto.

In the present invention, "aryloxy" is a monovalent substituent represented by RO-, wherein R means aryl having 6 to 60 carbon atoms. Examples of such aryloxy include, but are not limited to, phenyloxy, naphthyloxy, diphenyloxy, and the like.

In the present invention, "alkyloxy" is a monovalent substituent represented by R'O-, wherein R' means an alkyl having 1 to 40 carbon atoms, and has a linear, branched or cyclic structure. may include Examples of alkyloxy include, but are not limited to, methoxy, ethoxy, n-propoxy, 1-propoxy, t-butoxy, n-butoxy, pentoxy, and the like.

In the present invention, “alkoxy” may be a straight chain, branched chain or cyclic chain. Although the number of carbon atoms of alkoxy is not particularly limited, it is preferably from 1 to 20 carbon atoms. Specifically, methoxy, ethoxy, n-propoxy, isopropoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, Isopentyloxy, n-hexyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, benzyloxy, p-methylbenzyloxy, etc. may be, but is not limited thereto.

As used herein, "aralkyl" refers to an aryl-alkyl group wherein aryl and alkyl are as described above. Preferred aralkyls include lower alkyl groups. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. Binding to the parent moiety is through an alkyl.

In the present invention, “arylamino group” refers to an amine substituted with an aryl group having 6 to 30 carbon atoms.

In the present invention, “alkylamino group” refers to an amine substituted with an alkyl group having 1 to 30 carbon atoms.

In the present invention, “aralkylamino group” refers to an amine substituted with an aryl-alkyl group having 6 to 30 carbon atoms.

In the present invention, “heteroarylamino group” refers to an amine group substituted with an aryl group having 6 to 30 carbon atoms and a heterocyclic group.

In the present invention, “heteroaralkyl group” refers to an aryl-alkyl group substituted with a heterocyclic group.

In the present invention, “cycloalkyl” refers to a monovalent substituent derived from a monocyclic or polycyclic non-aromatic hydrocarbon having 3 to 40 carbon atoms. Examples of such cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantine, and the like.

In the present invention, “heterocycloalkyl” means a monovalent substituent derived from a non-aromatic hydrocarbon having 3 to 40 carbon atoms, and at least one carbon in the ring, preferably 1 to 3 carbons, is N, O, S or Se substituted with a hetero atom such as Examples of such heterocycloalkyl include, but are not limited to, morpholine and piperazine.

In the present invention, “alkylsilyl” refers to silyl substituted with alkyl having 1 to 40 carbon atoms, and “arylsilyl” refers to silyl substituted with aryl having 6 to 60 carbon atoms.

In the present invention, “condensed ring” refers to a condensed aliphatic ring, a condensed aromatic ring, a condensed heteroaliphatic ring, a condensed heteroaromatic ring, or a combination thereof.

In the present invention, 　 "adjacent 　 groups are combined with each other to form a ring" means 　 adjacent 　 groups are bonded to each other to form a substituted or unsubstituted aliphatic hydrocarbon ring; a substituted or unsubstituted aromatic hydrocarbon ring; substituted or unsubstituted aliphatic heterocycle; substituted or unsubstituted aromatic heterocycle; Or it means to form a condensed ring thereof.

In the present invention, the term “aliphatic hydrocarbon ring” refers to a non-aromatic ring and a ring composed of only carbon and hydrogen atoms.

Examples of the "aromatic hydrocarbon ring" in the present invention include, but are not limited to, a phenyl group, a naphthyl group, an anthracenyl group, and the like.

In the present invention, “aliphatic heterocycle” refers to an aliphatic ring including at least one heteroatom.

In the present invention, the term “aromatic heterocycle” refers to an aromatic ring including one or more heteroatoms.

In the present invention, the aliphatic hydrocarbon ring, the aromatic hydrocarbon ring, the aliphatic heterocycle and the aromatic heterocycle may be monocyclic or polycyclic.

In the present invention, "substitution" means that a hydrogen atom bonded to a carbon atom of a compound is replaced with another substituent, and the position to be substituted is not limited as long as the position at which the hydrogen atom is substituted, that is, a position where the substituent is substitutable, is not limited, and when two or more are substituted , two or more substituents may be the same as or different from each other. The substituent is hydrogen, deuterium, a cyano group, a nitro group, a halogen group, a hydroxy group, an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, a heteroalkyl group having 2 to 30 carbon atoms, a carbon number An aralkyl group having 6 to 30 carbon atoms, an aryl group having 5 to 30 carbon atoms, a heteroaryl group having 2 to 30 carbon atoms, a heteroarylalkyl group having 3 to 30 carbon atoms, an alkoxy group having 1 to 30 carbon atoms, an alkylamino group having 1 to 30 carbon atoms, a carbon number It may be substituted with one or more substituents selected from the group consisting of an arylamino group having 6 to 30 carbon atoms, an aralkylamino group having 6 to 30 carbon atoms, and a heteroarylamino group having 2 to 24 carbon atoms, but is not limited thereto.

The present invention inhibits neuronal cell death induced by dementia-induced toxic substances in neurons and has an excellent neuroprotective effect, thereby preventing, improving and treating neuronal damage, and activated microglia It has an excellent anti-inflammatory effect by effectively inhibiting inflammation-inducing factors induced in , thereby preventing or treating neuroinflammation-related diseases.

In addition, it was confirmed that it exhibits a protective action against neuronal apoptosis in nerve cells and suppressed neuroinflammation in activated microglia, which is a new therapeutic target in cranial nerve diseases accompanied by neuronal cell death and neuroinflammation. It can be effective with the established pharmaceutical composition.

1 is an experimental result regarding the neuronal cell death induced by H ₂ O ₂ using the SH-SY5Y (human neuroblastoma) cell line according to an embodiment of the present invention.
Figure 2 is an experimental result for the protective effect on the neuronal apoptosis induced by H ₂ O ₂ in SH-SY5Y cells.
3 is an experimental result regarding glutamate-induced neuronal cell death using a hippocampal neuronal cell line (HT22) cell line.
4 is an experimental result for the protective effect against glutamate-induced neuronal apoptosis in HT22 cells.
5 is an experimental result regarding the inhibition of the activity (phosphorylation) of STAT3 on BV2 (mouse microglial cell line) cells.
6 is an experimental result for inhibition of STAT3 activity in BV2 cells stimulated with LPS (lipopolysaccharide).
7 shows experimental results for inhibition of iNOS and COX-2 expression in LPS-stimulated BV2 cells.
8 is an experimental result for the inhibition of the expression of IL-6, TNF-α and iNOS in BV2 cells stimulated with LPS.

Hereinafter, embodiments of the present invention will be described in detail so that those of ordinary skill in the art can easily carry out the present invention. However, the present invention may be embodied in several different forms and is not limited to the embodiments described herein.

Recently, as the average lifespan increases and the aging of society progresses, the incidence of diseases related to aging is increasing. Accordingly, interest in aging and diseases related to aging are increasing.

Representative brain diseases include dementia, stroke, Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, and ischemia. , in particular, Alzheimer's disease, Parkinson's disease, stroke, etc. geriatric brain diseases including oxidative stress (oxidative stress) accompanying the formation of radicals in brain cells is a major etiology.

Oxidative stress is damage to cells or tissues by toxic free radicals. , is known to be involved in neurodegenerative diseases such as Parkinson's disease, Lou Gehrig's disease, and dementia.

Oxidative stress is proposed as a regulatory factor in aging and various neurological disorders. Oxidative stress is a condition created by an imbalance between oxidizing agents and antioxidants in biological systems. The imbalance leads to an increase in excessive levels of reactive oxygen species (ROS). In the human body, there are antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase, etc., so the antioxidant system is built to defend against cell damage.

However, when reactive oxygen/active nitrogen (ROS/RNS) is produced to a level that cannot be defended by the cell's own antioxidant system, it stresses the cell, which is called "oxidative stress". The generated reactive oxygen species attacks living cells and destroys lipids, proteins and nucleic acids (RNA, DNA) and inhibits various enzyme functions. By destroying it, it results in apoptosis. This oxidative stress and the resulting oxidative damage to cells are known to be involved in the pathogenesis of many diseases, and the brain is one of the organs particularly vulnerable to the effects of ROS because of its high oxygen demand and abundance of lipid cells sensitive to peroxidation.

Neurodegenerative diseases are related to neuronal cell death or decreased resistance, and there are two major mechanisms of neuronal cell death. First, it is caused by glutamate, an excitatory neurotransmitter present in the brain. Glutamate is an excitatory neurotransmitter in the central nervous system that acts on receptors in the brain nervous system and is involved in various physiological actions. However, when it is excessively secreted for various reasons, the influx into neurons is reduced and the extracellular glutamate concentration is increased. Increased glutamate induces toxicity resulting in neuronal cell death. The second is damage caused by direct oxidative stress. In the brain, the ratio of unsaturated fatty acids and oxygen consumption is high, so the generation of oxygen radicals is high, but the amount of antioxidant enzymes is relatively low compared to other organs, so the risk of damage by free radicals including oxygen radicals is high, which The mechanism of damage in post-ischemia reperfusion is also known.

Therefore, the design of antioxidant strategies that selectively target oxidative stress and redox imbalance could be an important therapeutic approach for neurological disorders. Antioxidants that remove or inhibit the production of reactive oxygen species can be used not only as anti-aging agents and anticancer agents, but also as a treatment for diseases such as diabetes and epilepsy, and as a treatment for neurodegenerative diseases such as dementia, Parkinson's disease, stroke, and Huntington's. can As described above, research on the mechanism of neurodegeneration related to neurodegenerative diseases is being actively conducted from various angles, and based on this, research to develop medicines that can prevent and treat them is being actively conducted.

On the other hand, inflammation is an immune response that occurs locally when cells or tissues are damaged or destroyed by external stimuli to restore the damaged area to normal and maintain it in its original state. Inflammation is a defense mechanism in vivo to maintain health in normal cases, but if it is not properly controlled and the inflammatory response is excessively increased, it can lead to damage to organs in the body and death due to shock. In addition, chronic inflammation due to a continuous inflammatory response is the cause of many diseases.

The central nervous system (CNS) consists of nerve cells (neurons) and glial cells (neuroglia). Glia cells make up about 90% of all brain cells. Glia cells are again composed of three types of astrocytes (astrocytes), microglia (microglia) and oligodendrocytes (oligodendrocytes).

Microglia account for about 10 to 15% of all cells in the brain in the central nervous system. It belongs to the resident innate immune system of the central nervous system, very similar to peripheral macrophages, and serves as the primary immune defense against exogenous threats as the main immune cells. As major players in the central nervous system immune system, microglia play a protective role in the brain in a healthy state and have a beneficial role in maintaining homeostasis of the central nervous system microenvironment.

Microglia act as the main inflammatory cell type in the brain and are “activated” to respond to pathogens and damage. That is, it moves to the site of infection/injury to destroy phagocytosis and pathogens, or to remove damaged cells. As part of the reaction, microglia secrete cytokines and chemokines as well as prostaglandin, nitric oxide (NO) and reactive oxygen species (ROS) to stimulate the immune response. elevate

The production of these substances induces an immune response in the short term, but its excessive or continuous production causes neurotoxicity and causes the death of nerve cells.

Therefore, microglia play an important role in finding and destroying pathogens and play a protective role in the body, whereas overactivation or continuous activation of microglia is caused by an inflammatory response or neuronal cell death (Alzheimer's Disease, AD), Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Creutzfelt-Jakob Disease (CJD) , stroke, and inflammatory and neuropathic pain (Inflammatory and Neuropathic pain) play an important role in the pathogenesis of various neurological diseases.

Neuronal cell death and inflammatory response increase due to increase in oxidative stress in brain nervous system diseases, resulting in loss of brain function. Accordingly, many drugs have been developed for the purpose of inhibiting apoptosis or inflammatory response of brain neurons.

The present invention confirmed that it exhibits a protective action against neuronal apoptosis in brain neurons, and suppresses neuroinflammation in activated microglia, a novel neurological disease in the brain accompanied by neuronal cell death and neuroinflammation A treatment target can be established.

Specifically, the composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor may include a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

[Formula 2]

here,

A is a substituent represented by Formula 2 or Formula 3,

* means the part to be joined,

L ₁ and L ₂ are the same or different from each other, and each independently represents a single bond, a substituted or unsubstituted C 1 to C 10 alkylene group and a substituted or unsubstituted C 6 to C 10 arylene group,

X ₁ is selected from the group consisting of O, S and N(R ₇ ),

Y ₁ And Y ₂ Are the same as or different from each other, each independently N or C (R ₈ ),

R ₁ to R ₈ are the same as or different from each other, and each independently hydrogen, deuterium, a cyano group, a nitro group, a halogen group, a hydroxy group, an alkylthio group having 1 to 4 carbon atoms, an alkyl group having 1 to 30 carbon atoms, 1 to 20 carbon atoms of a cycloalkyl group, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 5 to 60 nuclear atoms, 6 to carbon atoms 30 heteroarylalkyl group, C1-C30 alkoxy group, C1-C30 alkylamino group, C6-C30 arylamino group, C6-C30 aralkylamino group, C2-C24 hetero arylamino group, C1 to 30 alkylsilyl group, an arylsilyl group having 6 to 30 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms, and can form a substituted or unsubstituted ring by combining adjacent groups with each other,

When R ₁ to R ₈ are substituted, hydrogen, deuterium, cyano group, nitro group, halogen group, hydroxyl group, alkyl group having 1 to 30 carbon atoms, alkenyl group having 2 to 30 carbon atoms, alkynyl group having 2 to 24 carbon atoms, carbon number A heteroalkyl group having 2 to 30 carbon atoms, an aralkyl group having 6 to 30 carbon atoms, a cycloalkyl group having 3 to 20 carbon atoms, a heterocycloalkyl group having 3 to 20 carbon atoms, an aryl group having 5 to 30 carbon atoms, a heteroaryl group having 2 to 30 carbon atoms, a carbon number Substituted with a substituent selected from the group consisting of a 3 to 30 heteroarylalkyl group, an alkoxy group having 1 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, an arylsilyl group having 6 to 30 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms And, when substituted with a plurality of substituents, they are the same or different from each other.

L ₁ and L2 may be the same as or different from each other, and each independently may be a single bond or an alkylene group having 1 to 10 carbon atoms.

The Y ₁ and Y ₂ may be N.

The X ₁ may be O or S.

The composition may include the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as one or more active ingredients.

The compound represented by Formula 1 may be selected from the group consisting of the following compounds:

Preferably, the compound represented by Formula 1 is a compound represented by the following formula, but is not limited to the above examples, and as a protein expression inhibitor, a compound that can be used for antioxidant, anti-inflammatory and prevention or improvement of dementia is a substituent or a condensed structure Either way, you can use:

The pharmaceutical composition according to another embodiment of the present invention, including the composition, may exhibit excellent antioxidant, anti-inflammatory and preventive or ameliorating effects of dementia.

The pharmaceutical composition is prepared as an oral dosage form or parenteral dosage form according to a conventional method known in the art, including a pharmaceutically acceptable carrier, in addition to including the compound represented by Formula 1 as an active ingredient. can be Here, "pharmaceutically acceptable" means that it does not inhibit the activity of an active ingredient and does not have toxicity beyond what the application (prescription) target can adapt.

In addition, when the pharmaceutical composition is prepared as an oral dosage form, powders, granules, tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions, wafers, etc. according to methods known in the art together with a suitable carrier It can be prepared in a dosage form. Examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, and xylitol, starches such as corn starch, potato starch, wheat starch, cellulose, methylcellulose, ethylcellulose, Cellulose such as sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyol, vegetable and oil. In the case of formulation activity, if necessary, the formulation may include a diluent and/or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant.

When prepared as a parenteral formulation, it may be formulated in the form of an injection, transdermal administration, nasal inhalation, and suppository together with a suitable carrier according to methods known in the art. In the case of formulation for injection, suitable carriers include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof, preferably Ringer's solution, PBS (phosphate buffered saline) containing triethanolamine, or sterilization for injection. Water, an isotonic solution such as 5% dextrose, etc. may be used. When formulated for transdermal administration, it may be formulated in the form of an ointment, a cream, a lotion, a gel, an external solution, a pasta agent, a liniment agent, an air roll, and the like. In the case of a nasal inhalant, it can be formulated in the form of an aerosol spray using a suitable propellant such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, and the like. witepsol), tween 61, polyethylene glycols, cacao fat, laurin fat, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearate, sorbitan fatty acid esters, etc. may be used.

The present invention will be described in more detail using examples. However, these examples should not be construed as limiting the scope of the invention.

synthesis of compounds

Preparation Example 1. 3-((2,4-dichlorophenoxy)methyl-5-(trichloromethyl)-1,2,4-oxadiazole(3-((2,4-dichlorophenoxy)methyl)-5 Preparation of -(trichloromethyl)-1,2,4-oxadiazole; ODZ 10117)

<1-1> Preparation of 2-(2,4-dichlorophenoxy)acetonitrile

[Scheme 1]

After dissolving 2,4-dichlorophenol (1 g, 6.10 mmol) in dimethylformamide (8 mL), potassium carbonate (840 mg, 6.10 mmol) was added at room temperature, and then bromoacetonitrile (0.44 mL, 6.10 mmol) ) was dissolved in dimethylformamide (3 mL) and dropped slowly. After stirring at room temperature for 24 hours, water was added to the reaction mixture, followed by extraction with ethyl acetate. Thereafter, the organic layer was washed with a saturated aqueous solution of sodium sulfate, dried over magnesium sulfate, the solvent was removed under reduced pressure, and the target compound (1.18 g, 95%) was obtained through silica gel column chromatography (n-hexane: ethyl acetate = 3 : 1). obtained.

<1-2> Preparation of 2-(2,4-dichlorophenoxy)-N'-hydroxyacetimidamide

[Scheme 2]

Triethylamine (2.70 mL, 19.52 mmol) was dissolved in 50% aqueous ethanol solution (21 mL), and then hydroxylamine hydrochloride (1.36 g, 19.52 mmol) was added at room temperature. After stirring at room temperature for 5 minutes, the obtained 2-(2,4-dichlorophenoxy)acetonitrile was dissolved in ethanol (83 ml) and added, followed by refluxing at 100° C. for 3 hours. Thereafter, the reaction mixture was diluted with water, filtered and washed again with water to obtain the target compound (2.71 g, 77%).

¹ H NMR (500 MHz, CDCl3) δ4.58 (s, 2H), 4.85 (s, 2H), 6.53 (s, 1H), 6.96 (d, J=8.8 Hz,1H), 7.17 (dd, J= 2.3 Hz, 8.8 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H)

<1-3> Preparation of 3-((2,4-dichlorophenoxy)methyl-5-(trichloromethyl)-1,2,4-oxadiazole

[Scheme 3]

The obtained 2-(2,4-dichlorophenoxy)-N'-hydroxyacetimidamide (100 mg, 0.43 mmol) and trichloroacetonitrile (0.040 mL, 0.43 mmol) were mixed with dimethylformamide (1 mL) After dissolving in para-toluenesulfonic acid (41 mg, 0.22 mmol) and zinc chloride (30 mg, 0.22 mmol) were added. Then, it was refluxed at 80° C. for 16 hours, and the resulting reaction compound was washed with sodium bicarbonate and the organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. Then, the remaining residue was subjected to silica gel column chromatography (n-hexane : ethyl acetate = 10 : 1) to obtain the target compound (81 mg, 53%).

¹ H NMR (300 MHz, CDCl3) δ5.27 (s, 2H), 7.01 (d, J=8.8 Hz, 1H),7.20 (dd, J=2.5 Hz, 8.7 Hz, 1H),7.40 (d, J) =2.6 Hz, 1H)

Preparation Example 2. 3-((2,4-dichlorophenoxy)methyl)-5-propoxy-1,2,4-oxadiazole (3-((2,4-dichlorophenoxy)methyl)-5-propoxy Preparation of -1,2,4-oxadiazole; ODZ10181)

[Scheme 4]

3-((2,4-dichlorophenoxy)methyl-5-(trichloromethyl)-1,2, obtained after dissolving sodium propoxide (119 mg, 1.45 mmol) in dimethylformamide (10 mL) 4-oxadiazole (350 mg, 0.97 mmol) was added at room temperature and stirred at room temperature for 10 minutes.The reaction mixture was washed with a saturated aqueous sodium sulfate solution and brine, and the organic layer was dried over magnesium sulfate. The solvent was removed under the above conditions, and the residue was subjected to silica gel column chromatography (n-hexane : ethyl acetate = 10 : 1) to obtain the target compound (64 mg, 22%).

¹ H NMR (400 MHz, CDCl3) δ1.02 (t, J=7.4 Hz, 3H), 1.85 (qd, J=7.0 Hz, 14.1 Hz, 2H), 4.47 (t, J=6.6 Hz, 2H), 5.05 (s, 2H), 7.00 (d, J=8.8 Hz, 1H), 7.17 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H)

Preparation Example 3. 5-(Secondary-butoxy)-3-((2,4-dichlorophenoxy)methyl)-1,2,4-oxadiazole (5-(sec-butoxy)-3-(( Preparation of 2,4-dichlorophenoxy)methyl)-1,2,4-oxadiazole; ODZ8292)

[Scheme 5]

Sodium secondary-butoxide (613 mg, 6.37 mmol) was dissolved in dimethylformamide (20 mL), and the obtained 3-((2,4-dichlorophenoxy)methyl-5-(trichloromethyl)-1,2, 4-oxadiazole (462 mg, 1.27 mmol) was added at room temperature and stirred for 10 minutes at room temperature After washing the resulting reaction mixture with a saturated aqueous sodium sulfate solution and brine, the organic layer extracted with ethyl acetate was dried over magnesium sulfate Then, the solvent was removed under reduced pressure, and the residue was subjected to chromatography on silica gel column (n-hexane : ethyl acetate = 15 : 1) to obtain the target compound (78 mg, 19%).

¹ H NMR (400 MHz, CDCl3) δ0.97 (t, J=7.4 Hz, 3H), 1.42 (d, J=6.2 Hz, 3H), 1.67-1.87 (m, 2H), 5.05 (s, 2H) , 7.00 (d, J=8.8 Hz, 1H), 7.17 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H)

Example 1

Cytoprotective effect on neuronal cell death

The cytoprotective effect of compound 10117 on neuronal cell death induced by neurotoxic substances such as H ₂ O ₂ and glutamate was confirmed.

SH-SY5Y cells were cultured in an incubator at 37° C., 5% CO ₂ using Dulbecco's modified Eagle's medium (DMEM, Hyclone, Logan, UT) containing 10% FBS and 1% penicillin and streptomycin.

For neuronal death by H ₂ O ₂ treatment, the change in cell viability according to the pretreatment of Compound 10117 was measured by MTT assay. SH-SY5Y cells were cultured in a 96-well plate at a density of 1×10 ⁴ cells/well for 24 hours at 37° C. and 5% CO ₂ condition. After pretreatment with compound 10117 for 12 hours, 600 μM H ₂ O ₂ was treated for 24 hours. After the reaction was completed, 3-[4,5-dimethyl-thiazol]-2,5-diphenyl-tetrazolium bromide (MTT) reagent at a concentration of 1 mg/ml was added and reacted for 2 hours, followed by dimethyl sulfoxide (DMSO) It was dissolved and the absorbance was measured at 570 nm using a Microplate reader.

1A is a result confirming the neuronal cell death induced by H ₂ O ₂ , which is an oxidative stress stimulus. As shown in the figure, when H ₂ O ₂ was treated with a concentration gradient for 24 hours, cell viability was reduced.

Figure 1b, H ₂ O ₂ In order to confirm whether the apoptosis induced by ROS is apoptosis by ROS, apoptosis was confirmed by treatment with N-acetyl-L-cysteine (NAC), an inhibitor of ROS production. As a result, apoptosis by H ₂ O ₂ was inhibited in SH-SY5Y cells by treatment with NAC.

Figure 2a, H ₂ O ₂ It was confirmed that the cytoprotective effect of compound 10117 on the induced neuronal cell death. As a result, as shown in the figure, in SH-SY5Y cells, treatment with compound 10117 alone did not affect cell viability, and pretreatment with compound 10117 confirmed a significant cytoprotective effect against H ₂ O ₂ toxicity.

Example 2

Cytoprotective effect against neuronal cell death

To confirm the protective effect of compound 10117 against H ₂ O ₂ induced neuronal apoptosis in SH-SY5Y cells, activation of caspase-3 and caspase-9, which are proteins involved in apoptosis, and DNA damage repair The cleavage of poly (ADP-ribose) polymerase (PARP) was confirmed by extracting the protein and performing Western blot analysis.

Western blot analysis was performed by washing the cells with cold PBS, followed by cell lysis buffer (1% Triton X-100, 50 mM Tris-HCl (pH 7.4), 0.35 M NaCl, 0.5% Nonidet P-40, 10% glycerol, 0.1% SDS, 1mM EDTA, 1mM EGTA, 0.2mM Na3VO4, 1mM PMSF, 0.5mM NaF was dissolved using). After incubation on ice for 30 minutes, the dissolved solution was centrifuged at 13000 rpm at 4° C. for 15 minutes to remove the insolubilized residue and only the solution containing the protein was extracted.

Protein quantification was performed using a protein assay dye reagent (Bio-Rad, Hercules, CA, USA), and the protein at the same concentration was separated by electrophoresis in SDS-polyacrylamide through quantification, and nitrocellulose transferred to membranes (GE Healthcare, Pittsburgh, PA). The membrane was blocked for 1 hour at room temperature with TBS-T (Tris-buffered saline/0.05% Tween-20) solution containing 5% skim milk, and primary antibodies (p-STAT3, STAT3, β-action ) and reacted at 4 °C overnight (overnight). This was washed 3 times for 10 minutes each using TBS-T, and the secondary antibody labeled with HRP (horeradish peroxidase) was reacted at room temperature for 1 hour. For visualization, an enhanced chemiluminescence system was used.

1c , the expression of cleaved caspase-3 and cleaved PARP was increased by H ₂ O ₂ .

In FIG. 2c , the expression of cleaved caspase-3 and cleaved PARP was increased by H ₂ O ₂ , and the expression was significant when oxidative stress was induced by treatment with H ₂ O ₂ after 12 hours of pretreatment with compound 10117. was reduced to Through this, it was confirmed that compound 10117 inhibited caspase-3 and PARP-dependent apoptosis induction by H ₂ O ₂ .

Example 3

Cytoprotective effect on neuronal cell death

The cytoprotective effect of compound 10117 on apoptosis induced by neurotoxic substances such as H ₂ O ₂ and glutamate was confirmed.

HT22 cells were cultured in an incubator at 37° C., 5% CO ₂ using Dulbecco's modified Eagle's medium (DMEM, Hyclone, Logan, UT) containing 10% FBS and 1% penicillin and streptomycin. For neuronal death by glutamate treatment, the change in cell viability according to the pretreatment with Compound 10117 was measured by MTT assay. HT22 cells were cultured in a 96-well plate at a density of 5×103 cells/well for 24 hours at 37° C. and 5% CO 2 conditions. After pretreatment with compound 10117 for 12 hours, 5 mM glutamate was treated for 12 hours.

In Figure 3a, it is the result of confirming the neuronal cell death induced by glutamate. As shown in the figure, when glutamate was treated with a concentration gradient for 12 hours, cell viability decreased.

In Figure 3b, in order to determine whether apoptosis induced by glutamate is apoptosis by ROS, apoptosis was confirmed by treatment with NAC, an ROS generation inhibitory substance. As a result, glutamate-induced apoptosis was inhibited in HT22 cells by treatment with NAC.

In Figure 4a, cell viability was confirmed by treatment with compound 10117 alone. In Figure 4b, the cytoprotective effect of compound 10117 on neuronal cell death induced by glutamate was confirmed. After pre-treatment with compound 10117 for each hour, glutamate was treated for 12 hours. As a result, as shown in the figure, a significant cytoprotective effect was confirmed with respect to glutamate toxicity from the 3-hour pretreatment of compound 10117 in HT22 cells.

Example 4

neuroprotective effect

To confirm the neuroprotective effect of compound 10117 treatment from glutamate-induced cytotoxicity in HT22 cells, LDH (lactate dehydrogenase) release assay was performed.

HT22 cells were seeded at 5×10 ³ per well in a 96-well plate and cultured at 37° C., 5% CO ₂ conditions for 24 hours. After pretreatment with compound 10117 for 12 hours, 5 mM glutamate was treated for 12 hours. After centrifugation at 250 g for 10 minutes to collect only the supernatant from which LDH was released, an LDH assay kit (Takara bio inc, Tokyo, Japan) was used to measure the amount of LDH in the medium. After the reaction, absorbance was measured at 490 nm with a microplate reader.

In Figure 4d, the neuroprotective effect of the treatment of compound 10117 from glutamate-induced cytotoxicity was confirmed. LDH release was increased in glutamate-treated HT22 cells, and pretreatment with compound 10117 significantly reduced LDH release to a normal level.

Example 5

Neuroinflammation inhibitory effect

It was confirmed whether compound 10117 could inhibit neuroinflammation in microglia using the BV2 cell line, which is a mouse-derived microglia.

BV2 microglia were cultured in an incubator at 37° C., 5% CO ₂ using Dulbecco's modified Eagle's medium (DMEM, Hyclone, Logan, UT) containing 10% FBS and 1% penicillin streptomycin. The cultured cells were aliquoted in the number of 3×10 ⁵ wells in a 6-well plate and cultured overnight.

Whether compound 10117 had a reducing effect on the activity (phosphorylation) of STAT3 was confirmed by extracting the protein from the cells and performing Western blot analysis.

As shown in FIG. 5 , when compound 10117 was treated with each concentration (5, 10, 20, 30 μM) for 6 hours, the phosphorylated protein of STAT3 was significantly reduced. For quantitative comparison of p-STAT3 expression, total STAT3 and a housekeeping gene β-action antibody were used.

Example 6

Neuroinflammation inhibitory effect

It was confirmed whether compound 10117 could inhibit neuroinflammation in microglia using the BV2 cell line, which is a mouse-derived microglia. The production inhibitory activity of compound 10117 against iNOS, COX-2, IL-6 and TNF-α, which are representative inflammatory factors, was investigated in LPS (lipopolysaccharide)-stimulated microglia (BV2). After 2 hours of pretreatment with compound 10117 at different concentrations (5, 10, 20, 30 μM), cells were stimulated by treatment with 100 ng/ml LPS for 6 hours or 8 hours. Cells were harvested from each well, and Western blot and quantitative real-time PCR were performed.

For real-time PCR analysis, total RNA was isolated using 1 ml Trizol (Takara, Shiga, Japan). The concentration of RNA isolated at 260 nm was measured using a spectrophotometer, and RNA purity was evaluated by the ratio of absorbance measured at 260 nm and 280 nm. cDNA was synthesized from 1 μg of the isolated RNA using ReverTra Ace qPCR RT Master Mix (TOYOBO, Osaka, Japan). Afterwards, it was confirmed using EvaGreen qPCR Mastermix (Applied Biological Materials, BC, Canada) to confirm the mRNA expression of IL-6, TNF-α, iNOS and GAPDH.

As shown in FIG. 6 , it was confirmed that when 100ng/ml of LPS was treated, the protein expression of p-STAT3 was increased, and when the compound 10117 of the present invention was treated together, this phenomenon was suppressed. The results were confirmed by Western blot.

7, it was confirmed that when 100ng/ml of LPS was treated, iNOS and COX-2 protein expression was increased, and when the compound 10117 of the present invention was treated together, this phenomenon was suppressed. The results were confirmed by Western blot.

As shown in FIG. 8 , it was confirmed that L-6, TNF-α, iNOS mRNA expression increased when 100ng/ml of LPS was treated, and this phenomenon was inhibited when treated with the compound 10117 of the present invention. The results were confirmed through quantitative real-time PCR. For quantitative comparison, GAPDH was used.

Example 7

The antioxidant, anti-inflammatory, and preventive or therapeutic effects of compound 10117 were confirmed through the previous experiment. The effect of mixing the compound 10181 and the compound 8292 to the compound 10117 was confirmed.

At the time of mixing, each 20 μM concentration of the compound was mixed in the following weight ratio to proceed with the experiment.

ODZ 1 ODZ 2 ODZ 3 ODZ 4 10117 One One One One 10181 - One - One 8292 - - One One

(unit weight parts)

In SH-SY5Y cells, the cytoprotective effect on neuronal apoptosis induced by H ₂ O ₂ was tested in the same manner as in the previous experiment, and after performing the same experiment as in Example 6, cells of ODZ 1 The protective effect was set to index 5, and the confirmation of the cytoprotective effect on other compounds was carried out.

ODZ 1 ODZ 2 ODZ 3 ODZ 4 Cytoprotective effect on neuronal cell death 5 5 6 7 Neuroinflammation inhibitory effect 5 5 6 6

In light of the above experimental results, it was confirmed that the cytoprotective effect on neuronal cell death and the inhibitory effect of neuroinflammation also exhibited equal or superior effects even when the compound was mixed and used.

Accordingly, when the protein expression inhibitor of the present invention is used, it is possible to provide a composition for preventing or improving antioxidant, anti-inflammatory and dementia.

Although preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements by those skilled in the art using the basic concept of the present invention as defined in the following claims are also provided. is within the scope of the

Claims (8)

A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof comprising as an active ingredient
A composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor:
[Formula 1]

[Formula 2]

here,
A is a substituent represented by Formula 2 or Formula 3,
* means the part to be joined,
L ₁ and L ₂ are the same or different from each other, and each independently represents a single bond, a substituted or unsubstituted C 1 to C 10 alkylene group and a substituted or unsubstituted C 6 to C 10 arylene group,
X ₁ is selected from the group consisting of O, S and N(R ₇ ),
Y ₁ And Y ₂ Are the same as or different from each other, each independently N or C (R ₈ ),
R ₁ to R ₈ are the same as or different from each other, and each independently hydrogen, deuterium, a cyano group, a nitro group, a halogen group, a hydroxy group, an alkylthio group having 1 to 4 carbon atoms, an alkyl group having 1 to 30 carbon atoms, 1 to 20 carbon atoms of a cycloalkyl group, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, an aralkyl group having 7 to 30 carbon atoms, an aryl group having 6 to 30 carbon atoms, a heteroaryl group having 5 to 60 nuclear atoms, 6 to carbon atoms 30 heteroarylalkyl group, C1-C30 alkoxy group, C1-C30 alkylamino group, C6-C30 arylamino group, C6-C30 aralkylamino group, C2-C24 heteroarylamino group, C1 to 30 alkylsilyl group, an arylsilyl group having 6 to 30 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms, and can form a substituted or unsubstituted ring by bonding with adjacent groups,
When R ₁ to R ₈ are substituted, hydrogen, deuterium, a cyano group, a nitro group, a halogen group, a hydroxyl group, an alkyl group having 1 to 30 carbon atoms, an alkenyl group having 2 to 30 carbon atoms, an alkynyl group having 2 to 24 carbon atoms, a carbon number A heteroalkyl group having 2 to 30 carbon atoms, an aralkyl group having 6 to 30 carbon atoms, a cycloalkyl group having 3 to 20 carbon atoms, a heterocycloalkyl group having 3 to 20 carbon atoms, an aryl group having 5 to 30 carbon atoms, a heteroaryl group having 2 to 30 carbon atoms, a carbon number Substituted with a substituent selected from the group consisting of a 3 to 30 heteroarylalkyl group, an alkoxy group having 1 to 30 carbon atoms, an alkylsilyl group having 1 to 30 carbon atoms, an arylsilyl group having 6 to 30 carbon atoms, and an aryloxy group having 6 to 30 carbon atoms And, when substituted with a plurality of substituents, they are the same or different from each other. According to claim 1,
The L ₁ and L2 are the same as or different from each other, and each independently a single bond or an alkylene group having 1 to 10 carbon atoms.
A composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor. According to claim 1,
wherein Y ₁ and Y ₂ are N
A composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor. According to claim 1,
Wherein X ₁ is O or S
A composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor. According to claim 1,
The composition comprises the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as one or more active ingredients
A composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor. According to claim 1,
The compound represented by Formula 1 is selected from the group consisting of the following compounds
A composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor:

A composition comprising the compound according to any one of claims 1 to 6 in a pharmaceutically effective amount.
A pharmaceutical composition for preventing or improving antioxidant, anti-inflammatory and dementia comprising a protein expression inhibitor. 8. The method of claim 7,
The pharmaceutical composition suppresses neuroinflammation in activated microglia, and has excellent therapeutic effect on cranial nerve diseases accompanied by neuronal cell death and neuroinflammation.
Antioxidant and anti-inflammatory pharmaceutical composition comprising a protein expression inhibitor.

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