Novel aminoaromatic compound or pharmaceutically acceptable salt thereof, and pharmaceutical composition for preventing or treating neurodegenerative diseases comprising same as active ingredient

Abstract

To provide a pharmaceutical composition for preventing or treating neurodegenerative diseases and a health functional food composition for preventing or ameliorating neurodegenerative diseases.SOLUTION: The present invention provides a pharmaceutical composition for treating and preventing neurodegenerative diseases comprising, as active ingredient, an aminoaromatic compound represented by the chemical formula or a pharmaceutically acceptable salt thereof. (In the formula, Ar: substituted / unsubstituted phenylene, R1, R2: H, C1-C10 alkyl, R3: halogen, C1-C10 alkoxy, etc., n: an integer of 1 or 2).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel amino aromatic compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same as an active ingredient for preventing or treating neurodegenerative diseases, and a functional health food composition for preventing or ameliorating neurodegenerative diseases. [Background technology]

[0002] Neurodegenerative diseases are diseases that cause abnormalities in motor control, cognitive function, perceptual function, sensory function, and autonomic nervous system function due to a decrease or loss of nerve cell function. Representative examples include dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and memory disorders.

[0003] One of the main causes of neurodegenerative diseases is oxidative stress in neurons due to the generation of reactive oxygen species (ROS). Oxidative stress is defined as an imbalance between the antioxidant and oxidative systems in the body, and is known to occur due to the accumulation of intracellular reactive oxygen species (ROS). Such oxidative stress causes lipid peroxidation, intracellular DNA damage, and other conditions, leading to apoptosis and neuronal death.

[0004] In particular, the brain has high oxygen saturation and is rich in polyunsaturated fatty acids and metal ions, which are direct targets of oxidative stress. Brain neurotransmitters can also undergo autooxidation, and when subjected to oxidative stress by reactive oxygen species (ROS), the content of unsaturated fatty acids decreases but oxidation products that cause neurotoxicity increase, making the brain an organ highly vulnerable to oxidative stress and with limited antioxidant and recovery capabilities against oxidative stress.

[0005] Reactive oxygen species (ROS) are chemically reactive radicals and non-radical species that contain oxidizing capacity, such as the superoxide ion radical (·O2 - ), perhydroxyl radical (HO2·), hydroxyl radical (·OH), singlet oxygen (1O2), hydrogen peroxide (H2O2), alkoxy radical (·OR), and hydroperoxyl radical (·OOR).

[0006] Among reactive oxygen species (ROS), hydrogen peroxide (H2O2) is the most common product of various oxidation reactions (e.g., oxidases, dehydrogenases, and peroxidases) that primarily occur in the mitochondria of living organisms. More than just a by-product, H2O2 is generated as both a signaling molecule and a toxic molecule. During mitochondrial respiration, superoxide dismutase (SOD) catalyzes the conversion of superoxide anion radical (·O2-) to hydrogen peroxide (H2O2) and oxygen (O2).

[0007] Another source of hydrogen peroxide (H2O2) is NADPH oxidase (nicotinamide adenine dinucleotide phosphate oxidase), which catalyzes the oxidization of oxygen (O2) with superoxide anion radical (·O2-), resulting in the production of hydrogen peroxide (H2O2). Xanthine oxidase is responsible for the production of hydrogen peroxide (H2O2) during hypoxanthine oxidation, and the monoamine oxidase (MAO) family oxidizes monoamines (e.g., dopamine and noradrenaline) and polyamines (e.g., N-acetylputrescine) to produce hydrogen peroxide (H2O2). There are also various other ways to generate hydrogen peroxide (H2O2).

[0008] Appropriate amounts of hydrogen peroxide (H2O2) are extremely important in living organisms because they regulate cell growth, cell death, and immune functions through low concentrations of reactive oxygen species that are temporarily generated at specific sites in response to external signals. However, excessive amounts of hydrogen peroxide (H2O2) that cells cannot regulate can act as a toxic substance within cells. In other words, hydrogen peroxide (H2O2) is not only beneficial to health but also harmful.

[0009] At moderate levels, hydrogen peroxide (H2O2) acts as a cell signaling molecule (CSM), including transcription factors, protein kinases, and growth factors. However, intermediate levels of hydrogen peroxide (H2O2) can damage DNA, lipids, and proteins. H2O2-induced damage includes base decomposition, single- and double-stranded DNA breaks, protein cross-linking, and purine or pyrimidine modification of DNA. H2O2 disrupts membrane lipid bilayers, which in turn affects tissue stability through lipid peroxidation. H2O2 also causes protein fragmentation, protein cross-linking, and amino acid oxidation.

[0010] Various antioxidant systems have been established to control changing hydrogen peroxide (H2O2) levels. Catalase (CAT), glutathione peroxidase (GPx), and horseradish peroxidase (HRP) are known enzymes that degrade hydrogen peroxide (H2O2). CAT contains a heme cofactor and is a strong antioxidant enzyme that decomposes hydrogen peroxide (H2O2) into harmless water and oxygen. GPx is a selenium-cofactor enzyme, and its decomposition involves glutathione (GSH) oxidation. HRP also contains a heme cofactor and exhibits catalase-like activity, reducing hydrogen peroxide (H2O2) with water and oxygen. All of these antioxidant systems maintain equilibrium hydrogen peroxide (H2O2) levels under physiological conditions.

[0011] However, the balance of hydrogen peroxide (H2O2) levels is sometimes disrupted in pathological conditions, which is closely related to pathology. Generally, the balance of hydrogen peroxide (H2O2) is disrupted to excessive levels in neurodegenerative diseases, tumors, and autoimmune diseases. For example, amyloid-beta accumulation induces the proliferation of MAO-B (monoamine oxidase B) and reactive astrocytes.

[0012] Therefore, drugs that prevent hydrogen peroxide (H2O2)-induced oxidative stress have emerged as therapeutic targets. However, effective drug targets for preventing H2O2-induced damage have yet to be determined. Summary of the Invention [Problem to be solved by the invention]

[0013] Therefore, the present inventors have conducted extensive research to discover novel compounds that have preventive or therapeutic effects against neurodegenerative diseases. They have found that the level of hydrogen peroxide, a reactive oxygen species, is significantly higher in neurodegenerative diseases, particularly pathological conditions such as Alzheimer's disease, than in cases where it is produced as a by-product of endogenous oxidation reactions such as mitochondrial respiration. They then attempted to develop novel compounds that can scavenge hydrogen peroxide, a reactive oxygen species. As a result, they discovered that amino aromatic compounds with specific structures scavenge only hydrogen peroxide, not hydroxyl radicals, and thus completed the present invention.

[0014] An object of the present invention is to provide a novel aminoaromatic compound or a pharmaceutically acceptable salt thereof which is useful as a blood hydrogen peroxide scavenger.

[0015] The present invention also provides a pharmaceutical composition for preventing or treating neurodegenerative diseases, which comprises the novel amino aromatic compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] The present invention also provides a functional health food composition for preventing or ameliorating neurodegenerative diseases, which contains the novel amino aromatic compound of the present invention or a nutrient-friendly salt thereof as an active ingredient. [Means for solving the problem]

[0017] To achieve the above objectives, One aspect of the present invention provides an amino aromatic compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical formula 1] TIFF2025131672000001.tif3641In the above chemical formula 1, Ar is C6-C 20 Arylene, and the arylene of Ar is C1-C 10 Alkyl, C1-C 10 Alkoxy, amino, mono- or di-C1-C 10 Alkylamino, HaloC1-C 10 Alkyl, Halo C1-C 10may be further substituted with one or more selected from alkoxy and hydroxy; R 1 and R 2 are each independently hydrogen or C1-C 10 is alkyl, R 3 are halogens, C1-C 10 Alkoxy, Halo C1-C 10 Alkyl or halo C1-C 10 is an alkoxy, n is an integer of 1 or 2, However, R 3 When is a halogen, n is an integer equal to 1.

[0018] In another aspect, the present invention provides a pharmaceutical composition for preventing or treating a neurodegenerative disease, comprising the amino aromatic compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0019] In another aspect, the present invention provides a functional health food composition for preventing or ameliorating neurodegenerative diseases, comprising the amino aromatic compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. [Effects of the Invention]

[0020] The amino aromatic compound according to the present invention acts as a scavenger that removes hydrogen peroxide, a type of active oxygen.

[0021] The amino aromatic compounds of the present invention suppress cell death due to oxidative stress caused by H2O2 by scavenging hydrogen peroxide, an intracellular reactive oxygen species (ROS).

[0022] That is, the amino aromatic compound of the present invention acts together with an enzyme containing heme to reduce the concentration of H2O2, and therefore does not reduce the concentration of H2O2 excessively, but rather removes overproduced hydrogen peroxide to ensure an appropriate concentration required in the body.

[0023] The amino aromatic compound according to the present invention is a small molecule blood hydrogen peroxide scavenger, and has very high blood-brain barrier (BBB) ​​permeability, acting directly on the brain and exhibiting excellent effects in the treatment of brain diseases.

[0024] The aminoaromatic compounds according to the present invention exhibit hydrogen peroxide scavenging activity and exhibit antioxidant properties that can ameliorate cognitive and memory impairment by ameliorating hydrogen peroxide-induced cell death.

[0025] The amino aromatic compounds according to the present invention can decompose hydrogen peroxide in the presence of heme-containing peroxidase and hemoglobin (Hb) present in the body, thereby lowering the blood hydrogen peroxide level, thereby suppressing or treating the onset of neurodegenerative diseases.

[0026] 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 functional health food compositions for preventing or ameliorating neurodegenerative diseases by suppressing damage caused by harmful hydrogen peroxide. [Brief explanation of the drawings]

[0027] [Figure 1] This is a schematic image of hydrogen peroxide (H2O2) analysis by hemoglobin enzyme reaction between hydrogen peroxide (H2O2) and Amplex Red (10-acetyl-3,7-dihydroxyphenoxazine). [Figure 2]Experimental Example 2: In Vitro H2O2 Decomposition Analysis of Novel Compounds I [(A, B) Timeline of imaging using the cell-permeable H2O2 dye H2DCFDA-AM in primary cultured astrocytes and a schematic diagram of the chemical reaction showing the principle of hydrogen peroxide measurement; (C) Graph showing fluorescence intensity as a function of the concentration of the aminoaromatic compound KDS12008 (Example 1) of the present invention. Fluorescence intensity indicates the amount of intracellular H2O2, which is normalized to the control condition.] [Figure 3] Experimental Example 2: In vitro H2O2 decomposition analysis I results of novel compounds [(A) Graph showing the H2O2 decomposition effect of the aminoaromatic compound KDS12008 (Example 1) of the present invention (10 μM) and sodium pyruvate (10 mM); (B) Cell viability test results of the aminoaromatic compound KDS12008 (Example 1) of the present invention (100 μM) and sodium pyruvate (10 mM). Fluorescence intensity indicates the amount of intracellular H2O2, which is normalized by the control condition. **P<0.01; ***P<0.001; ns, non-significant.] [Figure 4] Experimental results of Experimental Example 3 on recovery of memory impairment (memory impairment) in APP / PS1 mice treated with the aminoaromatic compounds of the present invention [(A) Schematic timeline of drug treatment and passive avoidance test (PAT); (B) Bar graph showing the latency to the dark chamber in the passive avoidance test in APP / PS1 mice treated with the aminoaromatic compounds KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21) of the present invention. Data are expressed as mean ± SEM. Unpaired two-tailed t-test. *P<0.05, ****P<0.0001.] [Figure 5]1 shows the results of immunohistochemistry (IHC) of brain tissues from APP / PS1 mice treated with the amino aromatic compounds KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21) of the present invention in Experimental Example 4. [Figure 6] 1 shows the results of a passive avoidance test (PAT) in Experimental Example 5. [Figure 7] 1 shows the results of tissue staining (immunohistochemistry, IHC) II of brain tissue in Experimental Example 6. [Figure 8] 1 shows the results of electrophysiology experiments in Experimental Example 7. [Figure 9] The results of Experimental Example 8, a novel place recognition experiment, are shown below. [Figure 10] 1 shows the results of a passive avoidance test (PAT) in Experimental Example 8. [Figure 11] The results of single toxicity evaluation (lethal dose 50, LD50) in Experimental Example 9 are shown below. [Figure 12] The results of single toxicity evaluation (lethal dose 50, LD50) in Experimental Example 9 are shown below. [Figure 13] The results of single toxicity evaluation (lethal dose 50, LD50) in Experimental Example 9 are shown below. DETAILED DESCRIPTION OF THE INVENTION

[0028] The novel amino aromatic compound or its pharmaceutically acceptable salt will be described in detail below. In this regard, unless otherwise defined, the technical and scientific terms used have the meanings that are commonly understood by those skilled in the art to which the present invention pertains, and the description of known functions and structures that may obscure the gist of the present invention will be omitted.

[0029] The following terms used herein are defined as follows, but are for illustrative purposes only and are not intended to limit the invention, application, or use.

[0030] As used herein, the terms "substituent," "radical," "group," "moiety," and "fragment" may be used interchangeably.

[0031] As used herein, the term "C A -C B " means "having a carbon number of A or more and B or less."

[0032] As used herein, the term "alkyl" refers to a monovalent, straight- or branched-chain saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms. The alkyl can have 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. "Lower alkyl" refers to a straight- or branched-chain alkyl having 1 to 4 carbon atoms. By way of example, alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethylhexyl, and the like.

[0033] As used herein, the term "arylene" refers to an aromatic divalent organic radical derived from an aromatic hydrocarbon by the removal of two hydrogen atoms, and includes monocyclic or fused ring systems suitably containing 4 to 7, preferably 5 or 6, ring atoms in each ring, including multiple aryls linked by single bonds. Specific examples include, but are not limited to, phenylene, naphthylene, biphenylene, anthrylene, etc.

[0034] As used herein, 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, and the like.

[0035] As used herein, the term "halo" or "halogen" refers to an element of the halogen family and includes, for example, fluoro, chloro, bromo, and iodo.

[0036] As used herein, the term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms are replaced with halogen atoms, where alkyl and halogen are as defined above. For example, haloalkyl includes fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, perfluoroethyl, etc., and haloalkoxy includes fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy, difluoroethoxy, perfluoroethoxy, etc.

[0037] As used herein, the term "amino" means --NH.sub.2 and "hydroxy" means --OH.

[0038] As used herein, the term "alkylamino" refers to an amino radical substituted with one or two alkyl groups, and specific examples include, but are not limited to, methylamino (-NHMe), dimethylamino (-NMe), ethylamino (-NHEt), diethylamino (-NEt), etc.

[0039] As used herein, the term "pharmaceutically acceptable" means a composition that exhibits the property of being non-toxic to cells exposed to the composition or to individuals, such as humans, and is suitable for use as a pharmaceutical formulation, and generally means a composition that is considered safe for such use and is officially approved for such use by a national regulatory agency or listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to any and all organic or inorganic addition salts of the compounds of the present invention that are relatively non-toxic to patients and have innocuous effective concentrations, and the side effects attributable to the salt do not diminish the beneficial effects of the compounds of the present invention themselves.

[0041] As used herein, the terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to a substance that aids in the administration and absorption by a subject of an active agent.

[0042] As used herein, the term "oxidative stress" is used according to its ordinary meaning to refer to abnormal levels of reactive oxygen species.

[0043] As used herein, the term "prevention" refers to any action that inhibits or delays the onset, spread and recurrence of a neurodegenerative disease.

[0044] As used herein, the term "amelioration" refers to any action that at least reduces a parameter associated with the condition being treated, eg, the severity of a symptom.

[0045] As used herein, the term "treatment" refers to any action that reverses or favorably alters the symptoms of a neurodegenerative disease.

[0046] As used herein, the term "individual" refers to any animal, including humans, that is suffering from or may be suffering from a neurodegenerative disease. The animal may be, but is not limited to, a mammal such as a cow, horse, sheep, pig, goat, camel, antelope, dog, or cat that requires treatment for a similar condition to a human.

[0047] As used herein, the term "administration" means introducing the pharmaceutical composition of the present invention into an individual in a suitable manner, and the administration route of the composition of the present invention can be one of oral or parenteral administration routes that can reach the target tissue.

[0048] As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to any medical treatment and which does not cause side effects, and the level of an effective dose can be easily determined by one skilled in the art depending on factors including the patient's sex, age, weight, 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, concomitant or concomitant drugs, and other factors well known in the medical field.

[0049] In this specification, the term "food" includes meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, energy drinks, alcoholic beverages, vitamin complexes, functional health foods and health foods, and includes all foods in the ordinary sense.

[0050] In this specification, the term "health functional food" means food manufactured and processed using raw materials or ingredients that have functional properties that are beneficial to the human body in accordance with Act No. 6727 on Health Functional Foods, and "functional" means that the food is ingested for the purpose of regulating nutrients for the structure and function of the human body or obtaining beneficial effects for health purposes such as physiological effects.

[0051] As used herein, the term "phytochemically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound.

[0052] The present invention provides a novel amino aromatic compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, which is useful as a blood hydrogen peroxide scavenger.

[0053] [Chemical formula 1] TIFF2025131672000002.tif3641In the above chemical formula 1, Ar is C6-C 20 Arylene, and the arylene of Ar is C1-C10 Alkyl, C1-C 10 Alkoxy, amino, mono- or di-C1-C 10 Alkylamino, HaloC1-C 10 Alkyl, Halo C1-C 10 may be further substituted with one or more selected from alkoxy and hydroxy; R 1 and R 2 are each independently hydrogen or C1-C 10 is alkyl, R 3 are halogens, C1-C 10 Alkoxy, Halo C1-C 10 Alkyl or halo C1-C 10 is an alkoxy, n is an integer of 1 or 2, However, R 3 When is a halogen, n is an integer equal to 1.

[0054] The amino aromatic compound according to the present invention is a small molecule compound with low cytotoxicity, and can act as a scavenger that removes hydrogen peroxide, a type of reactive oxygen.

[0055] The amino aromatic compounds according to the present invention do not scavenge hydroxyl radicals and are not MAO-B inhibitors. The ROS-GLO analysis confirmed that the amino aromatic compounds according to the present invention act as catalysts for the decomposition of hydrogen peroxide into water in the presence of endogenous peroxidases, particularly heme-containing peroxidases, and hemoglobin (Hb).

[0056] That is, the amino aromatic compounds according to the present invention act together with heme-containing peroxidase and hemoglobin (Hb) present in the body to remove overproduced hydrogen peroxide to an appropriate concentration level, and thus the amino aromatic compounds according to the present invention can be useful for preventing, ameliorating, or treating neurodegenerative diseases by inhibiting the death of neurons caused by harmful hydrogen peroxide. Furthermore, the amino aromatic compounds according to the present invention have the ability to efficiently penetrate the blood-brain barrier (BBB), allowing for rapid, fast, and more effective therapeutic effects to be obtained even when administered in low doses.

[0057] In one embodiment of the present invention, Ar is C-C 12 Arylene, preferably phenylene or biphenylene, wherein Ar may be further substituted with one or more selected from C1-C7 alkyl, C1-C7 alkoxy, amino and hydroxy.

[0058] In one embodiment of the present invention, it is preferred that Ar is phenylene, and nitrogen atoms are introduced into the 1st and 4th positions of the phenylene.

[0059] The amino aromatic compound according to one embodiment of the present invention may be specifically represented by the following Chemical Formula 2 or 3.

[0060] The amino aromatic compound according to one embodiment of the present invention may be specifically represented by the following Chemical Formula 2 or 3.

[0061] [Chemical formula 2] TIFF2025131672000003.tif4250

[0062] [Chemical formula 3] TIFF2025131672000004.tif4250

[0063] In the above chemical formulas 2 and 3, R 1 and R 2are each independently hydrogen or C1-C7 alkyl; Hal is a halogen, R 3 is C1-C7 alkoxy or haloC1-C7 alkyl; R' is C1-C7 alkyl, C1-C7 alkoxy, amino or hydroxy; a is an integer from 0 to 4, n is an integer of 1 or 2.

[0064] Preferably, in Formulas 2 and 3 according to one embodiment of the present invention, R 1 and R 2 are each independently hydrogen or C1-C4 alkyl, Hal is halogen, and R 3 is C1-C4 alkoxy or haloC1-C4 alkyl, a is an integer of 0, and n can be an integer of 1 or 2.

[0065] According to one embodiment, Formula 2 can be represented by Formula 4 below.

[0066] [Chemical formula 4] TIFF2025131672000005.tif4242

[0067] In chemical formula 4, R 1 and R 2 are each independently hydrogen or C1-C4 alkyl; Hal is a halogen.

[0068] Specifically, in the chemical formula 4, the R 1 and R 2 are each independently C1-C4 alkyl, and Hal can be halogen.

[0069] Specifically, in the chemical formula 4, the R 1 is hydrogen and R 2 is C1-C4 alkyl and Hal can be halogen.

[0070] Specifically, in the chemical formula 4, the R 1 and R 2 can each independently be hydrogen and Hal can be halogen.

[0071] According to one embodiment, Formula 3 can be represented by Formula 5 below.

[0072] [Chemical formula 5] TIFF2025131672000006.tif4242

[0073] In chemical formula 5, R 1 and R 2 are each independently hydrogen or C1-C4 alkyl; R 3 is C1-C4 alkoxy or haloC1-C4 alkyl; n is an integer of 1 or 2.

[0074] Specifically, in the chemical formula 5, the R 1 and R 2 are each independently C1-C4 alkyl, and R 3 is C1-C4 alkoxy or haloC1-C4 alkyl, and n is an integer of 1 or 2.

[0075] Specifically, in the above-mentioned chemical formula 5, R 1 is hydrogen and R 2 is C1-C4 alkyl, and R 3 is C1-C4 alkoxy or haloC1-C4 alkyl, and n is an integer of 1 or 2.

[0076] Specifically, in the chemical formula 5, the R 1 and R 2 are each independently hydrogen, and R 3 is haloC1-C4 alkyl and n is an integer of 1 or 2.

[0077] In any of the compounds described herein, halogen or halo can be fluorine.

[0078] According to one embodiment, the amino aromatic compound may be any one selected from the following compound group, but is not limited thereto:

[0079] TIFF2025131672000007.tif80167TIFF2025131672000008.tif73167TIFF2025131672000009.tif80167

[0080] It will be apparent to those skilled in the art that the method for preparing an amino aromatic compound according to one embodiment of the present invention can be carried out using methods known in the art or with appropriate modifications. Furthermore, the reaction time for the method for preparing Formula 1 according to one embodiment of the present invention can vary depending on the type and amount of reactants and solvent. For example, the reaction is completed after confirming complete consumption of the starting materials via TLC, etc. After completion of the reaction, the solvent is distilled under reduced pressure, and the target product can be separated and purified by a conventional method such as column chromatography. For example, the compound can be prepared by reacting an arylenediamine compound with a phenylalkyl bromide compound, and further details are described in the following examples.

[0081] [Reaction Scheme 1] TIFF2025131672000010.tif42125

[0082] (In the above reaction formula 1, Ar, R 1 , R 2 , R 3 and n is the same as in Chemical Formula 1.

[0083] The present invention includes not only the amino aromatic compounds and their pharmaceutically acceptable salts, but also all possible prodrugs, hydrates and solvates that can be prepared therefrom.

[0084] That is, the amino aromatic compounds of the present invention can be used in the form of prodrugs, hydrates, solvates and pharmaceutically acceptable salts in order to enhance in vivo absorption or increase solubility, and the above prodrugs, hydrates, solvates and pharmaceutically acceptable salts also fall within the scope of the present invention.

[0085] The amino aromatic compounds of the present invention can be used in the form of pharmaceutically acceptable salts, which are salts prepared by conventional methods in the art and whose preparation methods are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable free acids and bases:

[0086] Acid addition salts formed with pharmaceutically acceptable free acids are derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid, and organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid, vanillic acid, and hydroiodic acid. Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butane-1,4-dioate, hexaphosphate, and the like. These include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0087] The acid addition salts can be prepared by a conventional method. For example, the amino aromatic compound of the present invention can be dissolved in a water-miscible organic solvent such as methanol, ethanol, acetone, dichloromethane, or acetonitrile, and an organic or inorganic acid can be added to the solution. The precipitate formed is filtered and dried, or the acid addition salts can be prepared by distilling the solvent and excess acid under reduced pressure, drying the residue, and crystallizing it in an organic solvent.

[0088] Pharmaceutically acceptable metal salts can also be prepared using a base. Alkali metal salts or alkaline earth metal salts can be obtained, for example, by dissolving the amino aromatic compound of the present invention in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved amino aromatic compound salt, and then evaporating and drying the filtrate. Here, sodium, potassium, or calcium salts are prepared as pharmaceutically acceptable metal salts, but are not limited to these. Corresponding silver salts can also be obtained by reacting alkali metal or alkaline earth metal salts with an appropriate silver salt (e.g., silver nitrate).

[0089] Preferably, the pharmaceutically acceptable salt of the amino aromatic compound according to one embodiment of the present invention may be a hydrochloride salt.

[0090] That is, the amino aromatic compound according to one embodiment of the present invention may be a hydrochloride salt compound selected from the following structures:

[0091] TIFF2025131672000011.tif80167TIFF2025131672000012.tif72167TIFF2025131672000013.tif80167

[0092] A hydrate of an aminoaromatic compound of the present invention means an aminoaromatic compound of the present invention or a pharmaceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0093] A solvate of an aminoaromatic compound of the present invention refers to an aminoaromatic compound of the present invention or a pharmaceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Solvents that can be used include volatile, non-toxic solvents.

[0094] The amino aromatic compounds of the present invention can be administered in the form of prodrugs that are broken down in the human or animal body to provide the compounds of the present invention as the 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 derivatized to form the prodrug.

[0095] For example, if a compound (prodrug) is liberated in the body to produce an aminoaromatic compound of the present invention or a salt thereof, such a compound is also included within the scope of the present invention. As used herein, unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide an active compound, particularly a compound of the present invention. Examples of prodrugs include compounds that are biohydrolyzed to produce a compound of the present invention, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs, but are not limited to such specific embodiments. Preferably, prodrugs of compounds having a carboxy functional group are lower alkyl esters of the carboxylic acid. Carboxylic esters are typically formed by esterifying a carboxylic acid moiety present in the molecule. Prodrugs can be readily prepared using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers GmbH).

[0096] The present invention provides a hydrogen peroxide scavenger comprising the amino aromatic compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0097] The present invention also provides a pharmaceutical composition for preventing or treating neurodegenerative diseases, comprising the amino aromatic compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0098] The term "neurodegenerative disease" refers to a disease or pathological condition resulting from impaired function of the nervous system of a subject, resulting in dysfunction of motor control, cognitive function, perceptual function, sensory function, and autonomic nervous function, and has the same meaning as "degenerative brain disease." Specific examples 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 ischemia, and amyotrophic lateral sclerosis.

[0099] The amino aromatic compound according to the present invention decomposes overproduced hydrogen peroxide in the presence of heme-containing peroxidase and hemoglobin (Hb) in the body, thereby reducing the blood hydrogen peroxide level to an appropriate level, thereby suppressing or treating the onset of neurodegenerative diseases.

[0100] In addition, the amino aromatic compound according to the present invention is a low-molecular-weight blood hydrogen peroxide scavenger, and has high blood-brain barrier (BBB) ​​permeability, acting directly on the brain and exhibiting excellent efficacy in treating brain diseases. Therefore, the amino aromatic compound according to the present invention can be effectively used for the prevention or treatment of neurodegenerative diseases.

[0101] In addition to the active ingredient, the pharmaceutical composition according to one embodiment may further contain conventional non-toxic pharmaceutically acceptable carriers and / or excipients to be formulated into a conventional formulation in the pharmaceutical field, i.e., an oral or parenteral administration formulation, and may further contain diluents such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

[0102] The pharmaceutically acceptable carrier, excipient, or diluent includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.

[0103] The pharmaceutical composition of the present invention can be formulated into various forms, such as oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, and sterile injection solutions, by conventional methods depending on the purpose of use, and can be administered orally or via various routes including intravenous, intraperitoneal, subcutaneous, rectal, and topical administration.

[0104] In addition, the pharmaceutical composition of the present invention may further comprise a filler, an anti-agglomerating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative, and the like.

[0105] Oral dosage forms include tablets, pills, hard / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs, etc., and these dosage forms may contain one or more commonly used diluents or excipients, such as fillers, extenders, wetting agents, disintegrants, lubricants, binders, surfactants, etc. Disintegrants may include agar, starch, alginic acid or its sodium salt, anhydrous calcium hydrogen phosphate, etc. Lubricants may include silica, talc, stearic acid or its magnesium or calcium salt, polyethylene glycol, etc. Binders may include magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low-substituted hydroxypropyl cellulose, etc. Other diluents that can be used include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc., and, in some cases, commonly known boiling mixtures, absorbents, coloring agents, flavoring agents, sweetening agents, etc. can also be used.

[0106] Examples of formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Examples of non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Examples of suppository bases include witepsol, macrogol, Tween 61, cocoa butter, lauric butter, glycerol, and gelatin. Injectable solutions may contain conventional additives such as solubilizers, isotonicity agents, suspending agents, emulsifiers, stabilizers, and preservatives. To prepare an injectable solution, the amino aromatic compound of the present invention or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to form a solution or suspension, which can then be packaged in a unit-dose form such as an ampule or vial.

[0107] The pharmaceutical compositions of the present invention may be sterilized or may further contain auxiliary substances such as preservatives, stabilizers, thickeners, wetting or emulsifying agents, salts for adjusting osmotic pressure and / or buffers, and may further contain other therapeutically useful substances, and may be formulated by conventional methods such as dissolving, dispersing, mixing, granulating, gelling, or coating.

[0108] The pharmaceutically effective amount of the amino aromatic compound of the present invention can be determined by factors including the patient's health condition, type and severity of the disease, drug activity, drug sensitivity, administration method, administration time, administration route, excretion rate, treatment duration, coadministered or concomitant drugs, and other factors well known in the medical field. Specifically, the effective amount of the compound in the pharmaceutical composition of the present invention varies depending on the patient's age, sex, and weight. Generally, it is about 0.01 to 500 mg / kg / day, preferably 0.1 to 100 mg / kg / day, and can be administered daily or every other day, or once or several times a day. However, the dosage may be increased or decreased depending on the administration route, disease severity, sex, weight, age, etc., and the above dosage does not limit the scope of the present invention in any way.

[0109] The pharmaceutical composition of the present invention can be administered orally or parenterally, preferably parenterally by subcutaneous injection, intravenous injection, intramuscular injection or intraperitoneal injection.

[0110] The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art.

[0111] The present invention also provides a method for preventing or treating a neurodegenerative disease, comprising administering the amino aromatic compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to an individual suffering from or at risk of developing a neurodegenerative disease.

[0112] The present invention also provides a method for preventing or treating a neurodegenerative disease, comprising administering the amino aromatic compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to an individual suffering from or at risk of developing a neurodegenerative disease.

[0113] The present invention also provides a functional health food composition for preventing or ameliorating neurodegenerative diseases, which contains the amino aromatic compound or a nutrient-acceptable salt thereof as an active ingredient.

[0114] The edibly acceptable salts can be obtained by reacting the amino aromatic compounds of the present invention with inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, and phosphoric acid, sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, and organic carboxylic acids such as tartaric acid, formic acid, citric acid, 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, and salicylic acid. Furthermore, the edible acceptable salts can also be obtained by reacting the compounds of the present invention with a base to form salts such as ammonium salts, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, salts of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, and tris(hydroxymethyl)methylamine, and salts of amino acids such as arginine and lysine, but are not limited thereto.

[0115] The functional health food composition can be provided in the form of powder, granules, tablets, capsules, syrup or beverage, and the functional health food can be used together with other foods or food additives in addition to the amino aromatic compound as an active ingredient, and can be used appropriately according to conventional methods. The amount of the active ingredient can be suitably determined depending on the purpose of use, such as prevention, health or therapeutic treatment.

[0116] The health functional food composition may contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and fillers (cheese, chocolate, etc.), pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, etc. In addition, it may contain natural fruit juice and fruit pulp for producing fruit juice drinks and vegetable drinks. These ingredients may be used independently or in combination.

[0117] In addition, the health functional food may further contain food additives, and whether or not a substance conforms to the "food additive" standard shall be determined based on the specifications and standards for that item in accordance with the general provisions and general test methods of the Food Additives Code approved by the Ministry of Food and Drug Safety, unless otherwise specified.

[0118] Examples of items listed in the "Food Additives Code" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon color, licorice extract, crystalline cellulose, and guar gum; and mixed preparations such as monosodium L-glutamate preparations, alkaline agents added to noodles, preservative preparations, and tar color preparations.

[0119] The amino aromatic compound contained in the health functional food composition can be used in an amount equivalent to the effective amount of the pharmaceutical composition. However, in the case of long-term intake for the purpose of health and hygiene or health regulation, the amount can be less than the above range, and it goes without saying that the active ingredient can be used in an amount greater than the above range since there is no safety issue.

[0120] The health functional food composition can be formulated into various dosage forms such as meat, sausage, bread, chocolate, candy, snacks, sweets, pizza, ramen, other noodles, gums, dairy products including ice cream, various soups, beverages, tea, energy drinks, alcoholic beverages, vitamin complexes, etc.

[0121] The present invention will be described in more detail below with reference to preferred embodiments, which are presented as examples of the present invention and are not intended to limit the scope of the present invention in any way, but rather are defined solely by the claims set forth below.

[0122] [Production Example 1] Production of tert-butyl(4-aminophenyl)(methyl)carbamate TIFF2025131672000014.tif42150

[0123] Production of N-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. The mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. The organic layer was separated and washed with ethyl acetate and brine. The separated organic layer was dried over sodium sulfate, and the ethyl acetate was removed under reduced pressure to yield 913.3 mg (84.6%) of the title compound as a yellow solid.

[0124] 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)

[0125] 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), and 4-dimethylaminopyridine (32.1 mg, 0.26 mmol) were dissolved in tetrahydrofuran and refluxed for 12 hours. The mixture was then cooled to room temperature and the solvent was removed under reduced pressure. The organic layer was separated and washed with ethyl acetate and brine. The separated organic layer was dried over sodium sulfate, and the ethyl acetate was removed under reduced pressure to yield 1.29 g (97.3%) of the title compound as a yellow oil.

[0126] 400 MHz 1 H NMR (DMSO-d6) δ 8.20 (d, 2H, J = 9.20), 7.60 (d, 2H, J = 9.16), 3.29 (s, 3H), 1.45 (s, 9H)

[0127] Preparation of tert-butyl(4-aminophenyl)(methyl)carbamate Tert-butylmethyl(nitrophenyl)carbamate (1.29 g, 5.11 mmol) was dissolved in a mixed solvent of distilled water (12 mL), methanol (25 mL), and tetrahydrofuran (6 mL), followed by the addition of iron powder (1.36 g, 26.1 mmol) and ammonium chloride (2.80 g, 52.4 mmol) and stirring at 50°C for 3 hours. The mixture was then cooled to room temperature and filtered through Celite. After filtration, the solvent was removed under reduced pressure. The organic layer was separated and washed with ethyl acetate and brine. The separated organic layer was dried over sodium sulfate, and the ethyl acetate was removed under reduced pressure to yield 890 mg (78.1%) of the title compound as a yellow solid.

[0128] 400 MHz 1 H 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)

[0129] Example I: Preparation of Amino Aromatic Compounds TIFF2025131672000015.tif44150

[0130] To a solution of p-phenylenediamine compound (a, 1.2 equivalents) in acetonitrile, potassium carbonate (3.0 equivalents), potassium iodide (0.1 equivalents), and phenylalkyl bromide compound (b, 1.0 equivalents) were added, and the mixture was stirred at 110°C for 36 hours. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with brine. The remaining organic layer was dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified through a column to obtain compound P1. The purified compound P1 was dissolved in dichloromethane (DCM) and then added with 4.0 M hydrogen chloride solution. The mixture was then stirred at room temperature for 48 hours, and the resulting precipitate was filtered to obtain compound P2 in hydrochloride form.

[0131] Using the above method, various amino aromatic compounds were prepared as shown in Table 1 below.

[0132] [Table 1] JPEG2025131672000017.jpg235169 JPEG2025131672000018.jpg198167 JPEG2025131672000019.jpg223167 JPEG2025131672000020.jpg203169 JPEG2025131672000021.jpg190169 JPEG2025131672000022.jpg235169

[0133] [Experimental Example] Primary cultured astrocytes Primary cortical astrocytes were prepared from day-old to day-3 C57BL / 6 mice. Cerebral cortices were dissected free of adherent meninges, minced, and dissociated into single-cell suspensions by trituration. Cells were grown in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen) supplemented with 25 mM glucose, 10% heat-inactivated horse serum, 10% heat-inactivated fetal calf serum (FCS), 2 mM glutamine, and 1,000 U / ml penicillin-streptomycin. Cultures were maintained at 37°C in a humidified 5% CO2 incubator. On day 3 of culture, cells were vigorously washed by repeated pipetting and the medium was replaced to remove debris and other floating cell types.

[0134] [Experimental Example 1] Evaluation of hydrogen peroxide elimination ability by enzymes present in the body To investigate the hydrogen peroxide scavenging ability of the proposed enzyme and the amino aromatic compound of the present invention, the following experiment was carried out.

[0135] Amplex Red converts to a fluorescent substance called resorufin in the presence of both HRP (horse radish peroxidase) and H2O2, enabling the measurement of H2O2 conversion, i.e., the H2O2 assay. However, HRP is an enzyme not found in the body. Experiments were conducted based on the idea that hemoglobin, like HRP, can interact with the amino aromatic compounds of the present invention as a heme-containing group. The Amplex Red H2O2 assay was performed using hemoglobin instead of HRP (Figure 1). The final concentrations of each substance were 10 μM H2O2 and 80 μg / ml hemoglobin. The amino aromatic compounds of the present invention were treated at different concentrations. After 30 minutes of incubation at 37°C, fluorescence (excitation: 540 nm, emission: 580 nm) was measured using a microplate reader. Here, the fluorescence is proportional to the amount of H2O2. After normalizing the fluorescence value at each concentration based on the value without the drug, the value at which this fluorescence value reaches 50% through statistical processing, i.e., the EC 50 The half maximal effective concentration (HAEC) was calculated by the program. The results are shown in Table 2 below, and AAD-2004 was used as a control.

[0136] [Table 2] JPEG2025131672000024.jpg217169 JPEG2025131672000025.jpg140165

[0137] As shown in Table 2, the amino aromatic compounds according to the present invention effectively react with hemoglobin (Hb) to reduce hydrogen peroxide. Therefore, the amino aromatic compounds according to the present invention are useful as hydrogen peroxide scavengers that act together with hemoglobin present in the body to reduce overproduced hydrogen peroxide and maintain it at an appropriate level.

[0138] [Experimental Example 2] In vitro H2O2 decomposition experiment I and cell viability evaluation To verify the H2O2 scavenging effect in cellular experiments, the amount of intracellular H2O2 was measured by fluorescence in astrocytes using the hydrogen peroxide probe H2DCFDA-AM (The cell-permeant 2',7'-dichlorodihydrofluorescein diacetate) [Figure 2(A, B)]. The aminoaromatic compound KDS12008 (Example 1) of the present invention was used as the test substance, and sodium pyruvate, which is known to be able to scavenge H2O2, was used as the control substance. When astrocytes were treated with the aminoaromatic compound KDS12008 (Example 1) of the present invention at various concentrations, it was confirmed that H2O2 decreased in a concentration-dependent manner [Figure 2(C)].

[0139] Figure 2(A) shows an experimental timeline for investigating the effect of the aminoaromatic compound KDS12008 (Example 1) of the present invention (10 μM) and sodium pyruvate (10 mM) on H2O2 decomposition in cultured astrocytes. Cultured astrocytes were allowed to stabilize for three days before treatment with the aminoaromatic compound KDS12008 (Example 1) and sodium pyruvate. After two days, intracellular H2O2 was measured using a cell-permeable H2O2 dye (H2DCFDA-AM). H2DCFDA-AM was used at 10 μM as a sample that reacts with H2O2 to emit green fluorescence. The results are shown in Figure 3(A). As shown in Figure 3(A), when the amino aromatic compound KDS12008 (Example 1) (10 μM) of the present invention was used, a statistically significant decrease in H2O2 was confirmed, and a tendency for H2O2 to decrease was observed compared to the high concentration of 10 mM sodium pyruvate.

[0140] Additionally, experiments were conducted using QuantiMax samples to examine cell viability. Cell viability was confirmed via QuantiMax luminescence, and the results are shown in Figure 3(B). Figure 3(B) shows that while sodium pyruvate reduces cell viability, the amino aromatic compound KDS12008 (Example 1) of the present invention had no effect on cell viability, even at a concentration of 100 μM, which is higher than the 10 μM concentration used to measure the H2O2 decomposition effect. This indicates that the compound exhibits significantly greater efficiency than existing known substances.

[0141] [Experimental Example 3] Passive avoidance test (PAT) I A passive avoidance experiment is an experiment to check an animal's memory, in which a weak electric stimulus is given to the animal in a dark room and whether the animal remembers the electric stimulus is evaluated.

[0142] Mice prefer dark rooms and, when placed in a bright room, will quickly move to the dark room. However, when a weak electrical stimulus is applied to a mouse in a dark room, it associates the dark room with the electrical stimulus and does not move from the light room to the dark room. The time it takes to move from the light room to the dark room (latency to dark room, seconds) can be measured to assess memory related to the association between electrical stimulus and the dark room. A passive avoidance experiment was conducted using APP / PS1 mice, which are used as an animal model of Alzheimer's disease (Figure 4). Wild-type (WT) mice served as a control group.

[0143] On the first day of the PAT, the acquisition session was conducted. Mice were kept in the bright room for a set time, after which the door to the dark room was opened and the time it took for the mice to enter the dark room was measured. When the mice entered the dark room, they received an electric shock (0.5 mA, 2 seconds) via a platform. On the second day, the retrieval session was conducted. The mice were placed in the bright room and the time it took to enter the dark room was measured. The door to the dark room was left open from the beginning. Mice with good memory would not enter the dark room due to their memory of the electrical stimulation, while mice with poor memory would enter the dark room again quickly. WT mice did not attempt to enter the dark room because they remembered the electrical stimulation they received the previous day (acquisition session). On the other hand, APP / PS1 dementia mice easily entered the dark room because they were unable to remember that they had received electrical stimulation in the dark room the previous day.

[0144] APP / PS1 dementia mice were intraperitoneally injected (IP) with an aminoaromatic compound of the present invention (KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21)) (KDS12008 (Example 1): 30 mg / kg / day (30 mpk); KDS12017 (Example 16): 30 mg / kg / day (30 mpk); KDS12025 (Example 21): 3 mg / kg / day (3 mpk)) for 16 days. A passive avoidance experiment was performed on the 26th day, confirming that the memory impairment in the APP / PS1 dementia mice was significantly improved (Figure 4).

[0145] That is, the Alzheimer's model APP / PS1 mice had poorer memory than wild-type mice, but APP / PS1 mice administered with the amino aromatic compounds of the present invention (KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21)) showed improved memory in passive avoidance and a significant increase in retention time. Therefore, it was found that the amino aromatic compounds of the present invention are effective against Alzheimer's.

[0146] [Experimental Example 4] Brain tissue staining method (immunohistochemistry, IHC) I In Experimental Example 3, the brains of the Alzheimer's animal model were fixed with formaldehyde and then thinly sliced. The sections were then imaged and measured using histological staining techniques to determine the amount of cells and specific proteins. In this experiment, an antibody that labels astrocytes was used to measure changes in astrocytes associated with dementia. The results are shown in Figure 5. In this experiment, the hippocampus of the brain was histologically stained to observe changes in astrocytes around the dementia substance amyloid beta. GFAP (Glial fibrillary acidic protein) stains astrocytes, and DAPI (4',6-diamidino-2-phenylindole) stains cell nuclei and amyloid beta substances.

[0147] Previous research has confirmed that amyloid beta accumulates in the hippocampus of Alzheimer's animal models, causing astrocytes to become reactive astrocytes in pathological conditions like Alzheimer's. At this time, these astrocytes produce the inhibitory neurotransmitters GABA and hydrogen peroxide, which inhibit nerves and induce the death of brain cells (neurons), worsening dementia. Meanwhile, previous research has also confirmed a tendency for astrocytes to decrease when anti-dementia drugs are used.

[0148] 5, it was confirmed that GFAP increased in the Alzheimer's animal model, indicating symptoms of astrocytes, whereas GFAP decreased in APP / PS1 mice treated with the amino aromatic compounds KDS12008 (Example 1), KDS12017 (Example 16), or KDS21025 (Example 21) of the present invention. This confirmed that astrocytes, which cause Alzheimer's, were effectively reduced, and that this effect was due to the removal of hydrogen peroxide.

[0149] [Experimental Example 5] Passive avoidance test (PAT) II APP / PS1 mice, used as an animal model of Alzheimer's disease, were intraperitoneally injected with the amino aromatic compound KDS12025 (Example 21) of the present invention at 3 mg / kg / day (3 mpk) and 10 mg / kg / day (10 mpk) for one 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.

[0150] Healthy normal mice (wild type, WT) remembered the electrical stimulation well during the retrieval process and spent a long time entering the black compartment where the stimulation had been administered, while the control group (WT+saline), which was an Alzheimer's disease animal model, forgot the electrical stimulation and immediately entered the black compartment where the stimulation had been administered.

[0151] Meanwhile, Alzheimer's model APP / PS1 mice treated with the amino aromatic compound KDS12025 (Example 21) of the present invention at 3 mg / kg / day (3 mpk) and 10 mg / kg / day (10 mpk) maintained memory at the same level as healthy normal mice, even though the drug administration was reduced from the conventional 16-day to one-week administration, showing a statistically significant difference from the Alzheimer's model APP / PS1 mice (Figure 6). Therefore, it was found that the amino aromatic compound of the present invention is effective against Alzheimer's disease.

[0152] [Experimental Example 6] Brain tissue staining method (immunohistochemistry, IHC) II Using the Alzheimer's animal model of Experimental Example 5, histological staining of brain tissue was performed in the same manner as in Experimental Example 4, and the results are shown in Figure 7. Figure 7 shows histological staining (IHC) of the hippocampal tissue of the brain of the animal model, where GFAP represents the staining result of astrocytes and Aβ represents the staining result of amyloid beta.

[0153] 7, it was confirmed that while astrocytes increased in the Alzheimer's disease animal model, astrocytes returned to a healthy normal level in APP / PS1 mice treated with the amino aromatic compound KDS21025 (Example 21) of the present invention at 3 mg / kg / day or 10 mg / kg / day. This result is consistent with the behavioral experiment results in Experimental Example 5, and indicates that treatment with the amino aromatic compound of the present invention returns overproduced H2O2 to a normal level.

[0154] [Experimental Example 7] Electrophysiology Experiment Using the Alzheimer's disease animal model of Experimental Example 5, the influence of astrocytes and the mechanism of inducing memory impairment due to dementia were confirmed by electrophysiology experiments.

[0155] Previous research has demonstrated that memory and cognitive impairment in Alzheimer's disease is induced through the sustained secretion of an inhibitory neurotransmitter called tonic GABA (also known as tonic current) by reactive astrocytes, and these changes can be confirmed by electrophysiology.

[0156] Therefore, in this experimental example, APP / PS1 mice, an Alzheimer's animal model, APP / PS1 mice treated with the amino aromatic compound KDS12025 (Example 21) of the present invention at 3 mg / kg / day or 10 mg / kg / day, and healthy normal mice (wild type, WT) were anesthetized, and brain tissue was obtained to measure electrical signals in living hippocampus cells. This measured the tonic gavage that inhibits neurotransmission in brain cells. The results are shown in Figure 8.

[0157] In an Alzheimer's animal model (APP / PS1, TG), tonic gaba increased compared to healthy normal mice (WT), whereas in an Alzheimer's animal model treated with the amino aromatic compound KDS12025 (Example 21) of the present invention, tonic gaba decreased. In this experimental example, changes in tonic gaba were confirmed electrophysiologically, thereby verifying the efficacy of the amino aromatic compounds of the present invention, i.e., their ability to inhibit tonic gaba, which inhibits neurotransmission. Therefore, it was found that the amino aromatic compounds of the present invention are effective against Alzheimer's.

[0158] [Experimental Example 8] Novel place recognition experiment and passive avoidance test (PAT) A novel place recognition experiment was used to evaluate hippocampus-related cognitive function and confirm cognitive impairment and recovery. Perfectly matched objects were placed in a controlled interaction for a set period of time, and then one object was moved after one hour. With normal cognitive function, past memories are maintained and interest in new objects increases, but with cognitive impairment, subjects are unable to distinguish new objects. The animal model used was the APP / PS1+GiD Alzheimer's model mouse, a mouse model developed to more closely resemble the phenomenon seen in Alzheimer's patients. The APP / PS1+GiD Alzheimer's model mouse was created with reference to Nature Neuroscience 23, 1555-1566 (2020).

[0159] In this experimental example, APP / PS1+GiD mice were produced by injecting the AAV-GFAP104-DTR-GFP virus into the hippocampus of APP / PS1 mice, and are hereinafter referred to as "APP+DTR." Furthermore, mice produced by injecting the AAV-GFAP104-GFP virus into the hippocampus of APP / PS1 mice were also referred to as "APP+GFP." Furthermore, mice produced by injecting the aminoaromatic compound KDS12025 (Example 21) of the present invention into the APP+DTR mice were also referred to as "APP+DTR+KDS12025." Furthermore, WT mice were APP / PS1 and littermate mice (one of the littermates). WT mice were produced by injecting the AAV-GFAP104-GFP virus into the hippocampus of WT mice, and were referred to as "WT+GFP." Furthermore, mice produced by injecting the AAV-GFAP104-DTR-GFP virus into the hippocampus of WT mice were also referred to as "WT+DTR."

[0160] Normal mice (WT+GFP, WT+DTR) had normal cognitive function. APP+GFP mice exhibited cognitive function at a level similar to that of normal mice, whereas APP+DTR mice exhibited cognitive impairment similar to that of Alzheimer's patients. When the aminoaromatic compound KDS12025 (Example 21) of the present invention (i.e., APP+DTR+KDS12025) was administered intraperitoneally (ip) at 3 mg / kg / day to APP / PS1+GiD Alzheimer's model mice exhibiting cognitive impairment, i.e., APP+DTR mice, cognitive function was confirmed to be restored (Figure 9).

[0161] Furthermore, in the PAT results, normal mice (WT+GFP) had a good memory for the dark room where they received electrical stimulation 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 memory problems. However, administration of the amino aromatic compound KDS12025 (Example 21) of the present invention, i.e., APP+DTR+KDS12025, demonstrated memory recovery (Figure 10).

[0162] That is, the hydrogen peroxide scavenging efficacy of the amino aromatic compounds of the present invention was confirmed in the APP / PS1+GiD Alzheimer's model mouse, which is a model mouse developed to more closely resemble the phenomenon seen in Alzheimer's dementia patients, and therefore, it was found to be effective against Alzheimer's.

[0163] [Experimental Example 9] Single toxicity evaluation (lethal dose 50, LD50) The aminoaromatic compounds KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21) of the present invention were administered intraperitoneally to approximately 8-week-old WT mice (C57BL / 6 mice) at doses of 100, 300, and 1000 mg / kg, respectively, and the mortality of the animals was evaluated. The results are shown in Figures 11 to 13. As a result, all three drugs exhibited toxicity at a concentration of 1000 mg / kg. Meanwhile, at 300 mg / kg, all three drugs exhibited toxicity, resulting in the death of approximately 50% of the animals, while at the lower concentration of 100 mg / kg, all three drugs did not exhibit lethal toxicity in the mice.

[0164] [Experimental Example 10] Analysis of blood-brain barrier (BBB) ​​permeability Based on the literature (J Med Chem. 2001 Mar 15;44(6):923-30), an artificial blood-brain barrier (BBB) ​​was constructed using a parallel artificial membrane permeability assay (PAMPA) and the drug permeability was evaluated.

[0165] As a result, in the case of the amino aromatic compound KDS12025 (Example 21) of the present invention, a high BBB permeability was observed at a concentration of 50 μM (KDS12025 (Example 21) 67.43 × 10 -6 On the other hand, AAD-2004, an existing drug that is expected to be able to remove reactive oxygen, had a BBB permeability of 3.56 × 10 cm / sec at the same concentration. -6 It was confirmed that the transmittance was quite low, at only cm / sec. Therefore, it was confirmed that the amino aromatic compound of the present invention has high transmittance.

[0166] The present invention has been described above using specific and limited examples and drawings, but these are provided to facilitate a more general understanding of the present invention. The present invention is not limited to the above examples, and various modifications and variations can be made from such descriptions by those having ordinary knowledge in the field to which the present invention pertains.

[0167] Therefore, the concept of the present invention should not be limited to the above-described embodiments, and it can be said that not only the scope of the claims described below, but also all modifications that are equivalent to or equivalent to the scope of the claims fall within the scope of the concept of the present invention.

Claims

1. An amino aromatic compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical formula 1] In the above Chemical 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 -C １０ Alkyl, haloC １ -C １０ may be further substituted with one or more selected from alkoxy and hydroxy; R １ and R ２ are each independently hydrogen or C １ -C １０ is alkyl, R ３ is a halogen, C １ -C １０ Alkoxy, HaloC １ -C １０ Alkyl or halo C １ -C １０ is an alkoxy, n is an integer of 1 or 2, However, R ３ When is halogen, n is an integer equal to 1.

2. The Ar is phenylene or biphenylene, and the Ar is C １ -C ７ Alkyl, C １ -C ７ 2. The amino aromatic compound of claim 1, or a pharmaceutically acceptable salt thereof, further substituted with one or more selected from alkoxy, amino, and hydroxy.

3. The amino aromatic compound according to claim 1 , wherein the amino aromatic compound is represented by the following formula 2: [Chemical formula 2] In the above Chemical Formula 2, R １ and R ２ are each independently hydrogen or C １ -C ７ is alkyl, Hal is a halogen; R' is C １ -C ７ Alkyl, C １ -C ７ alkoxy, amino or hydroxy; a is an integer of 0 to 4.

4. The amino aromatic compound according to claim 1 , wherein the amino aromatic compound is represented by the following formula 3, or a pharmaceutically acceptable salt thereof: [Chemical formula 3] In the above Chemical Formula 3, R １ and R ２ are each independently hydrogen or C １ -C ７ is alkyl, R ３ is C １ -C ７ Alkoxy or halo C １ -C ７ is 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.

5. The R １ and R ２ are each independently hydrogen or C １ -C ４ 4. The amino aromatic compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein Hal is alkyl, Hal is halogen, and a is an integer of 0.

6. The R １ and R ２ are each independently hydrogen or C １ -C ４ alkyl, and R ３ is C １ -C ４ Alkoxy or halo C １ -C ４ 5. The amino aromatic compound of claim 4, wherein n is alkyl, a is an integer of 0, and n is an integer of 1 or 2, or a pharmaceutically acceptable salt thereof.

7. The amino aromatic compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the amino aromatic compound is any one selected from the following compound group:

8. The amino aromatic compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein the amino aromatic compound is any one selected from the following compound group:

9. 2. The amino aromatic compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

10. A pharmaceutical composition for treating and preventing a neurodegenerative disease, comprising the amino aromatic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 as an active ingredient.

11. 11. The pharmaceutical composition of claim 10, further comprising an excipient and a carrier.

12. 11. The pharmaceutical composition of claim 10, wherein the neurodegenerative disease is 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.

13. A method for preventing or treating a neurodegenerative disease, comprising administering the amino aromatic compound or a pharmaceutically acceptable salt thereof according to claim 1, or the pharmaceutical composition according to claim 10, to an individual suffering from or at risk of developing a neurodegenerative disease.

14. A functional health food composition for preventing or ameliorating neurodegenerative diseases, comprising the amino aromatic compound or a nutrient-friendly salt thereof according to any one of claims 1 to 9 as an active ingredient.

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