KR102643653B1 - Novel aminoaromatic compounds or pharmaceutically acceptable salt thereof and pharmaceutical composition for prevention or treatment of neurodegenerative diseases comprising the same as an active ingredient - Google Patents

Abstract

The present invention provides a novel aminoaromatic compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for preventing or treating neurodegenerative diseases containing the same as an active ingredient, and a health functional food composition for preventing or improving neurodegenerative diseases. .

Description

A novel aminoaromatic compound or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases comprising the same as an active ingredient COMPRISING THE SAME AS AN ACTIVE INGREDIENT}

The present invention relates to a novel aminoaromatic compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases containing the same as an active ingredient, and a health functional food composition for the prevention or improvement of neurodegenerative diseases. .

Neurodegenerative disease is a disease that causes abnormalities in motor control ability, cognitive function, perceptual function, sensory function, and autonomic nerve function due to a decrease or loss of nerve cell function. Representative examples include dementia and Alzheimer's disease. disease: AD), Parkinson's disease (PD), and memory disorders.

One of the main causes of neurodegenerative diseases is oxidative stress in nerve cells caused by the generation of reactive oxygen species (ROS). Oxidative stress is a phenomenon defined as an imbalance in the antioxidant/oxidation system in vivo, and is known to be generated by the accumulation of reactive oxygen species (ROS) within cells. This oxidative stress causes lipid peroxidation and intracellular DNA damage, leading to apoptosis and neuronal death.

In particular, the brain has a high oxygen saturation and is rich in polyunsaturated fatty acids and metal ions, which are direct targets of oxidative stress. Meurotransmitters in the brain also undergo self-oxidation, leading to oxidation by reactive oxygen species (ROS). When stressed, the content of unsaturated fatty acids decreases, but oxidation products that cause neurotoxicity increase, so it is an organ that is very vulnerable to oxidative stress, and its antioxidant and recovery abilities against oxidative stress are limited.

Reactive oxygen species (ROS) are chemically reactive radicals and non-radical species containing oxidizing capacity, such as superoxide ion radical (ㆍO ₂ ^- ) and perhydroxyl radical (HO). ₂ ㆍ), hydroxyl radical (ㆍOH), singlet oxygen ( ¹ O ₂ ), hydrogen peroxide (H ₂ O ₂ ), alkoxy radical (ㆍOR), hydroperoxyl radical (hydroperoxyl radical, ㆍOOR), etc.

Among reactive oxygen species (ROS), hydrogen peroxide (H ₂ O ₂ ) is the most common product of various oxidation reactions (e.g. oxidative enzymes, dehydrogenases and peroxidases) that occur mainly in the mitochondria of living organisms. Hydrogen peroxide (H ₂ O ₂ ), which surpasses the byproduct itself, is simultaneously a signal transducer and a toxic molecule. During mitochondrial respiration, superoxide dismutase (SOD) catalyzes superoxide anion radicals (ㆍO ₂ ^- ) into hydrogen peroxide (H ₂ O ₂ ) and oxygen (O ₂ ).

Another source of hydrogen peroxide (H ₂ O ₂ ) is NADPH oxidase (Nicotinamide adenine), which catalyzes oxygen (O ₂ ) into superoxide anion radicals (ㆍO ₂ ^- ), ultimately producing hydrogen peroxide (H ₂ O ₂ ). dinucleotide phosphate oxidase). Additionally, xanthine oxidase is responsible for the generation of hydrogen peroxide (H ₂ O ₂ ) during hypoxanthine oxidation, and monoamine oxidase (MAO) family members produce monoamines (e.g. dopamine). and noradrenaline) and polyamines (e.g. Nacetylputrescine) to produce hydrogen peroxide (H ₂ O). In addition to this, there are many methods to generate hydrogen peroxide (H ₂ O ₂ ).

An appropriate amount of hydrogen peroxide (H ₂ O ₂ ) is very important in living organisms because low concentrations of active oxygen, which are temporarily generated in specific areas by external signals, can regulate cellular functions such as immunity as well as cell growth and death. , Large amounts of hydrogen peroxide (H ₂ O ₂ ) that cells cannot control can act as a toxic substance within cells. In other words, hydrogen peroxide (H ₂ O ₂ ) is not only beneficial to health, but also harmful.

At appropriate levels of hydrogen peroxide (H ₂ O ₂ ), it acts as a cell signaling molecule (CSM), including transcription factors, protein kinases, and growth factors. However, at moderate levels of hydrogen peroxide (H ₂ O ₂ ), it causes damage to DNA, lipids and proteins. DNA modifications, including base breakdown, single- or double-stranded DNA breaks, cross-linking with proteins, and purine or pyrimidine modifications, are caused by damage by hydrogen peroxide (H ₂ O ₂ ). Hydrogen peroxide (H ₂ O ₂ ) destroys the membrane lipid bilayer and sequentially affects tissue stability through lipid peroxidation. Fragmented proteins, protein cross-linking, and amino acid oxidation are also caused by hydrogen peroxide (H ₂ O ₂ ). .

To balance the body with changing hydrogen peroxide (H ₂ O ₂ ) levels, various antioxidant systems have been established. Catalase (CAT), glutathione peroxidase (GPx), and horseradish peroxidase (HRP) are known enzymes that decompose hydrogen peroxide (H ₂ O ₂ ). CAT is one of the powerful antioxidant enzymes that contains the heme cofactor and decomposes hydrogen peroxide (H ₂ O ₂ ) into intact water and oxygen. GPx is a selenium cofactor enzyme, and hydrogen peroxide (H ₂ O ₂ ) decomposition is accompanied by glutathione (GSH) oxidation. In addition, HRP contains heme as a cofactor and exhibits catalase-like activity that reduces hydrogen peroxide (H ₂ O ₂ ) to water and oxygen. All these antioxidant systems maintain equivalence of hydrogen peroxide (H ₂ O ₂ ) levels under physiological conditions.

However, the balance of hydrogen peroxide (H ₂ O ₂ ) levels is often disrupted in pathological conditions, which are closely related to pathology. In general, the balance of hydrogen peroxide (H ₂ O ₂ ) is tilted toward excessive levels in neurodegenerative diseases, tumors, and autoimmune diseases. For example, amyloid-beta accumulation induces the proliferation of monoamine oxidase B (MAO-B) and reactive astrocytes.

Therefore, drugs that prevent oxidative stress caused by hydrogen peroxide (H ₂ O ₂ ) are emerging as therapeutic targets. However, effective drug targets for preventing damage caused by hydrogen peroxide (H ₂ O ₂ ) have not yet been determined.

KR 10-2019-0035386 A

Journal of Biological Chemistry 282(42):30452-65

Accordingly, while the present inventors were conducting research to discover new compounds with preventive or therapeutic effects on neurodegenerative diseases, the level of hydrogen peroxide, one of the reactive oxygen species, was lower than when it was by-produced by endogenous oxidation reactions such as mitochondrial respiration. Considering that it is significantly high in pathological conditions such as neurodegenerative diseases, especially Alzheimer's disease, we attempted to develop a new compound that has a scavenging effect on hydrogen peroxide, one of various reactive oxygen species. As a result, it was discovered that an aminoaromatic compound with a specific structure removes only hydrogen peroxide, not hydroxyl radicals, and the present invention was completed.

The object of the present invention is to provide a novel aminoaromatic compound or a pharmaceutically acceptable salt thereof that is useful as a scavenger of hydrogen peroxide in the blood.

Additionally, the present invention provides a pharmaceutical composition for preventing or treating neurodegenerative diseases comprising the novel aminoaromatic compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a health functional food composition for preventing or improving neurodegenerative diseases, comprising the novel aminoaromatic compound of the present invention or a foodologically acceptable salt thereof as an active ingredient.

In order to achieve the above purpose,

One aspect of the present invention provides an aminoaromatic compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

[Formula 1]

In Formula 1,

Ar is C ₆ -C ₂₀ arylene, and the arylene of Ar is C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, amino, mono- or di-C ₁ -C ₁₀ alkylamino, haloC ₁ - may be further substituted with one or more selected from C ₁₀ alkyl, haloC ₁ -C ₁₀ alkoxy and hydroxy;

R ¹ and R ² are each independently hydrogen or C ₁ -C ₁₀ alkyl;

R ³ is halogen, C ₁ -C ₁₀ alkoxy, haloC ₁ -C ₁₀ alkyl or haloC ₁ -C ₁₀ alkoxy;

n is an integer of 1 or 2;

However, when R ³ is halogen, n is an integer of 1.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating neurodegenerative diseases, comprising the aminoaromatic compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, another aspect of the present invention provides a health functional food composition for preventing or improving neurodegenerative diseases, comprising an aminoaromatic compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The amino aromatic compound according to the present invention acts as a scavenger that removes hydrogen peroxide, a type of active oxygen.

The amino aromatic compound according to the present invention suppresses cell death caused by oxidative stress caused by H ₂ O ₂ by scavenging hydrogen peroxide, which is a reactive oxygen species (ROS) in cells.

In other words, the aminoaromatic compound according to the present invention works with an enzyme containing heme to lower the ROS concentration, so rather than excessively lowering the concentration of ROS, it is overproduced to reach the appropriate concentration required in vivo. This is to remove hydrogen peroxide.

The aminoaromatic compound according to the present invention is a small molecule scavenger of hydrogen peroxide in the blood, and has very high blood-brain barrier (BBB) permeability, so it acts directly on the brain and has excellent effects in treating brain diseases. It can be expressed.

The aminoaromatic compound according to the present invention exhibits antioxidant properties that can improve cognitive and memory disorders by exhibiting hydrogen peroxide scavenging activity and improving cell death induced by hydrogen peroxide.

The aminoaromatic compound according to the present invention decomposes hydrogen peroxide in the presence of heme-containing peroxidase and hemoglobin (Hb) present in the body, thereby lowering the level of hydrogen peroxide in the blood and consequently suppressing the onset of neurodegenerative diseases. It can be treated.

Therefore, the amino aromatic compound of the present invention can be used as an active ingredient in pharmaceutical compositions for preventing or treating neurodegenerative diseases and health functional food compositions for preventing or improving neurodegenerative diseases by inhibiting damage caused by harmful hydrogen peroxide.

Figure 1 - Schematic image of hydrogen peroxide (H ₂ O ₂ ) analysis through hemoglobin enzymatic reaction between hydrogen peroxide (H ₂ O ₂ ) and Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine)
Figure 2 - In vitro H ₂ O ₂ degradation analysis of the new compound of Experimental Example 2 I [(A,B) Cell-permeable H ₂ O ₂ dye H ₂ in primary cultured astrocytes A chemical reaction schematic showing the timeline of imaging using DCFDA-AM and the principle of hydrogen peroxide measurement; (C) A graph showing the fluorescence intensity according to the concentration of the aminoaromatic compound of the present invention, KDS12008 (Example 1). Fluorescence intensity represents the amount _of intracellular _H2O2 , normalized by control conditions]
Figure 3 - Results of H ₂ O ₂ decomposition analysis I of the new compound in vitro in Experimental Example 2 [(A) Aminoaromatic compound of the present invention KDS12008 (Example 1) (10 μM) and sodium pyruvate (10 mM) Graph showing the effect of H ₂ O ₂ decomposition by ); (B) Cell viability test results of the aminoaromatic compound of the present invention KDS12008 (Example 1) (100 μM) and sodium pyruvate (10 mM). Fluorescence intensity represents the amount of intracellular H ₂ O ₂ , normalized to the control condition. **P<0.01;***P<0.001; ns, non-significant.]
Figure 4 - Results of a recovery experiment for memory impairment (memory impairment) in APP/PS1 mice treated with the aminoaromatic compound of the present invention in Experimental Example 3 [(A) Schematic of drug treatment and passive avoidance test (PAT) timeline; (B) Retention time (latency) in the dark room in a passive avoidance test in APP/PS1 mice treated with the aminoaromatic compounds of the present invention KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21), respectively ) bar graph showing the Data are expressed as mean ± SEM. Unpaired two-tailed t-test. *P<0.05, ****P<0.0001.]
Figure 5 - Tissue staining (immunohistochemistry, IHC) I results
Figure 6 - Passive avoidance test (PAT) results of Experimental Example 5
Figure 7 - Immunohistochemistry (IHC) II results of brain tissue in Experimental Example 6
Figure 8 - Electrophysiology experiment results of Experimental Example 7
Figure 9 - New space recognition (novel place recognition) experiment results of Experimental Example 8
Figure 10 - Passive avoidance test (PAT) results of Experimental Example 8
11 to 13 - Single toxicity evaluation (lethal dose 50, LD50) results of Experimental Example 9

Hereinafter, the novel aminoaromatic compound of the present invention or its pharmaceutically acceptable salt will be described in detail. At this time, if there is no other definition in the technical and scientific terms used, they have meanings commonly understood by those skilled in the art to which this invention pertains, and the following description will not unnecessarily obscure the gist of the present invention. Descriptions of possible notification functions and configurations are omitted.

The following terms used in this specification are defined as follows, but this is merely illustrative and is not intended to limit the present invention, application, or use.

In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.

As used herein, the term "C _A -C _B "means "carbon number is greater than or equal to A and less than or equal to B."

As used herein, the term “alkyl” refers to a monovalent straight-chain or branched saturated hydrocarbon radical consisting only of carbon and hydrogen atoms. The alkyl may have 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. “Lower alkyl” means straight-chain or branched alkyl having 1 to 4 carbon atoms. For example, the alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethylhexyl, etc.

As used herein, the term "arylene" refers to a divalent aromatic ring organic radical derived from an aromatic hydrocarbon by removal of two hydrogen atoms, and each ring contains suitably 4 to 7 ring atoms, preferably 5 or 6 ring atoms. It includes single or fused ring systems, and even includes forms in which multiple aryls are connected by single bonds. Specific examples include, but are not limited to, phenylene, naphthylene, biphenylene, anthrylene, etc.

In this specification, the term “alkoxy” refers to an -O-alkyl radical, where ‘alkyl’ is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, etc.

As used herein, the term “halo” or “halogen” refers to elements of the halogen group and includes, for example, fluoro, chloro, bromo, and iodo.

As used herein, the term “haloalkyl” or “haloalkoxy” refers to an alkyl or alkoxy group in which one or more hydrogen atoms are replaced with a halogen atom, respectively, where alkyl and halogen are as defined above. For example, haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and perfluoroethyl, and haloalkoxy includes fluoromethoxy and difluorome. Toxi, trifluoromethoxy, fluoroethoxy, difluoroethoxy, perfluoroethoxy, etc. can be mentioned.

As used herein, the term “amino” means -NH ₂ and the term “hydroxy” means -OH.

As used herein, the term "alkylamino" refers to an amino radical in which one or two alkyls are substituted. Specific examples include methylamino (-NHMe), dimethylamino (-NMe ₂ ), ethylamino (-NHEt), di It includes ethyl amino (-NEt ₂ ), etc., but is not limited to this.

As used herein, the term “pharmaceutically acceptable” refers to a property that is non-toxic to cells or humans exposed to the composition, and is suitable for use as a pharmaceutical preparation, and is generally intended for such use. Considered safe, means officially approved by a national regulatory agency for such use or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

As used herein, the term “pharmaceutically acceptable salt” refers to a compound of the present invention in which the side effects due to the salt do not reduce the beneficial effects of the compound of the present invention itself, at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect. means any and all organic or inorganic addition salts of

As used herein, the terms “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to substances that assist the administration and absorption of the active agent by the subject.

The term “oxidative stress” is used herein according to its ordinary meaning and refers to abnormal levels of reactive oxygen species.

As used herein, the term “prevention” refers to all actions that inhibit or delay the occurrence, spread, and recurrence of neurodegenerative diseases.

As used herein, the term “improvement” refers to any action that at least reduces the severity of a parameter, such as a symptom, associated with the condition being treated.

As used herein, the term “treatment” refers to any action that improves or beneficially changes the symptoms of a neurodegenerative disease.

As used herein, the term “individual” refers to any animal, including humans, that has developed or is likely to develop a neurodegenerative disease. The animal may be not only a human, but also a mammal such as a cow, horse, sheep, pig, goat, camel, antelope, dog, or cat that requires treatment for similar symptoms, but is not limited thereto.

As used herein, the term "administration" means introducing the pharmaceutical composition of the present invention into an individual by any appropriate method, and the route of administration of the composition of the present invention is various oral or parenteral routes as long as it can reach the target tissue. It can be administered through

As used herein, the term "pharmaceutically effective amount" refers to an amount that is sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is determined by the patient's gender and age. , weight, health status, type and severity of the disease, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration, and factors including excretion rate, duration of treatment, drugs combined or used simultaneously, and other medical fields. It can be easily determined by a person skilled in the art according to well-known factors.

As used herein, the term "food" refers to meat, sausages, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, and alcoholic beverages. , vitamin complexes, health functional foods, and health foods, etc., and include all foods in the conventional sense.

In this specification, the term “health functional food” refers to food manufactured and processed using raw materials or ingredients with functionality useful to the human body in accordance with Act No. 6727 on Health Functional Food, and “functional” refers to food that is useful for the human body. It means ingestion for the purpose of controlling nutrients for structure and function or obtaining useful health effects such as physiological effects.

As used herein, the term “foodologically acceptable salt” refers to a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.

The present invention provides treatment of neurodegenerative diseases or a pharmaceutically acceptable salt thereof containing as an active ingredient a novel aminoaromatic compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof, which is useful as a scavenger of hydrogen peroxide in the blood. do:

[Formula 1]

In Formula 1,

Ar is C ₆ -C ₂₀ arylene, and the arylene of Ar is C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, amino, mono- or di-C ₁ -C ₁₀ alkylamino, haloC ₁ - may be further substituted with one or more selected from C ₁₀ alkyl, haloC ₁ -C ₁₀ alkoxy and hydroxy;

R ¹ and R ² are each independently hydrogen or C ₁ -C ₁₀ alkyl;

R ³ is halogen, C ₁ -C ₁₀ alkoxy, haloC ₁ -C ₁₀ alkyl or haloC ₁ -C ₁₀ alkoxy;

n is an integer of 1 or 2;

However, when R ³ is halogen, n is an integer of 1.

The aminoaromatic compound according to the present invention has low cytotoxicity, is a small molecule compound, and can act as a scavenger that removes hydrogen peroxide, a type of active oxygen.

The aminoaromatic compounds according to the present invention do not scavenge hydroxyl radicals and are not MAO-B inhibitors. As a result of ROS-GLO analysis, the aminoaromatic compound according to the present invention was found to act as a catalyst for the reaction of decomposing hydrogen peroxide into water in the presence of endogenous peroxidase, especially heme-containing peroxidase, and hemoglobin (Hb). Confirmed.

That is, the aminoaromatic compound according to the present invention acts together with heme-containing peroxidase and hemoglobin (Hb) present in the body to remove overproduced hydrogen peroxide to an appropriate concentration, so the aminoaromatic compound of the present invention It can be useful in preventing, improving, or treating neurodegenerative diseases by suppressing the death of nerve cells caused by harmful hydrogen peroxide. In addition, the amino aromatic compound according to the present invention has the ability to penetrate the blood brain barrier (BBB) with excellent efficiency, so that a rapid, rapid, and more efficient therapeutic effect can be obtained by administering a low amount.

In one embodiment of the present invention, Ar is C ₆ -C ₁₂ arylene, preferably phenylene or biphenylene; The Ar may be further substituted with one or more selected from C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, amino, and hydroxy.

In one embodiment of the present invention, Ar is phenylene, and it may be desirable for nitrogen atoms to be introduced into positions 1 and 4 of phenylene, respectively.

The amino aromatic compound according to an embodiment of the present invention may be specifically represented by the following formula (2) or (3).

The amino aromatic compound according to an embodiment of the present invention may be specifically represented by the following formula (2) or (3).

[Formula 2]

[Formula 3]

In Formulas 2 and 3,

R ¹ and R ² are each independently hydrogen or C ₁ -C ₇ alkyl;

Hal is halogen;

R ³ is C ₁ -C ₇ alkoxy or haloC ₁ -C ₇ alkyl;

R' is C ₁ -C ₇ alkyl, C 1 -C ₇ alkoxy, amino or hydroxy;

a is an integer from 0 to 4;

n is an integer of 1 or 2.

Preferably, in Formulas 2 and 3 according to an embodiment of the present invention, R ¹ and R ² are each independently hydrogen or C ₁ -C ₄ alkyl; Hal is halogen; R ³ is C ₁ -C ₄ alkoxy or haloC ₁ -C ₄ alkyl; a is an integer of 0; n may be an integer of 1 or 2.

Chemical Formula 2 according to one embodiment may be expressed as Chemical Formula 4 below:

[Formula 4]

In Formula 4,

R ¹ and R ² are each independently hydrogen or C ₁ -C ₄ alkyl;

Hal is halogen.

Specifically, in Formula 4, R ¹ and R ² are each independently C ₁ -C ₄ alkyl; Hal may be a halogen.

Specifically, in Formula 4, R ¹ is hydrogen; R ² is C ₁ -C ₄ alkyl; Hal may be a halogen.

Specifically, in Formula 4, R ¹ and R ² are each independently hydrogen; Hal may be a halogen.

Chemical Formula 3 according to one embodiment may be expressed as Chemical Formula 5 below:

[Formula 5]

In Formula 5,

R ¹ and R ² are each independently hydrogen or C ₁ -C ₄ alkyl;

R ³ is C ₁ -C ₄ alkoxy or haloC ₁ -C ₄ alkyl;

n is an integer of 1 or 2.

Specifically, in Formula 5, R ¹ and R ² are each independently C ₁ -C ₄ alkyl; R ³ is C ₁ -C ₄ alkoxy or haloC ₁ -C ₄ alkyl; n is an integer of 1 or 2.

Specifically, in Formula 5, R ¹ is hydrogen; R ² is C ₁ -C ₄ alkyl; R ³ is C ₁ -C ₄ alkoxy or haloC ₁ -C ₄ alkyl; n is an integer of 1 or 2.

Specifically, in Formula 5, R ¹ and R ² are each independently hydrogen; R ³ is haloC ₁ -C ₄ alkyl; n is an integer of 1 or 2.

Halogen or halo in any of the compounds described herein can be fluorine.

The amino aromatic compound according to one embodiment may be any one selected from the following compound group, but is not limited thereto.

It will be apparent to those skilled in the art that the method for producing an aminoaromatic compound according to an embodiment of the present invention can be performed using methods known in the art or by appropriately modifying them. In addition, the reaction time in the production method of Chemical Formula 1 according to an embodiment of the present invention may vary depending on the type of reactant, solvent, and amount of solvent. For example, the reaction is performed after confirming that the starting material is completely consumed through TLC, etc. completes. When the reaction is complete, the solvent can be distilled off under reduced pressure, and then the target product can be separated and purified through a conventional method such as column chromatography. For example, it can be prepared by reacting an arylenediamine compound and a phenylalkyl bromide compound, and further details are explained in the examples below.

[Scheme 1]

(In Scheme 1, Ar, R ¹ , R ² , R ³ and n are the same as in Chemical Formula 1.)

The present invention includes all of the above aminoaromatic compounds and their pharmaceutically acceptable salts, as well as possible prodrugs, hydrates and solvates that can be prepared therefrom.

In other words, the aminoaromatic compound of the present invention can be used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt to enhance in vivo absorption or increase solubility, so the above prodrug, hydrate, and solvent Carbohydrates and pharmaceutically acceptable salts are also within the scope of the present invention.

The aminoaromatic compound of the present invention can be used in the form of a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is a salt prepared according to a conventional method in the art, and the method of preparing the same is known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following free acids and bases that are pharmacologically or physiologically acceptable.

Acid addition salts formed with pharmaceutically acceptable free acids include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, and trihydrocytic acid. Fluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid. It is obtained from organic acids such as acid, carbonic acid, vanillic acid, and hydroiodic acid. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, Bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate Nate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxy Benzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydride. Includes oxybutyrate, glycolate, malate, tartrate, methanesulfonate, propane sulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

Acid addition salts can be prepared by conventional methods. For example, the amino aromatic compound of the present invention is dissolved in a water-miscible organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc. and an organic acid or inorganic acid is added to form a precipitate. It can be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

Additionally, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal salt or alkaline earth metal salt is obtained, for example, by dissolving the aminoaromatic compound of the present invention in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved aminoaromatic compound salt, and then evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium, or calcium salts as metal salts, but is not limited to these. Additionally, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate silver salt (e.g., silver nitrate).

Preferably, the pharmaceutically acceptable salt of the aminoaromatic compound according to an embodiment of the present invention may be hydrochloride.

That is, the amino aromatic compound according to an embodiment of the present invention may be a compound in the form of a hydrochloride salt selected from the following structures:

The hydrate of the aminoaromatic compound of the present invention is an aminoaromatic compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. It means a compound or a pharmaceutically acceptable salt thereof.

The solvate of the aminoaromatic compound of the present invention refers to the heterocyclic compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Solvents that can be used include volatile and non-toxic solvents.

The aminoaromatic compound of the present invention can be administered in the form of a prodrug that is decomposed in the body of a human or animal and provides the compound of the present invention as an active ingredient. Prodrugs can be used to alter and/or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains suitable groups or substituents that can be induced to form a prodrug.

If a compound (prodrug) is isolated in the body to produce the aminoaromatic compound or salt thereof of the present invention, such compound is also included within the scope of the present invention. As used herein and unless otherwise indicated, the term "prodrug" refers to a substance that is hydrolyzed, oxidized and undergoes other reactions under biological conditions (in vitro or in vivo) to provide an active compound, especially a compound of the invention. It means a compound of the present invention that can be used. Examples of prodrugs are biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, and biohydrolyzable esters. ureides, and biohydrolyzable phosphate analogs, which contain biohydrolyzable moieties, which biohydrolyze to produce compounds of the invention, but are not limited to these specific embodiments. It is not limited. Preferably, the prodrug of the compound having a carboxyl group functional group is a lower alkyl ester of carboxylic acid. Carboxylic esters are usually formed by esterifying a portion of the carboxylic acid present in the molecule. Prodrugs are listed in Burger's Medicinal Chemistry and Drug Discovery 6thed. (Donald J. Abrahamed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

The present invention provides a hydrogen peroxide scavenger containing the aminoaromatic compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Additionally, the present invention provides a pharmaceutical composition for the prevention or treatment of neurodegenerative diseases containing the aminoaromatic compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The neurodegenerative disease refers to a disease or condition in which the function of the subject's nervous system is impaired, such as motor control ability, cognitive function, perceptual function, sensory function, and autonomic nerve function, and has the same meaning as 'degenerative brain disease'. am. Specifically, dementia, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Lou Gehrig's disease (ALS), post-traumatic stress disorder (trauma), multiple sclerosis (MS), cerebral ischemic disease, and amyotrophic lateral sclerosis. It can be exemplified.

The aminoaromatic compound according to the present invention decomposes overproduced hydrogen peroxide in the presence of heme-containing peroxidase present in the body and hemoglobin (Hb) in the blood, thereby lowering the level of hydrogen peroxide in the blood to an appropriate level. It can suppress or treat the onset of neurodegenerative diseases.

In addition, the amino aromatic compound according to the present invention is a low-molecular-weight blood hydrogen peroxide scavenger, and has very high blood-brain barrier (BBB) permeability, so it can act directly on the brain and exhibit excellent effects in treating brain diseases. there is. Therefore, the aminoaromatic compound of the present invention can be usefully used in the prevention or treatment of neurodegenerative diseases.

The pharmaceutical composition according to one embodiment is a preparation commonly used in the pharmaceutical field, that is, a preparation for oral administration or a preparation for parenteral administration, by further comprising a conventional non-toxic pharmaceutically acceptable carrier and/or excipient in addition to the active ingredient. It can be formulated as: In addition, it may further include diluents such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

The pharmaceutically acceptable carriers, excipients or diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose. , methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil, but is not limited thereto.

The pharmaceutical composition of the present invention is formulated into various forms such as oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, and injections of sterile injectable solutions according to conventional methods to suit the intended use. It can be administered orally or through a variety of routes, including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration.

In addition, the pharmaceutical composition of the present invention may further include fillers, anti-coagulants, lubricants, wetting agents, flavorings, emulsifiers, preservatives, etc.

Dosage forms for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, etc. These dosage forms contain commonly used fillers in addition to the above active ingredients. , one or more diluents or excipients such as extenders, wetting agents, disintegrants, lubricants, binders, and surfactants can be used. As a disintegrant, agar, starch, alginic acid or its sodium salt, calcium monohydrogen phosphate, etc. can be used, and as a lubricant, silica, talc, stearic acid or its magnesium or calcium salt, polyethylene glycol, etc. can be used. , Magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low-substituted hydroxypropylcellulose, etc. can be used as binders. In addition, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc. can be used as diluents, and in some cases, commonly known boiling mixtures, absorbents, colorants, flavors, sweeteners, etc. can be used together.

Preparations for parenteral administration may include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, etc. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate. As a base for suppositories, witepsol, macrogol, Tween 61, cacao, laurel, glycerol, gelatin, etc. can be used. Meanwhile, injectables may contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, preservatives, etc. To formulate an injection, the aminoaromatic compound of the present invention or a pharmaceutically acceptable salt thereof is mixed in water with a stabilizer or buffer to prepare a solution or suspension, which can then be prepared in unit dosage form in ampoules or vials.

The pharmaceutical composition of the present invention may be sterilized, or may further contain auxiliaries such as preservatives, stabilizers, thickeners, wetting agents or emulsification accelerators, salts and/or buffers for adjusting osmotic pressure, and other therapeutically useful substances. It may further include, and may be formulated according to conventional methods such as dissolving, dispersing, mixing, granulating, gelling, or coating.

The pharmaceutically effective amount of the aminoaromatic compound of the present invention depends on the patient's health condition, type and severity of the disease, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, combination or simultaneous It can be determined based on factors including the drug used and other factors well known in the medical field. Specifically, the effective amount of the compound in the pharmaceutical composition of the present invention may vary depending on the patient's age, gender, and weight, and is generally about 0.01 to 500 mg/kg/day, preferably 0.1 to 100 mg/kg. /day, can be administered every day or every other day, or can be administered once or in divided doses several times a day. However, since it may increase or decrease depending on the route of administration, severity of disease, gender, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

The pharmaceutical composition of the present invention can be administered orally or parenterally, and parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection, or intraperitoneal injection is preferred.

The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. Considering all of the above factors, it is important to administer an amount that can achieve maximum effect with the minimum amount without side effects, and this can be easily determined by a person skilled in the art.

In addition, the present invention relates to the prevention or treatment of neurodegenerative diseases, comprising administering the aminoaromatic compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to an individual who has developed or is at risk of developing a neurodegenerative disease. Provides a method.

In addition, the present invention relates to the prevention or treatment of neurodegenerative diseases, comprising administering the aminoaromatic compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to an individual who has developed or is at risk of developing a neurodegenerative disease. Provides a method.

In addition, the present invention provides a health functional food composition for preventing or improving neurodegenerative diseases comprising the amino aromatic compound or a foodologically acceptable salt thereof as an active ingredient.

The food-chemically acceptable salt is the amino aromatic compound of the present invention mixed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, tartaric acid, formic acid, and citric acid. It can be obtained by reacting with organic carboxylic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc. In addition, the compound of the present invention is reacted with a base to produce salts such as alkali metal salts such as ammonium salts, sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, dicyclohexylamine, and N-methyl-D-glucamine. , may be obtained by forming salts of organic bases such as tris(hydroxymethyl)methylamine, and amino acid salts such as arginine and lysine, but are not limited thereto.

The health functional food composition may be provided in the form of powder, granules, tablets, capsules, syrup, or beverage, and the health functional food is used with other foods or food additives in addition to the amino aromatic compound as an active ingredient, using a conventional method. It can be used appropriately depending on the The mixing amount of the active ingredient can be appropriately determined depending on its purpose of use, for example, prevention, health, or therapeutic treatment.

The health functional food composition includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavors, colorants and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts. , organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, it may contain pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks. These ingredients can be used independently or in combination.

In addition, the above-mentioned health functional food may additionally contain food additives, and its suitability as a 'food additive' is determined in accordance with the general provisions of the Food Additives Code and General Test Methods approved by the Food and Drug Safety Administration, unless otherwise specified. Judgment is made according to specifications and standards.

Items listed in the 'Food Additives Code' include, for example, chemical compounds such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as subchromic pigment, licorice extract, crystalline cellulose, and guar gum, and sodium L-glutamate. Mixed preparations include preparations, noodle additive alkaline preparations, preservative preparations, and tar coloring preparations.

The amino aromatic compound contained in the health functional food composition can be used in accordance with the effective dose of the pharmaceutical composition, but in the case of long-term intake for the purpose of health and hygiene or health control, it should be less than the above range. Of course, since there is no problem in terms of safety, the active ingredient can be used in amounts exceeding the above range.

The health functional food composition includes meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes. It can be formulated into various dosage forms such as the like.

Hereinafter, the present invention will be described in more detail through preferred embodiments. However, this is presented as an example of the present invention and does not limit the scope of the present invention in any way, and the scope of the present invention is only defined according to the claims described later.

[Preparation Example 1] Preparation of tert-butyl (4-aminophenyl) (methyl) carbamate

N- -Preparation of methyl-4-nitroaniline

Fluoro-4-nitrobenzene (1.0 g, 7.1 mmol) and methylamine (3.41 g, 109.9 mmol) were dissolved in ethanol, and the solution was refluxed for 24 hours. Afterwards, it was cooled to room temperature and the solvent was removed by reducing the pressure. The organic layer was separated and washed with ethyl acetate and salt water. The separated organic layer was dried over sodium sulfate, and then ethyl acetate was removed under reduced pressure to obtain 913.3 mg (84.6%) of the title compound as a yellow solid. 400 MHz ^1H NMR (DMSO- d6 ) δ 8.01 (d, 2H, J = 9.28), 7.31 (d, 1H, J = 4.28), _6.61 (d, 2H, J = 9.36), 2.80 (d, 2H) , J = 5.00), 2.33 (s, 1H)

Preparation of tert-butyl methyl(4-nitrophenyl)carbamate

N-methyl-4-nitroaniline (800 mg, 5.26 mmol), di-tert-butyl dicarbonate (1.72 g, 7.89 mmol), 4-dimethylamino pyridine (32.1 mg, 0.26 mmol) in tetrahydrofuran. After dissolving, the solution was refluxed for 12 hours. Afterwards, it was cooled to room temperature and the solvent was removed by reducing the pressure. The organic layer was separated and washed with ethyl acetate and salt water. The separated organic layer was dried over sodium sulfate, and ethyl acetate was removed under reduced pressure to obtain 1.29 g (97.3%) of the title compound as a yellow oil. 400 MHz ¹ H NMR (DMSO- d ₆ ) δ 8.20 (d, 2H, J = 9.20), 7.60 (d, 2H, J = 9.16), 3.29 (s, 3H), 1.45 (s, 9H)

Preparation of tert-butyl (4-aminophenyl)(methyl)carbamate

Dissolve tert-butyl methyl(nitrophenyl)carbamate (1.29 g, 5.11 mmol) in a mixed solvent of distilled water (12 mL), methanol (25 mL), and tetrahydrofuran (6 mL), then iron powder (1.36 g, 26.1 mmol). mmol) and ammonium chloride (2.80 g, 52.4 mmol) were added and stirred at 50°C for 3 hours. Afterwards, it was cooled to room temperature and filtered with Celite. After filtration, the pressure was reduced to remove the solvent. The organic layer was separated and washed with ethyl acetate and salt water. The separated organic layer was dried over sodium sulfate, and ethyl acetate was removed under reduced pressure to obtain 890 mg (78.1%) of the title compound as a yellow solid. 400 MHz ^1H NMR (DMSO- d6 ) δ 6.86 (d, 2H, J = 8.52), 6.50 (d, 2H, J = 8.60), _5.01 (s, 2H), 3.06 (s, 3H), 1.35 ( s, 9H)

Example I: Preparation of aminoaromatic compounds

After adding potassium carbonate (3.0 equivalents), potassium iodide (0.1 equivalents), and phenylalkyl bromide compound (b, 1.0 equivalents) to an acetonitrile solution in which p - phenylenediamine compound (a, 1.2 equivalents) was dissolved, The mixture was stirred at 110°C for 36 hours. Afterwards, it was cooled to room temperature, diluted with ethyl acetate, and washed with salt water. The remaining organic layer was dried over Na ₂ SO ₄ and the solvent was removed under reduced pressure. The residue was purified through column to obtain compound P1. Purified compound P1 was dissolved in dichloromethane (DCM), and then 4.0M hydrogen chloride solution was added. Afterwards, the mixture was stirred at room temperature for 48 hours, and the resulting precipitate was filtered to obtain compound P2 in the form of hydrochloride.

Various aminoaromatic compounds shown in Table 1 below were prepared using the method described above.

Example compound structure transference number
Appearance ^1H NMR data One 86.4%
white solid 400 MHz ^1H NMR (DMSO- d6 ) δ 7.66 (d, 2H, J = 8.00), _7.51 (d, 2H, J = 7.96), 7.40 (s, 2H), 6.89 (s, 2H), 3.36 ( t, 2H, J = 7.28), 3.01 (s, 6H), 2.98 (t, 3H, J = 7.04) 2 60.1%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.71 (d, 1H, J = 8.00), 7.60 (t, 2H, J = 7.52), 7.51 (d, 1H, J = 7.72), 7.46 (d, 2H) , J = 9.08), 7.05 (d, 2H, J = 9.04), 3.50 (t, 2H, J = 7.56), 3.25 (s, 6H), 3.16 (t, 2H, J = 8.32) 3 99.7%
white solid 400 MHz ^1H NMR (MeOD- d4 ) δ 7.56 (d, 2H, J = 15.52), _7.53 (d, 2H, J = 7.76), 7.49 (d, 2H, J = 9.04), 7.16 (d, 2H) , J = 9.00), 3.57 (t, 2H, J = 7.28), 3.31 (s, 6H), 3.07 (t, 2H, J = 7.36) 4 54.4%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.50 (d, 2H, J = 9.04), 7.40 (m, 1H), 7.35 (m, 1H), 7.25 (m, 2H), 7.18 (d, 2H, J = 9.04), 3.52 (t, 2H, J = 7.60), 3.24 (s, 6H), 3.12 (t, 2H, J = 8.04) 5 54.4%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.54 (d, 2H, J = 9.20), 7.31 (d, 2H, J = 7.60), 7.27 (d, 2H, J = 11.20), 7.21 (d, 2H) , J = 7.60), 3.55 (t, 2H, J = 7.2), 3.24 (s, 6H), 3.00 (t, 2H, J = 7.6) 6 54.4%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.34 (d, 2H, J = 9.00) 7.30 (d, 2H, J = 10.28), 7.24 (d, 2H, J = 8.36), 6.99, 2H, J = 9.00), 3.46 (t, 2H, J = 7.28), 3.31 (s, 6H), 2.93 (t, 2H, J = 7.64) 7 25.0%
white solid 400 MHz ¹ H NMR (MeOD- d ₄ ) δ 7.29 (d, 2H, J = 9.04), 7.16 (d, 2H, J = 8.64), 7.04 (d, 2H, J = 9.00), 6.86 (d, 2H) , J = 8.68), 3.77 (s, 3H), 3.43 (t, 2H, J = 7.4), 3.17 (s, 6H) 8 72.0%
white solid 400 MHz ¹ H NMR (MeOD- d ₄ ) δ 7.64 (d, 2H, J = 9.00), 7.40 (d, 2H, 9.00), 7.30 (m, 2H), 7.05 (t, 2H, J = 8.72), 3.57 (t, 2H, J = 7.60), 3.26 (s, 6H), 3.02 (t, 2H, J = 8.04) 9 86.4%
brown solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.64 (d, 2H, J = 8.08), 7.50 (d, 2H, J = 8.08), 7.47 (s, 4H), 3.65 (t, 2H, J = 7.60) ), 3.15 (t, 2H, J = 8.16), 2.88 (t, 2H, J = 7.36), 10 46.7%
pink solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.59 (d, 2H, J = 8.12), 7.52 (d, 2H, J = 8.96), 7.42 (d, 2H, J = 8.04), 7.30 (d, 2H) , J = 8.92), 3.34 (t, 2H, J = 7.60), 3.23 (s, 6H), 2.85 (t, 2H, J = 7.68), 2.05 (quint, 2H, J = 7.48) 11 77.2%
brown solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.60 (d, 4H, J = 8.48), 7.55 (d, 2H, J = 8.76), 7.43 (d, 2H, J = 7.96), 3.43 (t, 2H) , J = 7.76), 2.86 (t, 2H, J = 7.68), 2.10 (quint, 2H, J = 7.60) 12 93.1%
purple solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.70 (d, 1H, J = 7.88), 7.60 (t, 1H, J = 7.40), 7.52, (d, 1H, J = 7.64), 7.44 (t, 1H, J = 7.60), 7.39 (d, 2H, J = 8.8), 7.26 (d, 2H, J = 8.8), 3.54 (t, 2H, J = 7.84), 3.18 (t, 2H, J = 8.56) 13 82.7%
brown solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.61 (s, 1H), 7.56 (m, 2H), 7.54 (d, 1H, J = 7.24), 7.45 (m, 4H), 3.64 (t, 2H, J = 7.68), 3.14 (t, 2H, J = 3.14) 14 91.2%
brown solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.48 (s, 4H) 7.34 (q, 1H, J = 6.28), 7.11 (d, 1H, J = 7.88), 7.06 (d, 1H, J = 9.92) , 6.98 (t, 1H, J = 8.64), 3.63 (t, 2H, J = 8.04), 3.07 (t, 2H, J = 8.08) 15 77.9%
white solid 400 MHz ¹ H NMR (MeOD- d ₄ ) δ 7.42 (m, 1H), 7.40 (m, 2H), 7.35 (m, 2H), 7.33 (m, 1H), 7.27 (m, 2H), 3.56 (t , 2H, J = 7.76), 3.16 (t, 2H, J = 8.16) 16 91.8%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.62 (d, 2H, J = 8.12), 7.48 (d, 2H, J = 8.08), 7.41 (d, 2H, J = 8.88), 7.28 (d, 2H) , J = 8.84), 3.60 (t, 2H, J = 7.44), 3.10 (d, 2H, J = 7.84), 3.03 (s, 3H) 17 77.9%
purple solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.60 (d, 2H, J = 8.16), 7.42 (d, 2H, J = 8.12), 7.39 (d, 2H, J = 8.96), 7.34 (d, 2H) , J = 8.92), 3.36 (t, 2H, J = 7.64), 3.02 (s, 3H), 2.84 (t, 2H, J = 7.72), 2.06 (quint, 2H, J = 7.60) 18 72.3%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.69 (d, 1H, J = 7.88), 7.59 (t, 1H, J = 7.32), 7.50 (d, 1H, J = 7.60), 7.43 (t, 1H) , J = 7.56), 7.33 (d, 2H, J = 8.92), 712 (d, 2H, J = 8.92), 3.50 (t, 2H, J = 7.72), 3.15 (t, 2H, J = 8.56), 3.01 (s, 3H) 19 95.6%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.55 (m, 4H), 7.43 (d, 2H, J = 8.92), 7.30 (d, 2H, J = 8.88), 3.60 (t, 2H, J = 7.88) ), 3.11 (t, 2H, J = 8.00), 3.03 (s, 3H) 20 95.4%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.29 (t, 4H, J = 7.24), 7.22 (m, 2H), 7.14 (d, 2H, J = 8.88), 3.53 (t, 2H, J = 7.36) ), 3.00 (s, 3H), 2.99 (t, 2H, J = 7.88) 21 91.2%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.34 (s, 4H), 7.25 (m, 1H), 7.17 (m, 1H), 6.97 (d, 2H, J = 7.88), 6.90 (m, 1H) , 3.85 (s, 3H), 3.52 (t, 2H, J = 7.68), 3.01 (s, 3H), 3.01 (t, 2H, J = 7.88) 22 80.5%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.31 (d, 2H, J = 8.52), 7.22 (m, 4H), 7.03 (d, 2H, J = 8.92), 3.47 (t, 2H, J = 7.32) ), 2.98 (s, 3H), 2.94 (t, 2H, J = 7.76) 23 65.0%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.43 (m, 4H), 7.19 (d, 2H, J = 8.64), 6.88 (d, 2H, J = 8.64), 3.77 (s, 3H), 3.55 ( t, 2H, J = 7.72), 3.04 (s, 3H), 2.96 (t, 2H, J = 8.08) 24 87.3%
white solid 400 MHz ^1H NMR (MeOD- d ₄ ) δ 7.45 (d, 2H, J = 11.56), 7.39 (d, 2H, J = 9.00), 7.26 (t, 1H, J = 8.08), 6.86 (m, 3H) ), 3.81 (s, 3H), 3.61 (t, 2H, J = 7.68), 3.06 (s, 3H), 3.02 (t, 2H, J = 8.04)

[Experimental example]

Primary cultured astrocyte

Primary cortical astrocytes were prepared from C57BL/6 mice from the day of birth to the third day after birth. The cerebral cortex was dissected without adherent meninges, minced, and dissociated into a single cell suspension by trituration. Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 25mM glucose, 10% heat-inactivated horse serum, 10% heat-inactivated fetal calf serum (FCS), 2mM glutamine, and 1,000 U/ml penicillin-streptomycin. ) (Invitrogen). Cultures were maintained at 37°C in a humidified 5% CO ₂ incubator. On the third day of culture, cells were washed vigorously by repeated pipetting, and medium was replaced to remove debris and other suspended cell types.

[Experimental Example 1] Evaluation of hydrogen peroxide scavenging ability through enzymes present in the body

In order to determine the hydrogen peroxide scavenging ability of the presented enzyme and the aminoaromatic compound of the present invention, the following experiment was performed.

Amplex Red is a means of measuring changes in H ₂ O ₂ , that is, H ₂ O _{2 assay} , as it changes into a fluorescent substance called resorufin when HRP (horse radish peroxidase) and H ₂ O 2 exist together. However, HRP is an enzyme that does not exist in the body, and the experiment was conducted based on the idea that hemoglobin, as a group with the same heme as HRP, could work with the aminoaromatic compound of the present invention. The H ₂ O ₂ assay using Amplex Red was performed by adding hemoglobin instead of HRP [Figure 1]. The final concentration of each substance was H ₂ O ₂ 10 μM, hemoglobin 80 μg/ml, and the amino aromatic compound of the present invention was treated according to concentration. After reacting at 37°C for about 30 minutes, fluorescence (excitation: 540 nm, emission: 580 nm) was measured using a microplate reader. At this time, fluorescence can be said to be proportional to the amount of H ₂ O ₂ . After normalizing each concentration based on the fluorescence value without drug, the program calculated the value at which this fluorescence value is 50%, i.e. EC ₅₀ (half maximal effective concentration), through statistical processing. The results are shown in Table 2 below, and AAD-2004 was used as a control group.

Example compound structure Hb-EC ₅₀
(μM) Example compound structure Hb-EC ₅₀
(μM) One 0.54 3 0.56 4 0.58 5 0.43 6 0.27 7 0.46 8 0.41 9 0.30 10 0.3
(DMSO) 11 0.54
(DMSO) 12 0.83 13 0.72 14 0.78 15 0.59 16 0.19 17 0.3
(DMSO) 18 0.21 19 0.19 20 0.26 21 0.06 22 0.52 23 0.62 24 0.61 control group 0.99

As shown in Table 2, it can be seen that the aminoaromatic compound according to the present invention effectively reacts with hemoglobin (Hb) to reduce hydrogen peroxide. Therefore, it can be seen that the aminoaromatic compound according to the present invention is useful as a hydrogen peroxide scavenger that acts with hemoglobin present in the body to reduce overproduced hydrogen peroxide to an appropriate level.

[Experimental Example 2] In vitro H ₂ O ₂ decomposition experiment I and cell viability evaluation

In order to verify the effect of H ₂ O ₂ scavenging in a cellular level experiment, H ₂ DCFDA-AM (The cell-permeant 2',7'-dichlorodihydrofluorescein diacetate), a hydrogen peroxide probe, was used in astrocytes to The amount of H ₂ O ₂ inside was measured by fluorescence [Figure 2(A,B)]. The amino aromatic compound KDS12008 (Example 1) of the present invention was used as a test material, and sodium pyruvate, known to be able to remove H ₂ O ₂ , was used as a control material. When glial cells were treated with the aminoaromatic compound KDS12008 (Example 1) of the present invention at various concentrations, it was confirmed that H ₂ O ₂ decreased depending on the concentration [Figure 2(C)].

An experiment to determine the effect of _decomposing H ₂ O ₂ naturally occurring in cultured astrocytes by the aminoaromatic compound KDS12008 (Example 1) (10 μM) and _sodium pyruvate (10 mM) of the present invention. The timeline is shown in Figure 2(A). After waiting for 3 days for the cultured astrocytes to stabilize, they were treated with the aminoaromatic compound of the present invention, KDS12008 (Example 1) and sodium pyruvate. After two days, a cell-permeable H _{2 O 2 dye} (H ₂ DCFDA-AM) was used to measure intracellular H ₂ O 2 . H ₂ DCFDA-AM was measured using 10 μM as a sample that reacts with H ₂ O ₂ and generates green fluorescence. The results are shown in Figure 3(A). From Figure 3(A), the aminoaromatic compound KDS12008 (Example 1) (10 μM) of the present invention confirmed a statistically significant decrease in H ₂ O ₂ , and H ₂ O ₂ increased compared to a high concentration of 10 mM sodium pyruvate. A decreasing trend was seen.

Additionally, to determine cell viability, an experiment was performed using QuantiMax samples. Cell survival rate was confirmed through the degree of luminescence of QuantiMax, and the results are shown in Figure 3(B). From Figure 3(B), sodium pyruvate lowers the cell survival rate, while the aminoaromatic compound KDS12008 (Example 1) of the present invention is used at a concentration of 100 μM, which is higher than the concentration of 10 μM used in measuring the H ₂ O ₂ decomposition effect. Despite having , there was no effect on cell survival rate. In other words, it can be seen that it shows considerably better efficiency than existing known materials.

[Experimental Example 3] Passive avoidance test (PAT) I

The passive avoidance test is an experiment to check the memory of an animal by providing a weak electrical stimulus in a dark room to evaluate whether the animal remembers the electrical stimulus.

Rats prefer dark rooms, so when they are in a bright room, they tend to quickly move to the dark room. However, if a weak electrical stimulation is given to a rat in a dark room, it remembers the dark room and the electrical stimulation in combination, so it does not move from the bright room to the dark room. By measuring the time it takes to move from a bright room to a dark room (latency to dark room, sec), memory combining electrical stimulation and a dark room can be measured. A passive avoidance experiment was performed using APP/PS1 mice, which are used as an Alzheimer's animal model [Figure 5]. Wild type (WT) mice were used as a control group.

The first day of PAT is an acquisition session. The rat is kept in a bright room for a certain period of time, and after a certain period of time, the door to the dark room is opened and the time taken for the rat to enter the dark room is measured. When the rat enters the dark room, an electric shock (0.5 mA, 2 sec) is given through the footrest. The second day is a Retrieval session, where the rat is placed in a bright room and the time taken to enter the dark room is measured. At this time, the door to the dark room is open from the beginning. If your memory is good, you will not enter the dark room because of the memory of the electrical stimulation. If your memory is bad, you will quickly enter the dark room again. WT mice do not try to enter the dark room because they remember receiving electrical stimulation the previous day (acquisition session). On the other hand, APP/PS1 dementia mice do not remember that they received electrical stimulation the day before in a dark room, so they easily enter the dark room.

APP/PS1 dementia mice were intraperitoneally injected with an aminoaromatic compound of the present invention (KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21)) at 30 mg/kg/day (KDS12008 (Example 1)). (30 mpk); KDS12017 (Example 16) 30 mg/kg/day (30 mpk); KDS12025 (Example 21) 3 mg/kg/day (3 mpk)) were injected (intraperitoneal injection, IP) for 16 days. When a passive avoidance experiment was performed on the 26th day, it was confirmed that memory impairment in APP/PS1 dementia mice was significantly recovered [Figure 4].

In other words, Alzheimer's model APP/PS1 mice had poor memory compared to wild type mice, but when administered the aminoaromatic compound of the present invention (KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21)) In APP/PS1 mice, memory for passive avoidance was improved, and retention time showed a significant tendency to increase. Therefore, it was found that the aminoaromatic compound of the present invention is effective against Alzheimer's.

[Experimental Example 4] Brain tissue staining (immunohistochemistry, IHC) I

In the Alzheimer's disease animal model of Experimental Example 3, the brain was fixed with formaldehyde and then cut into thin pieces. The amount of cells or specific proteins in the cut brain is measured using tissue staining techniques. In this experimental example, changes in glial cells related to dementia were measured using an antibody that labels glial cells. The results are shown in Figure 5. That is, in this experimental example, the hippocampus of the brain is stained to observe changes in glial cells around the dementia substance amyloid beta. GFAP (Glial fibrillary acidic protein) indicates staining of glial cells, and DAPI (4',6-diamidino-2-phenylindole) indicates cell nuclei and amyloid beta material.

Through existing research, changes such as amyloid beta accumulation in the hippocampus of an Alzheimer's animal model and glial cells becoming reactive astrocytes in pathological conditions such as Alzheimer's were confirmed. At this time, astrocytes produce GABA and hydrogen peroxide, which are inhibitory neurotransmitters, which inhibit nerves and induce death of brain cells (neurons), worsening dementia. On the other hand, the tendency for astrocytes to decrease through anti-dementia drugs has also been confirmed through existing research.

From Figure 5, while GFAP increases in an Alzheimer's animal model and symptoms of astrocytes appear, APP treated with the aminoaromatic compounds of the present invention KDS12008 (Example 1), KDS12017 (Example 16), or KDS21025 (Example 21), respectively In the case of /PS1 mice, GFAP was confirmed to be decreased. Through this, it was confirmed that astrocytes, which are the cause of Alzheimer's, were effectively reduced, and that this effect occurred through the removal of hydrogen peroxide.

[Experimental Example 5] Passive avoidance test (PAT) II

Intraperitoneal injection of the aminoaromatic compound KDS12025 (Example 21) of the present invention into APP/PS1 mice used as an animal model for Alzheimer's disease at 3 mg/kg/day (3 mpk) and 10 mg/kg/day (10 mpk). was injected for a week, and a passive avoidance test (PAT) was performed in the same manner as in Experimental Example 3. The results are shown in Figure 6.

Healthy normal rats (wild type, WT) remembered the electrical stimulation well during the retrieval process and spent a long time entering the black room where they received the electrical stimulation. Although it is an Alzheimer's animal model, the control group (WT+saline) that was not treated with drugs received electrical stimulation. I forgot and quickly entered the black room where I received electrical stimulation.

On the other hand, Alzheimer's model APP/PS1 mice treated with the aminoaromatic compound KDS12025 (Example 21) of the present invention at 3 mg/kg/day (3 mpk) and 10 mg/kg/day (10 mpk) treated the drug with the existing 16 Even though administration was reduced from daily to weekly administration, memory was maintained similar to that of healthy normal mice, showing a statistically significant difference from the Alzheimer's model APP/PS1 mouse (Figure 6). Therefore, it was found that the aminoaromatic compound of the present invention is effective against Alzheimer's.

[Experimental Example 6] Brain tissue staining (immunohistochemistry, IHC) II

Using the Alzheimer's disease animal model of Experimental Example 5, tissue staining of brain tissue was performed in the same manner as Experimental Example 4, and the results are shown in FIG. 7. Figure 7 shows histological staining (IHC) of the brain hippocampus tissue of an animal model, where GFAP refers to the staining result of glial cells and Aβ refers to the staining result of amyloid beta.

From Figure 7, although glial cells increased in the Alzheimer's animal model, glial cells were healthy in APP/PS1 mice treated with 3 mg/kg/day or 10 mg/kg/day of the aminoaromatic compound KDS21025 (Example 21) of the present invention. It was confirmed that it had returned to normal levels. This result is consistent with the behavioral test results of Experimental Example 5, and it can be seen that the treatment with the aminoaromatic compound of the present invention returns the overproduced H ₂ O ₂ to a normal level.

[Experimental Example 7] Electrophysiology experiment

Using the Alzheimer's disease animal model of Experimental Example 5, electrophysiology experiments were performed to confirm the influence of glial cells and the mechanism causing memory impairment in dementia.

Previous research has demonstrated a mechanism that causes memory and cognitive impairment in the Alzheimer's group through the continuous secretion of an inhibitory neurotransmitter called tonic GABA (tonic current) by reactive astrocytes, and this is demonstrated through electrophysiology. You can check the change through.

Therefore, in this experimental example, APP/PS1 mice, an Alzheimer's animal model, were treated with the aminoaromatic compound KDS12025 (Example 21) of the present invention at 3 mg/kg/day or 10 mg/kg/day, respectively. , and healthy normal rats (wild type, WT) were each anesthetized, brain tissue was obtained, and electrical signals of living hippocampus cells were measured. Through this, tonic GABA, which inhibits nerve transmission in brain cells, was measured. The results are shown in Figure 8.

In Alzheimer's animal models (APP/PS1, TG), tonic GABA increased compared to healthy normal rats (WT), whereas in Alzheimer's animal models treated with the aminoaromatic compound KDS12025 (Example 21) of the present invention, tonic GABA decreased. did. In this experimental example, changes in tonic GABA were confirmed electrophysiologically, and through this, the efficacy of the amino aromatic compound of the present invention, that is, the inhibitory ability of tonic GABA to inhibit nerve transmission, could be verified. Therefore, it was found that the aminoaromatic compound of the present invention is effective against Alzheimer's.

[Experimental Example 8] Novel place recognition experiment and passive avoidance test (PAT)

Through a novel place recognition experiment, cognitive function related to the hippocampus was evaluated to confirm cognitive function impairment and recovery. The same objects are left to interact for a certain period of time, and after one hour, only the position of one object is changed. If you have normal cognitive function, your past memories will be maintained and your interest in new objects will increase, but if you have cognitive impairment, you will not be able to distinguish new places. At this time, the APP/PS1+GiD Alzheimer's model rat, which is a model rat developed to more closely resemble the phenomenon seen in Alzheimer's dementia patients, is used as an animal model. APP/PS1+GiD Alzheimer's model mice were prepared with reference to Nature Neuroscience 23, 1555-1566 (2020).

In this experimental example, APP/PS1+GiD was prepared by puncturing the hippocampus of APP/PS1 mice with the AAV-GFAP104-DTR-GFP virus, hereinafter referred to as 'APP+DTR'. In addition, the product produced by puncturing the hippocampus of APP/PS1 mice with the AAV-GFAP104-GFP virus was called 'APP+GFP'. In addition, the aminoaromatic compound KDS12025 (Example 21) of the present invention administered to the APP+DTR was called 'APP+DTR+KDS12025'. In addition, APP/PS1 and littermate were used for WT mice, and the product prepared by injecting the AAV-GFAP104-GFP virus into the hippocampus of WT mice was called 'WT+GFP', and the AAV-GFAP104 virus was injected into the hippocampus of WT mice. The product prepared by stabbing the -DTR-GFP virus was called 'WT+DTR'.

Normal mice (WT+GFP, WT+DTR) had normal cognitive function. APP+GFP showed a similar level of cognitive function as normal mice, but APP+DTR showed impaired cognitive function like an Alzheimer's patient. When the aminoaromatic compound KDS12025 (Example 21) of the present invention was administered intraperitoneally (i.p.) at 3 mg/kg/day to APP/PS1+GiD Alzheimer's model mice, i.e., APP+DTR, showing impaired cognitive function (i.e. , APP+DTR+KDS12025), it was confirmed that cognitive function was restored (Figure 9).

Additionally, as a result of PAT, normal mice (WT+GFP) remembered the dark room in which they received electrical stimulation well and spent a long time entering the dark room. On the other hand, APP/PS1+GiD Alzheimer's model mice, i.e., APP+DTR, showed problems with memory, but when administered with the aminoaromatic compound of the present invention, KDS12025 (Example 21), i.e., APP+DTR+KDS12025, showed memory problems. Recovery was confirmed (Figure 10).

In other words, the hydrogen peroxide removal efficacy of the aminoaromatic compound of the present invention was confirmed in the APP/PS1+GiD Alzheimer's model mouse, a model mouse developed to more closely resemble the phenomenon seen in Alzheimer's dementia patients, and therefore, it was found to be effective in Alzheimer's disease. .

[Experimental Example 9] Single toxicity evaluation (lethal dose 50, LD50)

The aminoaromatic compounds of the present invention, KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21), were administered to 8-week-old WT mice (C57BL/6 mice) at 100, 300, and 1000 mg/kg, respectively. A single dose intraperitoneal injection was administered to the animals and death was assessed. The results are shown in Figures 11 to 13. As a result, all three drugs showed toxicity at a concentration of 1000 mg/kg. On the other hand, at 300 mg/kg, all three drugs showed toxicity that killed only about 50% of animals, and at a lower concentration of 100 mg/kg, it was confirmed that all three drugs did not show fatal toxicity to mice.

[Experimental Example 10] Analysis of blood brain barrier (BBB) permeability

Reference J Med Chem. Based on 2001 Mar 15;44(6):923-30., drug permeability was measured by creating an artificial blood brain barrier (BBB) through an artificial lipid membrane permeability assay (PAMPA). was evaluated.

As a result, it was confirmed that the aminoaromatic compound of the present invention, KDS12025 (Example 21), penetrates the BBB at a concentration of 50 μM with a high transmittance (KDS12025 (Example 21) 67.43 × 10 ^-6 cm/sec). On the other hand, in the case of AAD-2004, an existing drug expected to remove reactive oxygen, the BBB permeability was found to be significantly low at 3.56 × 10 ^-6 cm/sec at the same concentration. Therefore, it was confirmed that the aminoaromatic compound of the present invention had high transmittance.

As described above, the present invention has been described with specific details, limited embodiments, and drawings, but these are provided only to facilitate a more general understanding of the present invention, and the present invention is not limited to the above embodiments, and the present invention Anyone skilled in the art can make various modifications and variations from this description.

Accordingly, the spirit of the present invention should not be limited to the described embodiments, and the scope of the patent claims described below as well as all modifications that are equivalent or equivalent to the scope of this patent claim shall fall within the scope of the spirit of the present invention. .

Claims (14)

Aminoaromatic compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
Ar is C ₆ -C ₂₀ arylene, and the arylene of Ar is C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, amino, mono- or di-C ₁ -C ₁₀ alkylamino, haloC ₁ - may be further substituted with one or more selected from C ₁₀ alkyl, haloC ₁ -C ₁₀ alkoxy and hydroxy;
R ¹ and R ² are each independently hydrogen or C ₁ -C ₁₀ alkyl;
R ³ is halogen, C ₁ -C ₁₀ alkoxy, haloC ₁ -C ₁₀ alkyl or haloC ₁ -C ₁₀ alkoxy;
n is an integer of 1 or 2;
However, when R ³ is halogen, n is an integer of 1. According to clause 1,
Ar is phenylene or biphenylene; The Ar is an aminoaromatic compound or a pharmaceutically acceptable salt thereof that may be further substituted with one or more selected from C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, amino and hydroxy. According to clause 1,
The aminoaromatic compound is an aminoaromatic compound or a pharmaceutically acceptable salt thereof represented by the following formula (2):
[Formula 2]

In Formula 2,
R ¹ and R ² are each independently hydrogen or C ₁ -C ₇ alkyl;
Hal is halogen;
R' is C ₁ -C ₇ alkyl, C 1 -C ₇ alkoxy, amino or hydroxy;
a is an integer from 0 to 4. According to clause 1,
The aminoaromatic compound is an aminoaromatic compound or a pharmaceutically acceptable salt thereof represented by the following formula (3):
[Formula 3]

In Formula 3 above,
R ¹ and R ² are each independently hydrogen or C ₁ -C ₇ alkyl;
R ³ is C ₁ -C ₇ alkoxy or haloC ₁ -C ₇ alkyl;
R' is C ₁ -C ₇ alkyl, C 1 -C ₇ alkoxy, amino or hydroxy;
a is an integer from 0 to 4;
n is an integer of 1 or 2. According to clause 3,
R ¹ and R ² are each independently hydrogen or C ₁ -C ₄ alkyl; Hal is halogen; a is an integer of 0, an aminoaromatic compound or a pharmaceutically acceptable salt thereof. According to clause 4,
R ¹ and R ² are each independently hydrogen or C ₁ -C ₄ alkyl; R ³ is C ₁ -C ₄ alkoxy or haloC ₁ -C ₄ alkyl; a is an integer of 0; n is an integer of 1 or 2, an aminoaromatic compound or a pharmaceutically acceptable salt thereof. According to clause 3,
The aminoaromatic compound is any one selected from the following compound group, an aminoaromatic compound or a pharmaceutically acceptable salt thereof:

According to clause 4,
The aminoaromatic compound is any one selected from the following compound group, an aminoaromatic compound or a pharmaceutically acceptable salt thereof:

According to clause 1,
The pharmaceutically acceptable salt is hydrochloride, an aminoaromatic compound or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for the treatment and prevention of neurodegenerative diseases containing the aminoaromatic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 as an active ingredient. According to clause 10,
The pharmaceutical composition further includes an excipient and a carrier. According to clause 10,
The neurodegenerative diseases include dementia, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Lou Gehrig's disease (ALS), post-traumatic stress disorder (trauma), multiple sclerosis (MS), cerebral ischemic disease, or amyotrophic lateral sclerosis. Phosphorus, pharmaceutical composition. delete A health functional food composition for preventing or improving neurodegenerative diseases, containing the aminoaromatic compound or a foodologically acceptable salt thereof according to any one of claims 1 to 9 as an active ingredient.