Novel amino aromatic compounds or pharmaceutically acceptable salts thereof and pharmaceutical compositions for preventing or treating neurodegenerative diseases containing the same as an active ingredient

Abstract

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

Description

Technical Field

[0001] The present invention relates to a novel amino aromatic 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.

Background Art

[0002] Neurodegenerative diseases are diseases that cause abnormal motor regulation ability, cognitive function, perceptual function, sensory function, and autonomic nerve function due to the decrease or disappearance of nerve cell function. Typical examples include dementia, Alzheimer's disease (AD), Parkinson's disease (PD), and memory impairment.

[0003] One of the main causes of neurodegenerative diseases is oxidative stress of 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 caused by the accumulation of intracellular reactive oxygen species (ROS). Such oxidative stress causes lipid peroxidation, intracellular DNA damage, etc., leading to apoptosis and nerve cell death.

[0004] In particular, the brain has a high oxygen saturation, is rich in polyunsaturated fatty acids and metal ions that are direct targets of oxidative stress, and the neurotransmitters in the brain may undergo auto-oxidation. When subjected to oxidative stress by reactive oxygen species (ROS), instead of a decrease in the content of unsaturated fatty acids, the oxidative products that cause neurotoxicity increase, so it is a very fragile organ to oxidative stress, and its antioxidant and recovery ability against oxidative stress is limited.

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

[0006] Among reactive oxygen species (ROS), hydrogen peroxide (H2O2) is the most common product of various oxidation reactions (e.g., oxidase, dehydrogenase, and peroxidase) mainly generated from the mitochondria of living organisms. Hydrogen peroxide (H2O2) exceeding the by-product itself acts as a signaling molecule and is generated as a toxic molecule. During mitochondrial respiration, superoxide dismutase (SOD) catalyzes superoxide anion radical (·O2-) into hydrogen peroxide (H2O2) and oxygen (O2).

[0007] Another source of hydrogen peroxide (H2O2) is NADPH oxidase, which catalyzes oxygen (O2) with superoxide anion radical (·O2-) to consequently produce hydrogen peroxide (H2O2). In addition, xanthine oxidase is responsible for the production of hydrogen peroxide (H2O2) during the hypoxanthine oxidization process, 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 produce hydrogen peroxide (H2O2).

[0008] An appropriate amount of hydrogen peroxide (H2O2) can regulate cell functions such as cell growth, death, and immunity by low concentrations of reactive oxygen species that are temporarily generated at specific sites by external signals, and is very important in living organisms. However, a large amount of hydrogen peroxide (H2O2) that cannot be regulated by cells can act as a toxic substance within cells. That is, hydrogen peroxide (H2O2) is not only beneficial to health but also harmful.

[0009] At an appropriate level of hydrogen peroxide (H2O2), it acts as a cell signaling molecule (CSM) including transcription factors, protein kinases, and growth factors. However, at an intermediate level of hydrogen peroxide (H2O2), it causes damage to DNA, lipids, and proteins. DNA modifications including base decomposition, single-stranded or double-stranded DNA breaks, cross-linking with proteins, and purine or pyrimidine deformations are due to damage by hydrogen peroxide (H2O2). Hydrogen peroxide (H2O2) destroys the membrane lipid bilayer, in turn affecting tissue stability by lipid peroxidation, and fragmented proteins, protein cross-linking, and amino acid oxidation are also generated by hydrogen peroxide (H2O2).

[0010] To control the changing hydrogen peroxide (H2O2) levels, various antioxidant systems have been established. Catalase (CAT), glutathione peroxidase (GPx), and horseradish peroxidase (HRP) are known hydrogen peroxide (H2O2)-degrading enzymes. CAT contains a heme cofactor and is one of the strong antioxidant enzymes that decomposes hydrogen peroxide (H2O2) into water and oxygen without causing damage. GPx is a selenium cofactor enzyme, and the decomposition of hydrogen peroxide (H2O2) involves glutathione (GSH) oxidation. Also, HRP contains heme as a cofactor and exhibits catalase-like activity that reduces hydrogen peroxide (H2O2) to water and oxygen. All such antioxidant systems maintain the equivalence of hydrogen peroxide (H2O2) levels under physiological conditions.

[0011] However, the balance of hydrogen peroxide (H2O2) levels sometimes collapses under pathological conditions, which is closely related to pathology. Generally, the balance of hydrogen peroxide (H2O2) collapses 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 oxidative stress caused by hydrogen peroxide (H2O2) have emerged as therapeutic targets. However, effective drug targets for preventing damage caused by hydrogen peroxide (H2O2) have not yet been determined.

Summary of the Invention

Problems to be Solved by the Invention

[0013] Accordingly, the inventors of the present invention have conducted intensive research to find a novel compound having a preventive or therapeutic effect against neurodegenerative diseases. As a result, they focused on the fact that the level of hydrogen peroxide, which is one of the reactive oxygen species, is considerably higher in pathological conditions such as neurodegenerative diseases, particularly Alzheimer's disease, compared to the case where it is by-produced by endogenous oxidation reactions such as mitochondrial respiration, and attempted to develop a novel compound that scavenges hydrogen peroxide, which is one of the various reactive oxygen species. As a result, they found that an aminoaromatic compound having a specific structure removes 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 that is useful as a blood hydrogen peroxide scavenger.

[0015] The present invention also 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.

[0016] The present invention also provides a health functional food composition for preventing or improving neurodegenerative diseases, comprising the novel aminoaromatic compound of the present invention or a food-acceptable salt thereof as an active ingredient.

Means for Solving the Problems

[0017] To achieve the above object, One aspect of the present invention provides an aminoaromatic compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof. [Chemical Formula 1] TIFF0007717160000001.tif3641In the above Chemical Formula 1, Ar is C6-C 20 arylene, and the arylene of the Ar is C1-C 10 alkyl, C1-C 10 alkoxy, amino, mono- or di-C1-C 10 alkylamino, halo C1-C 10 alkyl, halo C1-C 10One or more selected from alkoxy and hydroxy may be further substituted, R 1 and R 2 are each independently hydrogen or C1-C 10 alkyl, R 3 is halogen, C1-C 10 alkoxy, halo C1-C 10 alkyl or halo C1-C 10 alkoxy, n is an integer of 1 or 2, provided that when R 3 is halogen, n is an integer of 1.

[0018] In addition, another aspect of the present invention provides a pharmaceutical composition for preventing or treating neurodegenerative diseases containing the amino aromatic compound represented by the chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0019] In addition, another aspect of the present invention provides a health functional food composition for preventing or improving neurodegenerative diseases containing the amino aromatic compound represented by the 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, which is a kind of reactive oxygen species.

[0021] The amino aromatic compound according to the present invention suppresses cell death caused by oxidative stress caused by H2O2 by eliminating hydrogen peroxide, which is an intracellular reactive oxygen species (ROS).

[0022] That is, the amino aromatic compound according to the present invention acts together with an enzyme having heme and lowers the H2O2 concentration. Therefore, it does not excessively lower the H2O2 concentration, but removes the overproduced hydrogen peroxide so as to reach an appropriate concentration at the necessary level in the living body.

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

[0024] The amino aromatic compound according to the present invention exhibits hydrogen peroxide scavenging activity and antioxidant properties that can improve cognitive and memory impairments by improving hydrogen peroxide-induced cell death.

[0025] The amino aromatic compound according to the present invention decomposes hydrogen peroxide in the presence of heme-containing peroxidase and hemoglobin (Hb) present in the body, reduces the blood hydrogen peroxide level, and as a result, can suppress or treat the onset of neurodegenerative diseases.

[0026] Therefore, the amino aromatic compound of the present invention can be used as an active ingredient in a pharmaceutical composition for preventing or treating neurodegenerative diseases and a health functional food composition for preventing or improving neurodegenerative diseases by suppressing damage caused by harmful hydrogen peroxide. BRIEF DESCRIPTION OF THE DRAWINGS

[0027]

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Figure 13

Mode for Carrying Out the Invention

[0028] Hereinafter, the novel amino aromatic compound of the present invention or a pharmaceutically acceptable salt thereof will be described in detail. At this time, in the technical terms and scientific terms used, unless otherwise defined, they have the meanings commonly understood by those having ordinary knowledge in the technical field to which the present invention belongs, and descriptions of known functions and configurations that may obscure the gist of the present invention in the following description are omitted.

[0029] The following terms used in this specification are defined as follows, but this is merely exemplary and does not limit the present invention, application, or use.

[0030] As used herein, the terms "substituent", "radical", "group", "moiety", and "fragment" can be used interchangeably with one another.

[0031] As used herein, the term "C A -C B " means having from A to B carbon atoms.

[0032] As used herein, the term "alkyl" means a monovalent straight-chain or branched-chain saturated hydrocarbon radical consisting of only 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" means a straight-chain or branched alkyl having 1 to 4 carbon atoms. By way of example, the 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" is an aromatic ring divalent organic radical derived from an aromatic hydrocarbon by removal of two hydrogen atoms, and includes a monocyclic or fused ring system appropriately containing 4 to 7, preferably 5 or 6 ring atoms in each ring, and includes forms in which a number of aryls are linked by single bonds. Specific examples include, but are not limited to, phenylene, naphthylene, biphenylene, anthrylene, and the like.

[0034] As used herein, the term "alkoxy" is 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 a halogen group element and includes, for example, fluoro, chloro, bromo, and iodo.

[0036] As used herein, the terms "haloalkyl" or "haloalkoxy" each mean an alkyl or alkoxy group in which one or more hydrogen atoms are replaced by 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 -NH2, and "hydroxy" means -OH.

[0038] As used herein, the term "alkylamino" means an amino radical substituted with one or two alkyls, and specific examples include, but are not limited to, methylamino (-NHMe), dimethylamino (-NMe2), ethylamino (-NHEt), diethylamino (-NEt2), etc.

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

[0040] As used herein, the term "pharmaceutically acceptable salt" means any and all organic or inorganic addition salts of the compounds of the present invention that are relatively non-toxic and harmless to patients and for which the side effects resulting from this salt at a concentration having a beneficial effect do not reduce the good efficacy of the compounds of the present invention itself.

[0041] As used herein, the terms "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" mean substances that aid in the administration and absorption of the active agent by the subject.

[0042] As used herein, the term "oxidative stress" is used in its ordinary meaning and means an abnormal level of reactive oxygen species.

[0043] As used herein, the term "prevention" means all acts that suppress or delay the occurrence, spread, and recurrence of neurodegenerative diseases.

[0044] As used herein, the term "amelioration" means all acts that at least reduce a parameter related to the condition being treated, such as the degree of symptoms.

[0045] As used herein, the term "treatment" means all acts by which the symptoms of a neurodegenerative disease improve or change favorably.

[0046] As used herein, the term "individual" means all animals, including humans, in whom a neurodegenerative disease has developed or may develop. The animals can be, but are not limited to, mammals such as cows, horses, sheep, pigs, goats, camels, llamas, dogs, and cats that require treatment for similar symptoms as humans.

[0047] As used herein, the term "administration" means introducing the pharmaceutical composition of the present invention into an individual by a suitable method, and the administration route of the composition of the present invention can be administered via various oral or parenteral 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 medical treatment and that does not cause side effects. The level of effective volume can be easily determined by those skilled in the art according to factors including the patient's gender, age, weight, health status, type of disease, severity, activity of the drug, sensitivity to the drug, method of administration, administration time, administration route, and rate of excretion, treatment period, ingredients including drugs used in combination or simultaneously, and other factors well known in the medical field.

[0049] As used herein, the term "food" includes meat, sausage, bread, chocolate, candies, snacks, confectioneries, pizza, ramen, other noodles, gums, dairy products including ice creams, various soups, beverages, tea, drink agents, alcoholic beverages, vitamin complexes, health functional foods, and health foods, and includes any food in its ordinary meaning.

[0050] As used herein, the term "health functional food" means a food manufactured and processed using raw materials and ingredients having functional properties useful to the human body according to Law No. 6727 regarding health functional foods. "Functionality" means to regulate nutrients with respect to the structure and function of the human body or to be ingested for the purpose of obtaining useful effects such as physiological effects for health care uses.

[0051] As used herein, the term "food pharmaceutically acceptable salt" means a dosage form of a compound that does not cause serious irritation to the organism to which the compound is administered and does not damage 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] TIFF0007717160000002.tif3641 In the above Chemical Formula 1, Ar is C6-C 20 arylene, and the arylene of the said Ar is C1-C10 alkyl, C1-C 10 alkoxy, amino, mono- or di-C1-C 10 alkylamino, halo C1-C 10 alkyl, halo C1-C 10 optionally further substituted with one or more selected from alkoxy and hydroxy, R 1 and R 2 are each independently hydrogen or C1-C 10 alkyl, R 3 is halogen, C1-C 10 alkoxy, halo C1-C 10 alkyl or halo C1-C 10 alkoxy, n is an integer of 1 or 2, provided that when R 3 is halogen, n is an integer of 1.

[0054] The amino aromatic compound according to the present invention has low cytotoxicity, is a small molecule compound, and can act as a scavenger for removing hydrogen peroxide, which is a kind of reactive oxygen species.

[0055] The amino aromatic compound according to the present invention does not remove hydroxyl radicals and is not an MAO-B inhibitor. The amino aromatic compound according to the present invention was confirmed to play a role as a catalyst for the reaction of decomposing hydrogen peroxide into water in the presence of ROS-GLO analysis results, endogenous peroxidase, particularly heme-containing peroxidase and hemoglobin (Hb).

[0056] That is, the amino aromatic compound according to the present invention acts together with heme-containing peroxidase and hemoglobin (Hb) present in the body to remove the over-produced hydrogen peroxide to an appropriate concentration level. Therefore, the amino aromatic compound of the present invention can be usefully used to suppress the death of nerve cells caused by harmful hydrogen peroxide and to prevent, improve or treat neurodegenerative diseases. In addition, since the amino aromatic compound according to the present invention has a function of permeating the blood-brain barrier (BBB) with excellent efficiency, a low content can be administered to obtain a rapid, quick and more efficient therapeutic effect.

[0057] In one embodiment of the present invention, the Ar is C6-C 12 arylene, preferably phenylene or biphenylene, and the Ar can 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, the Ar is phenylene, and nitrogen atoms are preferably introduced at the 1st and 4th positions of the phenylene.

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

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

[0061] [Chemical Formula 2] TIFF0007717160000003.tif4250

[0062] [Chemical Formula 3] TIFF0007717160000004.tif4250

[0063] In Chemical Formulas 2 and 3, R 1 and R 2is, independently of each other, hydrogen or C1-C7 alkyl, Hal is halogen, R 3 is C1-C7 alkoxy or halo C1-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 Chemical Formulas 2 and 3 according to an embodiment of the present invention, the R 1 and R 2 are, independently of each other, hydrogen or C1-C4 alkyl, Hal is halogen, R 3 is C1-C4 alkoxy or halo C1-C4 alkyl, a is an integer of 0, and n can be an integer of 1 or 2.

[0065] Chemical Formula 2 according to an embodiment can be represented by the following Chemical Formula 4.

[0066] [Chemical Formula 4] TIFF0007717160000005.tif4242

[0067] In Chemical Formula 4, R 1 and R 2 are, independently of each other, hydrogen or C1-C4 alkyl, Hal is halogen.

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

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

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

[0071] The chemical formula 3 according to one embodiment can be represented by the following chemical formula 5.

[0072] [Chemical formula 5] TIFF0007717160000006.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 halo C1-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, R 3 is C1-C4 alkoxy or halo C1-C4 alkyl, and n is an integer of 1 or 2.

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

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

[0078] The amino aromatic compound according to one embodiment can be any one selected from the following group of compounds, but is not limited thereto.

[0079] TIFF0007717160000007.tif80167TIFF0007717160000008.tif73167TIFF0007717160000009.tif80167

[0080] It is obvious to those skilled in the art that the method for producing the amino aromatic compound according to one embodiment of the present invention can be carried out using a method known in the art or appropriately modified. Also, the reaction time in the production method of Chemical Formula 1 according to one embodiment of the present invention can vary depending on the reactants, the type of solvent, and the amount of the solvent. As an example, after confirming that the starting material is completely consumed through TLC or the like, the reaction is completed. When the reaction is completed, the solvent is distilled under reduced pressure, and then the target product can be separated and purified by a conventional method such as column chromatography. As an example, it can be produced by reacting an arylenediamine compound with a phenylalkyl bromide compound, and more detailed content will be described in the following examples.

[0081] [Reaction Formula 1] TIFF0007717160000010.tif42125

[0082] (In the above Reaction Formula 1, Ar, R 1 , R 2 , R 3 and n are the same as those in Chemical Formula 1 above.)

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

[0084] That is, the amino aromatic compound of the present invention can be used in the form of a prodrug, hydrate, solvate, and pharmaceutically acceptable salt in order to enhance in vivo absorption or increase solubility. The above-mentioned prodrug, hydrate, solvate, and pharmaceutically acceptable salt also belong to the scope of the present invention.

[0085] The amino aromatic compound of the present invention can be used in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is a salt produced by a conventional method in the art, and the production method is known to those skilled in the art. Specifically, the pharmaceutically acceptable salt includes, but is not limited to, salts derived from the following free acids and bases that are pharmacologically or physiologically acceptable.

[0086] Acid addition salts formed by pharmaceutically acceptable free acids are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, 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, hydroiodic acid. Such 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, suberate, sebacate, fumarate, maleate, butane-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, etc.

[0087] The acid addition salts can be produced by ordinary 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., an organic acid or an inorganic acid is added, and the resulting precipitate is filtered and dried, or after distilling the solvent and the excess acid under reduced pressure, it is dried and crystallized under an organic solvent to produce it.

[0088] Also, using a base, pharmaceutically acceptable metal salts can be produced. 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 of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble amino aromatic compound salt, and then evaporating and drying the filtrate. Here, as the metal salts, it is pharmaceutically suitable to produce sodium, potassium, or calcium salts, but it is not limited thereto. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

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

[0090] That is, the amino aromatic compound according to an embodiment of the present invention can be a compound in the hydrochloride form selected from the following structures.

[0091] TIFF0007717160000011.tif80167TIFF0007717160000012.tif72167TIFF0007717160000013.tif80167

[0092] The hydrate of the amino aromatic compound of the present invention means the amino aromatic compound of the present invention or its pharmaceutically acceptable salt containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0093] The solvate of the amino aromatic compound of the present invention means the amino aromatic compound of the present invention or a pharmaceutically acceptable salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Solvents that can be used include volatile and non-toxic solvents.

[0094] The amino aromatic compound of the present invention can be decomposed in the body of a human or animal and administered in the form of a prodrug that provides the compound of the present invention as an active ingredient. Prodrugs can be used to modify and / or improve the physical and / or pharmacokinetic profile of the parent compound and can be formed when suitable groups or substituents are included that can be induced to cause the parent compound to form the prodrug.

[0095] For example, when a certain compound (prodrug) is separated in the body to produce the amino aromatic compound of the present invention or a salt thereof, such a compound is also included in the scope of the present invention. As used herein and unless otherwise indicated, the term "prodrug" means an active compound, particularly a compound of the present invention that is hydrolyzed, oxidized, and capable of other reactions under biological conditions (in vitro or in vivo) to supply the compound of the present invention. Examples of prodrugs include compounds that are biohydrolyzed to produce the compounds of the present invention, including biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs, but are not limited to such specific embodiments. Preferably, the prodrug of a compound having a carboxy group functional group is a lower alkyl ester of a carboxylic acid. A carboxylic ester is usually formed by esterifying a part of the carboxylic acid present in the molecule. Prodrugs can be easily manufactured using well-known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abrahamed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

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

[0098] The neurodegenerative disease refers to a disease or pathological condition that means abnormal motor regulation ability, cognitive function, perceptual function, sensory function, and autonomic nervous function in which the nervous system function of a subject is damaged, and has the same meaning as "degenerative brain disease". Specifically, it can be exemplified by 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 disease, and amyotrophic lateral sclerosis, etc.

[0099] The amino aromatic compound according to the present invention can decompose hydrogen peroxide over-produced in the presence of heme-containing peroxidase present in the body and hemoglobin (Hb) in the blood, lower the blood hydrogen peroxide level to an appropriate level, and as a result, suppress or treat 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, has very high blood-brain barrier (BBB) permeability, acts directly on the brain, and can show excellent effects in the treatment of brain diseases. Therefore, the amino aromatic compound of the present invention can be effectively used for the prevention or treatment of neurodegenerative diseases.

[0101] The pharmaceutical composition according to one embodiment further includes a normal non-toxic pharmaceutically acceptable carrier and / or excipient in addition to the active ingredient, and can be formulated into a normal preparation in the pharmaceutical field, that is, an oral administration preparation or a parenteral administration preparation. Further, diluents such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants can be further included.

[0102] Examples of the pharmaceutically acceptable carrier, excipient or diluent include, but are 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] Depending on the intended use, the pharmaceutical composition of the present invention can be formulated into various forms, such as oral dosage forms including powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., and injection solutions such as sterile injection solutions, by conventional methods, and can be used orally or administered via various routes including intravenous, intraperitoneal, subcutaneous, rectal, topical administration, etc.

[0104] In addition, the pharmaceutical composition of the present invention can further contain a filler, an anticoagulant, a lubricant, a wetting agent, a flavor, an emulsifier, a preservative, etc.

[0105] Examples of oral dosage forms include tablets, pills, hard / soft capsule formulations, solutions, suspensions, emulsions, syrups, granules, elixirs, etc. These dosage forms can use one or more diluents or excipients such as fillers, extenders, wetting agents, disintegrants, lubricants, binders, surfactants, etc. that are commonly used in addition to the active ingredient. As disintegrants, agar, starch, alginic acid or its sodium salt, calcium hydrogen phosphate anhydrous salt, etc. can be used. As lubricants, silica, talc, stearic acid or its magnesium or calcium salt, polyethylene glycol, etc. can be used. As binders, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low-substituted hydroxypropylcellulose, etc. can be used. In addition, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc. can be used as diluents, and in some cases, commonly known effervescent mixtures, absorbents, colorants, flavoring agents, sweetening agents, etc. can be used together.

[0106] Examples of formulations for parenteral administration can include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, suppositories, etc. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc. can be used. As suppository bases, witepsol, macrogol, Tween 61, cocoa butter, laurin fat, glycerol, gelatin, etc. can be used. On the other hand, injections can contain conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, preservatives, etc. To formulate into an injection, the amino aromatic compound of the present invention or its pharmaceutically acceptable salt is mixed with water together with a stabilizer or buffer to produce a solution or suspension, and this can be produced into a unit dosage form of an ampoule or vial.

[0107] The pharmaceutical composition of the present invention can be sterilized or can further contain adjuvants such as preservatives, stabilizers, thickeners, hydrating agents or emulsification promoters, salts for osmotic pressure adjustment and / or buffers, and can further contain other therapeutically useful substances, and can be formulated by ordinary methods such as dissolution, dispersion, mixing, granulation, gelation or coating.

[0108] The pharmaceutically effective amount of the amino aromatic compound of the present invention can be determined by the patient's health condition, disease type, severity, drug activity, sensitivity to the drug, administration method, administration time, administration route and excretion rate, treatment period, ingredients including drugs formulated or used concomitantly, and other elements well-known in the medical field. Specifically, the effective amount of the compound in the pharmaceutical composition of the present invention can vary according to the patient's age, gender, and weight, and generally 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 divided into one to several times a day. However, it can be increased or decreased according to the administration route, disease severity, gender, 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, and parenteral administration such as subcutaneous injection, intravenous injection, intramuscular injection or intraperitoneal injection is preferred.

[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 in sequence or simultaneously with conventional therapeutic agents, and can be administered singly or multiply. Considering all the above elements, it is important to administer an amount that can obtain the maximum effect with the minimum amount without side effects, and this can be easily determined by those skilled in the art. [[ID=]14]

[0111] Furthermore, the present invention provides a method for preventing or treating a neurodegenerative disease, which includes administering the amino aromatic compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to an individual with an existing or potential neurodegenerative disease.

[0112] Furthermore, the present invention provides a method for preventing or treating a neurodegenerative disease, which includes administering the amino aromatic compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition to an individual with an existing or potential neurodegenerative disease.

[0113] In addition, the present invention provides a health functional food composition for preventing or improving a neurodegenerative disease, which contains the amino aromatic compound or a food-acceptable salt thereof as an active ingredient.

[0114] The food-acceptable salt can be obtained by reacting the amino aromatic compound 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, isobutyric acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, and salicylic acid. Also, the salt can be obtained by reacting the compound 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 amino acid salts such as arginine and lysine, without being limited thereto.

[0115] The health functional food composition can be provided in the form of powder, granule, tablet, capsule, syrup or beverage, and the health functional food can be used together with other foods or food additives in addition to the amino aromatic compound which is the active ingredient, and can be appropriately used according to the normal method. The mixing amount of the active ingredient can be preferably determined according to its purpose of use, for example, prevention, health or therapeutic treatment.

[0116] The health functional food composition can contain various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and fillers (such as cheese and chocolate), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, it can contain natural fruit juices and fruit juice beverages and the pulp for the production of vegetable beverages. Such components can be used independently or in combination.

[0117] Also, the health functional food can further contain food additives, and the conformity as a "food additive" is determined according to the standards and criteria regarding the item by the general rules and general test methods of the Food Additive Codex approved by the Food and Drug Safety Office, unless there are other regulations.

[0118] Examples of the items listed in the "Food Additive Codex" include chemically synthesized products such as ketones, glycine, potassium citrate, nicotinic acid, cinnamic acid, natural additives such as kaki pigment, licorice extract, crystalline cellulose, guar gum, and mixed preparations such as sodium L-glutamate preparations, alkaline agents for noodles, preservative preparations, and tar pigment preparations.

[0119] The amino aromatic compound contained in the health functional food composition can be used according to the effective volume of the pharmaceutical composition. However, in the case of long-term intake for health and hygiene purposes or for health regulation purposes, it can be below the above range. Needless to say, since the active ingredient has no problem in terms of safety, it can also be used in an amount above the above range.

[0120] The health functional food composition can be formulated into various dosage forms including meats, sausages, breads, chocolates, candies, snacks, confectioneries, pizzas, ramen, other noodles, gums, dairy products including ice creams, various soups, beverages, teas, drink agents, alcoholic beverages, vitamin complexes, and the like.

[0121] Hereinafter, the present invention will be described in more detail with reference to preferred examples. However, this is presented as an exemplification of the present invention and in no way limits the scope of the present invention. The scope of the present invention is only defined by the scope of claims described later.

[0122] [Production Example 1] Production of tert-butyl(4-aminophenyl)(methyl)carbamate TIFF0007717160000014.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. Next, it was cooled to room temperature and the solvent was removed under reduced pressure. The residue was separated into an organic layer through ethyl acetate and brine and washed. 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.

[0124] 400 MHz 11H 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] Production of tert-butylmethyl(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 the solution was refluxed for 12 h. Next, it was cooled to room temperature and the solvent was removed under reduced pressure. The residue was separated into organic layers through ethyl acetate and brine and washed. The separated organic layer was dried over sodium sulfate and then ethyl acetate was removed under reduced pressure to obtain 1.29 g (97.3%) of the title compound as a yellow oil.

[0126] 400 MHz 1 1H 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] Production of tert-butyl(4-aminophenyl)(methyl)carbamate tert-Butyl methyl (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). Then, iron powder (1.36 g, 26.1 mmol) and ammonium chloride (2.80 g, 52.4 mmol) were added and the mixture was stirred at 50 °C for 3 h. Next, it was cooled to room temperature and filtered through celite. After filtration, the solvent was removed under reduced pressure. The residue was separated into organic layers through ethyl acetate and brine and washed. The separated organic layer was dried over sodium sulfate and then ethyl acetate was removed under reduced pressure to obtain 890 mg (78.1%) of the title compound as a yellow solid.

[0128] 400 MHz 1 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)

[0129] Example I: Production of Amino Aromatic Compounds TIFF0007717160000015.tif44150

[0130] A solution of potassium carbonate (3.0 eq), potassium iodide (0.1 eq), and phenylalkyl bromide compound (b, 1.0 eq) was added to an acetonitrile solution in which p-phenylenediamine compound (a, 1.2 eq) was dissolved. Then, the mixture was stirred at 110 °C for 36 hours. Next, it was cooled to room temperature and diluted via ethyl acetate and washed with brine. The remaining organic layer was dried over Na2SO4 and then the solvent was removed under reduced pressure. The residue was purified via column to obtain compound P1. After dissolving the purified compound P1 in dichloromethane (DCM), a 4.0 M hydrogen chloride solution was added. Next, it was 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 in Table 1 below were produced.

[0132]

Table 1

[0133] [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. The 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. The cultures were maintained at 37 °C in a humidified 5% CO2 incubator. On the third day of culture, the 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 the ability to eliminate hydrogen peroxide by enzymes present in vivo In order to investigate the ability to eliminate hydrogen peroxide by the presented enzyme and the amino aromatic compound of the present invention, the following experiments were conducted.

[0135] Amplex Red can be used to measure the change in H2O2 because when both HRP (horse radish peroxidase) and H2O2 are present, it changes into a fluorescent substance called resorufin, that is, it can be used to perform an H2O2 assay. However, since HRP is an enzyme that does not exist in the body, experiments were conducted based on the idea that hemoglobin, as a group having a heme like HRP, can act with the amino aromatic compound of the present invention. In the H2O2 assay using Amplex Red, hemoglobin was used instead of HRP [Figure 1]. The final concentration of each substance was 10 μM of H2O2, 80 μg / ml of hemoglobin, and the amino aromatic compound of the present invention was treated at different concentrations. After reacting at about 37 °C for about 30 minutes in this way, fluorescence (excitation; 540 nm, emission; 580 nm) was measured using a microplate reader. Here, it can be said that the fluorescence is proportional to the amount of H2O2. After normalizing each concentration based on the fluorescence value without the drug, the value at which this fluorescence value becomes 50%, that is, the EC 50 (half maximal effective concentration) was obtained by a program. The results are shown in Table 2 below, and AAD-2004 was used as a control group.

[0136]

Table 2

[0137] As shown in Table 2 above, it can be seen that the amino aromatic compound according to the present invention effectively reacts with hemoglobin (Hb) to reduce hydrogen peroxide. Therefore, it can be seen that the amino aromatic compound according to the present invention is useful as a hydrogen peroxide scavenger that acts together with hemoglobin present in the body to reduce over-produced hydrogen peroxide to an appropriate level.

[0138] [Experimental Example 2] Evaluation of H2O2 decomposition experiment I and cell viability in vitro To verify whether there is an H2O2 elimination effect in cell-level experiments, the amount of intracellular H2O2 was measured by fluorescence using the hydrogen peroxide probe H2DCFDA-AM (The cell-permeant 2',7'-dichlorodihydrofluorescein diacetate) drug in astrocytes [Figure 2 (A, B)]. The amino aromatic compound KDS12008 (Example 1) of the present invention was used as the test substance, and sodium pyruvate, which is known to be able to remove H2O2, was used as the control substance. When the astrocytes were treated with the amino aromatic compound KDS12008 (Example 1) of the present invention at various concentrations, it was confirmed that H2O2 decreased according to the concentration [Figure 2 (C)].

[0139] Figure 2(A) illustrates the experimental timeline for examining the H2O2 decomposition effect of the amino aromatic compound KDS12008 (Example 1) (10 μM) and sodium pyruvate (10 mM) of the present invention against endogenously generated H2O2 in cultured astrocytes. The cultured astrocytes were allowed to stand for 3 days to achieve stability, and then treated with the amino aromatic compound KDS12008 (Example 1) and sodium pyruvate of the present invention. After two days, a cell-permeable H2O2 dye (H2DCFDA-AM) was used as a method for measuring intracellular H2O2. H2DCFDA-AM was used at 10 μM as a sample that reacts with H2O2 to generate green fluorescence for measurement. The results are shown in Figure 3(A). From 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 shown compared to a high concentration of 10 mM sodium pyruvate.

[0140] In addition, to examine cell viability, experiments were conducted using QuantiMax samples. Cell viability was confirmed through the degree of luminescence of QuantiMax, and the results are shown in Figure 3(B). From Figure 3(B), sodium pyruvate decreased cell viability, whereas the amino aromatic compound KDS12008 (Example 1) of the present invention had no effect on cell viability despite having a concentration of 100 μM, which is higher than the concentration of 10 μM used during the measurement of the H2O2 decomposition effect. That is, it can be seen that the present invention exhibits considerably superior efficiency compared to existing known substances.

[0141] [Experimental Example 3] Passive Avoidance Test (PAT) I The passive avoidance test is an experiment for confirming the memory of animals. At this time, a weak electric shock is given in a dark room to evaluate whether the animals remember the electric shock.

[0142] Since mice prefer dark rooms, they have the property of quickly moving to a dark room when in a bright room. However, if a weak electric shock is applied to a mouse in a dark room, it will not move from the bright room to the dark room because it associates the dark room with the electric shock and remembers it. By measuring the time it takes for the mouse to move from the bright room to the dark room (latency to dark room, sec), the memory ability of the association between the electric shock and the dark room can be measured. A passive avoidance experiment was conducted using APP / PS1 mice, which are used as an Alzheimer's disease animal model [Figure 4]. Wild type (WT) mice were used as the control group.

[0143] On the first day of PAT, as an Acquisition session, the mouse is left in the bright room for a predetermined time, and after the predetermined time, the time it takes for the door of the dark room to open and the mouse to enter the dark room is measured. When the mouse enters the dark room, an electric shock (0.5 mA, 2 sec) is applied via a footbridge. On the second day, as a Retrieval session, the mouse is placed in the bright room and the time it takes for it to enter the dark room is measured. At this time, the door of the dark room is open from the beginning. If the memory ability is good, due to the memory of the electric shock, it will not enter the dark room, and if the memory ability is poor, it will quickly enter the dark room again. Since WT mice have the memory of receiving an electric shock the previous day (acquisition session), they do not try to enter the dark room. On the other hand, APP / PS1 dementia mice cannot remember the fact of receiving an electric shock in the dark room the previous day, so they easily enter the dark room.

[0144] APP / PS1 transgenic mice were intraperitoneally injected (IP) with the aminoaromatic compounds of the present invention (KDS12008 (Example 1), KDS12017 (Example 16) or KDS12025 (Example 21)) at a dose of 30 mg / kg / day (30 mpk) for KDS12008 (Example 1), 30 mg / kg / day (30 mpk) for KDS12017 (Example 16), and 3 mg / kg / day (3 mpk) for KDS12025 (Example 21) for 16 days. When the passive avoidance test was performed on the 26th day, it was confirmed that the memory impairment in APP / PS1 transgenic mice was significantly recovered [Figure 4].

[0145] That is, the memory of Alzheimer's model APP / PS1 mice was not as good as that of wild type mice. However, it was confirmed that the APP / PS1 mice administered with the aminoaromatic compounds of the present invention (KDS12008 (Example 1), KDS12017 (Example 16) or KDS12025 (Example 21)) had improved memory for passive avoidance and showed a significant increasing trend in residence time. Therefore, it was found that the aminoaromatic compounds of the present invention are effective against Alzheimer's disease.

[0146] [Experimental Example 4] Histological Staining Method of Brain Tissue (Immunohistochemistry, IHC) I After fixing the brains of the Alzheimer's animal models in Experimental Example 3 with formaldehyde, they were cut into thin sections. The amount of cells and specific proteins in the cut brains was measured by image through histological staining techniques. In this experimental example, an antibody that labels astrocytes was used to measure the changes in astrocytes related to dementia. The results are shown in Figure 5. That is, in this experimental example, the hippocampus of the brain was histologically stained to observe the changes in astrocytes around the amyloid beta, a dementia substance. GFAP (Glial fibrillary acidic protein) means staining of astrocytes, and DAPI (4',6-diamidino-2-phenylindole) indicates the cell nucleus and amyloid beta substances.

[0147] Through existing research, amyloid-beta has been found to accumulate in the hippocampus of Alzheimer's animal models, and astrocytes become reactive astrocytes in pathological conditions such as Alzheimer's. At this time, the above astrocytes produce the inhibitory neurotransmitter GABA and hydrogen peroxide, which also inhibit nerves and induce the 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 by existing research.

[0148] From Figure 5, it can be seen that GFAP increases in the Alzheimer's animal model, indicating symptoms of astrocytes. In contrast, in the case of APP / PS1 mice treated with the amino aromatic compounds KDS12008 (Example 1), KDS12017 (Example 16), or KDS21025 (Example 21) of the present invention, it was confirmed that GFAP decreased. Thus, it was confirmed that astrocytes, which are the cause of Alzheimer's, effectively decreased, and this was confirmed to be the effect expressed by the removal of hydrogen peroxide.

[0149] [Experimental Example 5] Passive Avoidance Test (PAT) II The amino aromatic compound KDS12025 (Example 21) of the present invention was intraperitoneally injected into APP / PS1 mice used as Alzheimer's animal models at 3 mg / kg / day (3mpk) and 10 mg / kg / day (10mpk) for one week, and the 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) remember the electric shock well during the retrieval process and take a long time to enter the black room where they received the electric shock. However, the control group (WT + saline), which is an Alzheimer's animal model but not treated with drugs, forgot the electric shock and immediately entered the black room where they received the electric shock.

[0151] On the one hand, 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 their memory as well as healthy normal mice even though the drug administration was reduced from 16 days to one week, showing a statistically significant difference from 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] Histological Staining Method of Brain Tissue (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 the histological staining (IHC) of the hippocampus tissue of the animal model. GFAP represents the staining result of astrocytes, and Aβ represents the staining result of amyloid beta.

[0153] From Figure 7, it was confirmed that in the Alzheimer's animal model, the number of astrocytes increased, but 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, the astrocytes returned to a healthy normal level. This result is consistent with the behavioral experiment results of Experimental Example 5, indicating that the treatment with the amino aromatic compound of the present invention can return the overproduced H2O2 to the normal level.

[0154] [Experimental Example 7] Electrophysiology Experiment Using the Alzheimer's animal model of Experimental Example 5, the electrophysiology experiment was conducted to confirm the effect on astrocytes and the mechanism inducing memory impairment in dementia.

[0155] Previous studies have demonstrated a mechanism by which tonic GABA (or tonic current) secreted continuously by reactive astrocytes induces memory and cognitive impairments in Alzheimer's disease patients. This can be confirmed by electrophysiology.

[0156] Therefore, in this experimental example, after anesthetizing APP / PS1 mice, which are Alzheimer's disease animal models, APP / PS1 mice treated with the aminoaromatic 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), respectively, brain tissues were obtained and the electrical signals of living hippocampus cells were measured. Thereby, tonic GABA that suppresses neurotransmission in brain cells was measured. The results are shown in FIG. 8.

[0157] In the Alzheimer's disease animal model (APP / PS1, TG), tonic GABA increased compared to healthy normal mice (WT). In contrast, in the Alzheimer's disease animal model treated with the aminoaromatic compound KDS12025 (Example 21) of the present invention, tonic GABA decreased. In this experimental example, the change in tonic GABA was confirmed electrophysiologically, thereby verifying the efficacy of the aminoaromatic compound of the present invention, that is, the ability to suppress tonic GABA that suppresses neurotransmission. Therefore, it was found that the aminoaromatic compound of the present invention is effective against Alzheimer's disease.

[0158] [Experimental Example 8] Novel place recognition experiment and passive avoidance test (PAT) The cognitive functions related to the hippocampus were evaluated by a novel place recognition experiment to confirm the impairment and recovery of cognitive functions. Objects that are completely identical are placed so as to interact with each other for a certain period of time, and after 1 hour, only the position of one object is changed. When there is normal cognitive function, past memories are maintained and the interest in new items increases, but when there is cognitive impairment, discrimination of new places becomes impossible. At this time, as an animal model, an APP / PS1+GiD Alzheimer's model mouse, which is developed to be closer to the phenomenon seen in Alzheimer's dementia patients, is used. The APP / PS1+GiD Alzheimer's model mouse was manufactured with reference to Nature Neuroscience 23, 1555 - 1566 (2020).

[0159] In this experimental example, APP / PS1+GiD was manufactured by administering the AAV-GFAP104-DTR-GFP virus to the hippocampus of APP / PS1 mice, and hereinafter is referred to as "APP+DTR". Also, the one manufactured by administering the AAV-GFAP104-GFP virus to the hippocampus of APP / PS1 mice was referred to as "APP+GFP". Further, the one obtained by administering the amino aromatic compound KDS12025 (Example 21) of the present invention to the APP+DTR was referred to as "APP+DTR+KDS12025". Also, for WT mice, APP / PS1 and a littermate were used, and the one manufactured by administering the AAV-GFAP104-GFP virus to the hippocampus of WT mice was referred to as "WT+GFP", and the one manufactured by administering the AAV-GFAP104-DTR-GFP virus to the hippocampus of WT mice was referred to as "WT+DTR".

[0160] Normal mice (WT+GFP, WT+DTR) had normal cognitive function. APP+GFP showed a cognitive function level similar to that of normal mice, while APP+DTR showed cognitive impairment like that of Alzheimer's patients. It was confirmed that when the amino aromatic compound KDS12025 (Example 21) of the present invention was intraperitoneally injected (i.p.) into APP / PS1+GiD Alzheimer's model mice showing cognitive impairment, that is, APP+DTR, at a dose of 3 mg / kg / day (i.e., APP+DTR+KDS12025), the cognitive function was restored (Figure 9).

[0161] Also, in the PAT results, normal mice (WT+GFP) well remembered the dark room that received electrical stimulation and spent a long time entering the dark room. On the other hand, APP / PS1+GiD Alzheimer's model mice, that is, APP+DTR showed problems with memory, but when the amino aromatic compound KDS12025 (Example 21) of the present invention was administered, that is, APP+DTR+KDS12025, it was confirmed that the memory was restored (Figure 10).

[0162] That is, the hydrogen peroxide removal efficacy of the amino aromatic compound of the present invention was confirmed in APP / PS1+GiD Alzheimer's model mice, which are model mice developed closer to the phenomena seen in Alzheimer's dementia patients. Therefore, it was found that it is effective against Alzheimer's.

[0163] [Experimental Example 9] Single toxicity evaluation (lethal dose 50, LD50) The amino aromatic compounds KDS12008 (Example 1), KDS12017 (Example 16), or KDS12025 (Example 21) of the present invention were each intraperitoneally injected at a single volume into 8-week-old WT mice (C57BL / 6 mice) at 100, 300, and 1000 mg / kg, and the animals were evaluated for death. The results are shown in FIGS. 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 caused only about 50% of the animals to die, and it was confirmed that all three drugs did not show fatal toxicity to mice at a lower concentration of 100 mg / kg.

[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 prepared by a parallel artificial membrane permeability assay (PAMPA), and the permeability of the drug was evaluated.

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

[0166] As described above, the present invention has been described with reference to specific matters, examples, and drawings, but these are provided to facilitate a more general understanding of the present invention, and the present invention is not limited to the above-described examples. Those having ordinary knowledge in the field to which the present invention pertains can make various modifications and variations from such descriptions.

[0167] Therefore, the idea of the present invention should not be defined only by the above-described examples, and it can be said that not only the scope of the claims described below but also all those having modifications equivalent or equivalent to the scope of the present claims belong to the scope of the idea of the present invention.

Claims

Claim 1 An amino aromatic compound represented by the following Chemical Formula 4 or a pharmaceutically acceptable salt thereof. [Chemical Formula 4] In the Chemical Formula 4, R １ is hydrogen, and R ２ is C １ -C ４ alkyl, Hal is a halogen. Claim 2 An amino aromatic compound represented by the following Chemical Formula 5 or a pharmaceutically acceptable salt thereof. [Chemical Formula 5] In the Chemical Formula 5, R １ and R ２ are each independently C １ -C ４ alkyl, R ３ is halo C １ -C ４ alkyl, and n is an integer of 1 or 2. Claim 3 An amino aromatic compound represented by the following Chemical Formula 5 or a pharmaceutically acceptable salt thereof. [Chemical Formula 5] In the Chemical Formula 5, R １ is hydrogen, and R ２ is C １ -C ４ alkyl, and R ３ is halo C １ -C ４ alkyl, and n is an integer of 1 or 2. Claim 4 The amino aromatic compound according to Claim 1, wherein the amino aromatic compound is any one selected from the following group of compounds. Claim 5 The amino aromatic compound according to Claim 2, wherein the amino aromatic compound is any one selected from the following group of compounds. Claim 6 The amino aromatic compound according to Claim 3, wherein the amino aromatic compound is any one selected from the following group of compounds. Claim 7 The pharmaceutically acceptable salt according to Claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride. Claim 8 The pharmaceutically acceptable salt according to Claim 2, wherein the pharmaceutically acceptable salt is a hydrochloride. Claim 9 The pharmaceutically acceptable salt according to Claim 3, wherein the pharmaceutically acceptable salt is a hydrochloride.

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