Compound for treating ischemic cerebrovascular disease and sequelae thereof, and composition comprising same

Abstract

The present invention relates to a composition for preventing, alleviating, or treating ischemic cerebrovascular disease and sequelae thereof. A composition comprising an aminoaromatic compound according to one aspect has an effect of significantly reducing the size of physical wounds and infarctions in the brain due to ischemic cerebrovascular disease, thereby having an effect of enabling recovery from sequelae due to ischemic cerebrovascular disease.

Description

Compounds for the treatment of ischemic cerebrovascular disease and its sequelae and compositions containing the same

[0001] It relates to a composition for preventing, improving or treating ischemic cerebrovascular disease and its sequelae.

[0002] Cerebrovascular disease (CVD) is a temporary brain disease caused by the blockage or rupture of a blood vessel supplying the brain. It is one of the three leading causes of death, along with heart disease and cancer. Stroke, a type of cerebrovascular disease, can be broadly categorized into ischemic stroke, which occurs due to a decrease or blockage of blood supply to the brain tissue, resulting in ischemia, and hemorrhagic stroke, which occurs due to the rupture of a blood vessel and bleeding into the brain tissue. Ischemic stroke is known to account for approximately 80% of all stroke cases. Causes of brain neuron damage caused by CVD include the release of excessive excitatory neurotransmitters, the production of free radicals, inhibition of protein synthesis, abnormal gene expression, and activation of the immune response. However, due to the complexity of the mechanisms of brain neuron damage, no treatment has yet been developed that can protect brain neurons.

[0003] Cerebrovascular disease leaves a significant number of survivors with serious sequelae. Depending on the site of bleeding or occlusion caused by the disease, it can cause various neurological symptoms, such as cognitive impairment, speech impairment, and motor paralysis, significantly reducing the patient's quality of life. Currently, treatment for the sequelae of ischemic cerebrovascular disease primarily relies on rehabilitation therapies, including physical therapy, occupational therapy, and pharmacological treatments. These treatments have limited effectiveness and, if the extent of brain cell damage is extensive, complete recovery is difficult. While treatments that supplement damaged neural pathways or activate new ones are being developed, pharmacological mechanisms-based therapies are still in their infancy in terms of neuroprotection and brain cell regeneration. Cases directly leading to sequelae relief are rare, making it difficult to guarantee long-term relief from sequelae.

[0004] These researchers have sought to overcome the technical limitations of treating ischemic cerebrovascular disease and its sequelae. They discovered that aminoaromatic compounds, according to one specific example, can reduce the size of initial cerebral infarction, restore nerve bundles, repair existing damage, and alleviate the sequelae of ischemic cerebrovascular disease. Through this, they hope to overcome the limitations of rehabilitation treatment, fundamentally reduce brain damage, and propose a novel approach that can aid in the functional recovery of patients.

[0005] One aspect is to provide a pharmaceutical composition for preventing, improving or treating ischemic cerebrovascular disease or its sequelae, comprising an aminoaromatic compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0006] [Chemical Formula 1]

[0007]

[0008] In the above chemical formula 1,

[0009] Ar is C6-C 20Arylene, and the arylene of the above Ar is C1-C 10 Alkyl, C1-C 10 Alkoxy, amino, mono- or di-C1-C 10 Alkylamino, haloC1-C 10 Alkyl, haloC1-C 10 may be further substituted with one or more selected from alkoxy and hydroxy;

[0010] R 1 and R 2 are each independently hydrogen or C1-C 10 It is alkyl;

[0011] R 3 is halogen, C1-C 10 Alkoxy, haloC1-C 10 Alkyl or haloC1-C 10 It is alkoxy;

[0012] n is an integer of 1 or 2;

[0013] Only R 3 If is a halogen, n is an integer greater than 1.

[0014] Another aspect is to provide a health functional food for preventing or improving ischemic cerebrovascular disease or its sequelae, which comprises a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0015] Another aspect is to provide a method for preventing, improving or treating ischemic cerebrovascular disease or its sequelae, comprising administering to a subject in need thereof an effective amount of an aminoaromatic compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0016] Another aspect provides a use of an aminoaromatic compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical preparation for preventing, improving or treating ischemic cerebrovascular disease or its sequelae.

[0017] One aspect is to provide a pharmaceutical composition for preventing, improving or treating ischemic cerebrovascular disease or its sequelae, comprising an aminoaromatic compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0018] [Chemical Formula 1]

[0019]

[0020] In the above chemical formula 1,

[0021] Ar is C6-C 20 Arylene, and the arylene of the above Ar is C1-C 10 Alkyl, C1-C 10 Alkoxy, amino, mono- or di-C1-C 10 Alkylamino, haloC1-C 10 Alkyl, haloC1-C 10 may be further substituted with one or more selected from alkoxy and hydroxy;

[0022] R 1 and R 2 are each independently hydrogen or C1-C 10 It is alkyl;

[0023] R 3 is halogen, C1-C 10 Alkoxy, haloC1-C 10 Alkyl or haloC1-C 10 It is alkoxy;

[0024] n is an integer of 1 or 2;

[0025] Only R 3 If is a halogen, n is an integer greater than 1.

[0026] In this specification, the term "C A -C B " means "the number of carbon atoms is greater than or equal to A and less than or equal to B".

[0027] As used herein, the term “substituted” means substituted with one or more substituents, for example, a hydroxy group, an alkyl group, an alkoxy group, a mercapto group, a cycloalkyl group, a substituted cycloalkyl group, a heterocyclic group, a substituted heterocyclic group, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl group, an aryloxy group, a substituted aryloxy group, a halogen group, a trifluoromethyl group, a cyano group, a nitro group, an oxo group, an amino group, an amido group, an aldehyde group, an acyl group, an oxyacyl group, a carboxyl group, a carbamate group, a sulfonyl group, a sulfonamide, a sulfuryl group, and the like.

[0028] In this specification, the terms “substituent”, “radical”, “group”, “moiety”, and “fragment” are used interchangeably.

[0029] As used herein, the term "alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon radical composed solely of carbon and hydrogen atoms. The alkyl may have 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. "Lower alkyl" refers to a straight-chain or branched alkyl having 1 to 4 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, ethylhexyl, and the like.

[0030] The term "arylene" as used herein refers to an aromatic ring divalent organic radical derived from an aromatic hydrocarbon by the removal of two hydrogen atoms, including a single or fused ring system, suitably containing 4 to 7, preferably 5 or 6 ring atoms in each ring, and even including a form in which multiple aryls are connected by single bonds. Specific examples include, but are not limited to, phenylene, naphthylene, biphenylene, and anthrylene.

[0031] 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.

[0032] As used herein, the term “halo” or “halogen” refers to a halogen group element, including, for example, fluoro, chloro, bromo, and iodo.

[0033] As used herein, the term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms are replaced by a halogen atom, wherein 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.

[0034] As used herein, the term “amino” means -NH2 and “hydroxy” means -OH.

[0035] As used herein, the term “alkylamino” means an amino radical substituted with one or two alkyl groups, and specific examples include, but are not limited to, methylamino (-NHMe), dimethylamino (-NMe2), ethylamino (-NHEt), diethylamino (-NEt2), and the like.

[0036] In one specific example, the Ar is C6-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.

[0037] In one specific example, the Ar is phenylene, and it may be preferable that nitrogen atoms are introduced at positions 1 and 4 of the phenylene.

[0038] In one specific example, the aminoaromatic compound may be a compound represented by the following chemical formula 2:

[0039] [Chemical Formula 2]

[0040]

[0041] In the above chemical formula 2,

[0042] R 1 and R 2 are each independently hydrogen or C1-C7 alkyl;

[0043] R 3 is halogen, C1-C7alkoxy, haloC1-C7alkyl;

[0044] R' is C1-C7 alkyl, C1-C7 alkoxy, amino or hydroxy;

[0045] a is an integer from 0 to 4;

[0046] n is an integer of 1 or 2.

[0047] In one specific example, R1 and R2 are each independently hydrogen or C1-C4 alkyl; R3 is C1-C4 alkoxy or haloC1-C4 alkyl; a is an integer of 0; and n may be an integer of 1 or 2.

[0048] In one specific example, the R 1 and R 2 are each independently hydrogen or C1-C7 alkyl; R 3 is C1-C7 alkoxy; R' is hydroxy; a is an integer from 0 to 4; and n can be an integer of 1 or 2.

[0049] In one specific example, the aminoaromatic compound may be any one selected from the group consisting of the following chemical formulas 3 to 6:

[0050] [Chemical Formula 3]

[0051]

[0052]

[0053] [Chemical Formula 4]

[0054]

[0055]

[0056] [Chemical Formula 5]

[0057]

[0058]

[0059] [Chemical Formula 6]

[0060]

[0061]

[0062]

[0063] It will be apparent to those skilled in the art that the method for producing an aminoaromatic compound according to one embodiment of the present invention can be performed using a method known in the art or by appropriately modifying it.

[0064] The present invention encompasses the above aminoaromatic compounds and pharmaceutically acceptable salts thereof, as well as possible prodrugs, hydrates and solvates that can be prepared therefrom.

[0065] That is, the aminoaromatic compound of the present invention can be made into and used in the form of a prodrug, a hydrate, a solvate, and a pharmaceutically acceptable salt to promote absorption in the body or increase solubility, and therefore the above prodrug, hydrate, solvate, and pharmaceutically acceptable salt also fall within the scope of the present invention.

[0066] The term “pharmaceutically acceptable” as used herein means physiologically acceptable and, when administered to humans, does not typically cause allergic reactions such as gastrointestinal upset, dizziness, or similar reactions.

[0067] The term “pharmaceutically acceptable salt” as used herein refers to a salt according to one aspect of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Salts of the parent compound can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base, such as sodium, calcium, magnesium, or potassium, or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. These reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used, where practical. The pharmaceutically acceptable salts include both acid or base addition salts and stereochemically isomeric forms thereof, and may be, for example, addition salts of organic or inorganic acids. The above salt includes any salt that maintains the activity of the parent compound in the subject of administration and does not cause undesirable effects, and is not particularly limited thereto.

[0068] The addition salt of an acid according to one specific example is obtained from an inorganic acid such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., and an organic acid 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, carbonic acid, vanillic acid, hydroiodic acid, etc. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, Includes 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, etc.

[0069] Acid addition salts can be prepared by a conventional method, for example, by dissolving the aminoaromatic compound of the present invention in a water-miscible organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess of acid under reduced pressure, drying, and crystallizing in the presence of an organic solvent.

[0070] In addition, a pharmaceutically acceptable metal salt can be prepared using a base. An alkali metal salt or an alkaline earth metal salt is obtained, for example, by dissolving the aminoaromatic compound of the present invention in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved aminoaromatic compound salt, and then evaporating and drying the filtrate. At this time, sodium, potassium, or calcium salts are pharmaceutically suitable as the metal salt, but are not limited thereto. In addition, 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).

[0071] In one specific embodiment, the pharmaceutically acceptable salt of the amino aromatic compound according to one embodiment may be a hydrochloride salt. Specifically, in one embodiment, the amino aromatic compound may be a compound in the form of a hydrochloride salt selected from the following structures.

[0072] As used herein, the term "cerebrovascular disease" refers to all diseases in which a blood vessel supplying blood to the brain becomes blocked or ruptured, causing damage to brain tissue and resulting in various physical disabilities. Cerebrovascular disease is categorized into hemorrhagic cerebrovascular disease and ischemic cerebrovascular disease.

[0073] As used herein, the term "ischemic cerebrovascular disease" refers to all diseases that occur when a cerebral blood vessel is blocked by a thrombus, resulting in insufficient blood supply to the brain. Specifically, the ischemic cerebrovascular disease may be a stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, lacunar infarction, transient ischemic attack, cerebral vascular occlusion, moyamoya disease, small infarction, or leukodermatitis.

[0074] As used herein, "sequelae of ischemic cerebrovascular disease" collectively refers to the pathological symptoms that persist after ischemic cerebrovascular disease. Specifically, the sequelae of ischemic cerebrovascular disease may include motor impairment, speech impairment, cognitive impairment, dysphagia, balance impairment, unilateral neglect, emotional and behavioral changes, and / or sensory impairment.

[0075] The above movement disorders collectively refer to conditions in which conscious control of movements of the limbs, trunk, neck, and / or face is impaired due to disease of the motor nerve pathways. These movement disorders may include hemiplegia, ataxia, rigidity, muscle weakness, muscle tension abnormalities, hypotonia, and / or involuntary movements. These disorders can cause functional impairments, including difficulties performing activities of daily living, maintaining balance, and changing posture.

[0076] An amino aromatic compound according to one specific embodiment of the present invention can reduce the size of infarction and restore the number of nerve bundles. By reducing the size of infarction and restoring the number of nerve bundles, the compound of the present invention can reduce brain cell damage and necrosis that have already occurred and promote brain plasticity, thereby promoting normal nerve recovery and reorganization. Consequently, the compound of the present invention can preserve brain regions, thereby reducing the severity of sequelae caused by ischemic cerebrovascular disease and helping patients recover functionally. The compound of the present invention is particularly effective in the recovery, alleviation, and prevention of recurrence of movement disorders.

[0077] The term "prevention" as used herein collectively refers to partially or completely delaying or preventing the onset or recurrence of a disease, disorder, or its secondary symptoms, preventing the acquisition or reacquisition of a disease or disorder, or reducing the risk of acquiring a disease or disorder. The term "prevention" refers to any action that inhibits or delays the onset of a cerebrovascular disease, disorder, or symptom by administering a composition according to the present invention.

[0078] As used herein, the term "improvement" refers to any action that at least reduces a parameter associated with the condition being treated, for example, the severity of a symptom.

[0079] As used herein, the term “treatment” refers to any action that improves or beneficially alters a disease, disorder, or its accompanying symptoms.

[0080] As used herein, the term "therapeutic agent" or "pharmaceutical composition" refers to a molecule or compound that, when administered to a subject, imparts some beneficial effect. Beneficial effects include enabling diagnostic determination; improving a disease, symptom, disorder, or condition; reducing or preventing the onset of a disease, symptom, disorder, or condition; and generally counteracting a disease, symptom, disorder, or condition.

[0081] In one embodiment, the composition may further comprise an antioxidant, wherein the antioxidant may be at least one selected from the group consisting of nicotinamide, anthocyanins, benzenediol abietane diterpene, carnosine, carotenoids, xanthophylls, and carotenoids in saffron, curcuminoids, cyclopentenone prostaglandins, flavonoids, prenylflavonoids, retinoids, stilbenoids, uric acid, vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B9, vitamin B12, vitamin C, vitamin E, selenium, zinc, inhibitors and scavengers of lipid peroxidation and its byproducts, tirilazad and analogs, derivatives, salts and combinations thereof.

[0082] In addition, the composition may additionally contain a pharmaceutically effective amount of a physiologically active ingredient or one or more pharmaceutically acceptable carriers, excipients, or diluents. The pharmaceutically effective amount refers to an amount of the physiologically active ingredient sufficient to exhibit the desired physiological or pharmacological activity when administered to an animal or human. The pharmaceutically effective amount may be appropriately varied depending on the age, weight, health condition, sex, administration route, and treatment period of the subject of administration.

[0083] The term “physiologically active ingredient” as used herein refers to a chemical or biological substance or compound suitable for administration to an animal or human, which is a substance that can induce a desired biological or pharmacological effect by promoting or inhibiting a physiological function in the body of an animal or human, and has a preventive effect on organisms by preventing undesired biological effects such as infection prevention, and can alleviate conditions caused by diseases, for example, alleviate pain or infection resulting from diseases, and play a role in alleviating, reducing, or completely eliminating diseases from organisms.

[0084] The above physiologically active ingredient may be selected from the group consisting of, but is not limited to, proteins, anticancer agents, anti-inflammatory analgesics, antibiotics, antimicrobial agents, hormones, genes, and vaccines.

[0085] The above pharmaceutical composition may be formulated using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants by methods known in the art, and such formulations may be oral or parenteral dosage forms. Oral dosage forms may be granules, powders, liquids, tablets, capsules, dry syrups, or combinations thereof, and parenteral dosage forms may be injections, but are not limited thereto.

[0086] The above administration can be administered by methods known in the art. Administration can be administered directly to the subject by any means, such as intraperitoneal, oral, intravenous, intramuscular, transdermal, subcutaneous, mucosal, intranasal, intrapulmonary, or rectal administration. The above administration can be systemic or local.

[0087] The subject may include, but is not limited to, a mammal, such as a human, cow, horse, pig, dog, sheep, goat, or cat. The subject may be an individual in need of an improvement effect in a condition related to cerebrovascular disease.

[0088] The therapeutically effective dosage of the pharmaceutical composition may be administered in one to several divided doses in an amount of 0.01 to 1000 mg, for example, 0.1 to 500 mg or 0.1 to 300 mg per kg of body weight per day. However, the therapeutically effective dosage or therapeutically effective amount may vary depending on the formulation method, administration method, administration time, and / or administration route of the pharmaceutical composition. In addition, the type and degree of the response to be achieved by administration of the composition, the type, age, weight, general health condition, symptoms or degree of the disease, sex, diet, excretion, drugs used simultaneously or simultaneously in the subject, other components of the composition, etc., may vary depending on various factors, and similar factors well known in the pharmaceutical field. A person having ordinary skill in the art can easily determine and prescribe an effective dosage for the desired treatment.

[0089] Another aspect provides a method for preventing, improving or treating ischemic cerebrovascular disease or its sequelae, comprising administering to a subject in need thereof an effective amount of an aminoaromatic compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0090] Another aspect provides the use of an aminoaromatic compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical preparation for preventing, improving or treating ischemic cerebrovascular disease or its sequelae.

[0091]

[0092] Another aspect provides a health functional food for preventing or improving ischemic cerebrovascular disease or its sequelae, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0093] [Chemical Formula 1]

[0094]

[0095]

[0096] In the above chemical formula 1,

[0097] Ar is C6-C 20 Arylene, and the arylene of the above Ar is C1-C 10 Alkyl, C1-C 10 Alkoxy, amino, mono- or di-C1-C 10 Alkylamino, haloC1-C 10 Alkyl, haloC1-C 10 may be further substituted with one or more selected from alkoxy and hydroxy;

[0098] R 1 and R 2 are each independently hydrogen or C1-C 10 It is alkyl;

[0099] R 3 is halogen, C1-C 10 Alkoxy, haloC1-C 10 Alkyl or haloC1-C 10 It is alkoxy;

[0100] n is an integer of 1 or 2;

[0101] Only R 3 If is a halogen, n is an integer greater than 1.

[0102] The term "health functional food" as used herein refers to a food manufactured or processed for the purpose of health supplementation using specific ingredients as raw materials or by extracting, concentrating, refining, mixing, or other methods of specific ingredients contained in food raw materials. It refers to a food designed and processed so that the above ingredients can sufficiently exert bioregulatory functions on the body, such as biodefense, regulation of biological rhythms, and disease prevention and recovery, and can be used for the purpose of preventing or improving ischemic cerebrovascular disease and its sequelae.

[0103] There are no special restrictions on the types of the above foods. Examples of the above foods include formulations selected from the group consisting of powders, granules, tablets, capsules, pills, gels, jellies, suspensions, emulsions, syrups, tea bags, infused teas, gums, candies, and health drinks, and may include all health foods in the conventional sense, and may include foods used as feed for animals.

[0104] The health functional food of the present invention can be used as a food additive. When using the composition of the present invention as a food additive, the composition can be added as is or combined with other foods or ingredients, and can be used appropriately according to conventional methods. The amount of active ingredients mixed can be appropriately determined depending on the intended use.

[0105] The above "food additive" refers to substances intentionally added to food, usually in small quantities, to improve appearance, flavor, texture, or storability. It also refers to substances used to improve the quality of food, enhance its storability or palatability, and enhance its nutritional value and practical value. As defined in Article 2, Paragraph 2 of the Food Sanitation Act, these may be substances added to, mixed with, infiltrated into, or otherwise used in the manufacturing, processing, or preservation of food.

[0106] In addition, the food composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. In addition, it may contain fruit pulp for the production of natural fruit juice, fruit juice drinks, and vegetable drinks.

[0107] In addition, the above food can be manufactured in the form of tablets, granules, powders, capsules, liquid solutions, pills, etc., according to known manufacturing methods. Aside from including the compound of the present invention as an active ingredient, there are no special restrictions on other ingredients, and various conventional flavoring agents or natural carbohydrates can be included as additional ingredients.

[0108] In one specific example, a health functional food in tablet form may be prepared by mixing the compound of the above chemical formula 1, which is the active ingredient of the present invention, with excipients, binders, disintegrants, and other additives, granulating the mixture using a conventional method, and then adding a lubricant, etc., and compression molding the mixture, or directly compression molding the mixture. In addition, the health functional food in tablet form may contain a maturing agent, etc., as necessary.

[0109] The above granular formulation can be manufactured into a granular form by mixing a compound of the above chemical formula 1, which is an effective ingredient of the present invention, with excipients, binders, disintegrants, etc., using a method known in the art, and may contain a flavoring agent, a flavoring agent, etc., as needed.

[0110] Among the above capsule formulations, hard capsules can be manufactured by filling a mixture of the compound of the above chemical formula 1, which is the active ingredient of the present invention, with additives such as excipients, into a conventional hard capsule, and soft capsules can be manufactured by filling a mixture of the compound of the above chemical formula 1, which is the active ingredient of the present invention, with additives such as excipients, into a capsule base such as gelatin, and may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, etc., as necessary.

[0111] The above-mentioned ring formulation can be prepared by molding a mixture of the compound of the above-mentioned chemical formula 1, which is an effective ingredient of the present invention, and an excipient, a binder, a disintegrant, etc., using a method known in the art, and, if necessary, can be coated with white sugar or another coating agent, or the surface can be coated with a material such as starch or talc.

[0112] The terms and methods described for the above compounds and diseases also apply to the above health functional foods.

[0113]

[0114] The present invention is susceptible to various modifications and embodiments. Specific embodiments are illustrated in the drawings and described in detail in the following detailed description. However, this is not intended to limit the present invention to specific embodiments, but rather to encompass all modifications, equivalents, and alternatives falling within the spirit and technical scope of the present invention. In describing the present invention, detailed descriptions of related known technologies will be omitted if they are deemed to obscure the gist of the present invention.

[0115] Aminoaromatic compounds according to the daily aspect have the effect of significantly reducing the size of physical scars and infractions in the brain caused by ischemic cerebrovascular disease, and thus have a recovery effect in the aftereffects of ischemic cerebrovascular disease.

[0116] Figure 1 is an image showing the experimental outline of the cylinder evaluation (top) and food access evaluation (bottom) in an ischemic stroke mouse model.

[0117] Figure 2 is an image comparing the immunostaining results according to the presence or absence of drug injection according to one specific example in an ischemic stroke mouse model.

[0118] Figure 3 is a graph showing the quantification of the diameter of permanent wounds in the brain according to the presence or absence of drug injection according to one specific example in an ischemic stroke mouse model.

[0119] Figure 4 is an image of the cylinder test method and results.

[0120] Figure 5 is an image showing the evaluation method and results of the single pellet reaching test. Figure 6 is an image showing the experimental outline in an ischemic stroke monkey model.

[0121] Figure 7 is an MRI image and a quantitative analysis graph showing the size of a lesion according to the presence or absence of drug injection according to one specific example in an ischemic stroke monkey model.

[0122] Figure 8 is an MRI image and a quantitative analysis graph showing the number of functional nerve bundles according to the presence or absence of drug injection according to one specific example in an ischemic stroke monkey model.

[0123] Figure 9 is a graph showing the results of a lesion hand motor function test according to the presence or absence of drug injection according to one specific example in an ischemic stroke monkey model.

[0124] The following examples are provided for more detailed description. However, these examples are provided solely to illustrate one or more specific examples, and the scope of the present invention is not limited to these examples.

[0125]

[0126] Example 1. Preparation of KDS12025

[0127] KDS12025, which is an example according to one specific example of the present invention, was manufactured by the same method as disclosed in Korean Patent Publication No. 10-2022-0065706.

[0128]

[0129] Experimental Example 1. Confirmation of the wound regeneration ability of KDS12025 in a mouse model.

[0130] An experiment was conducted to confirm the wound regeneration ability of a compound according to one specific example in mice with ischemic stroke.

[0131] First, ischemic stroke was induced in 8-week-old C57BL / 6 mice by intracranial surgery, intravenous injection of rose Bengal drug, and 532 nm laser irradiation. Starting on day 1 after stroke induction, KDS12025 was administered intraperitoneally at a concentration of 10 mpk once daily for a total of 3 days. Brain tissue was extracted on day 28. During the extraction process, the brain tissue was fixed by perfusion with 4% PFA and immersed in the same solution for 24 hours for post-fixation. The fixed brain tissue was made into blocks using OCT compound and sectioned at 30 μm thickness using a cryostat. Afterwards, the sections were blocked with 5% Normal Donkey serum and 0.3% Trinton-X solution for 1 hour, and immunostained with GFAP (1:500, ab5541, Millipore), NeuN (1:500, ABN90, Millipore), and Collagen I (1:500, ab34710, abcam) for 1 day. Afterwards, the corresponding fluorescent secondary staining was performed, and the tissues were mounted on slides. The completed tissues were imaged using a confocal microscope (Zeiss LSM 900), and the results are shown in Fig. 2.

[0132] Additionally, the diameter of the permanent wound in the brain was quantified and compared, and the results are shown in Figure 3.

[0133]

[0134] Figure 1 is an image showing an outline of an experiment in an ischemic stroke mouse model.

[0135] As shown in Figure 2, after ischemic stroke modeling, the KDS12025-untreated group observed permanent intracerebral scarring, including collagen and glial barriers, and a decrease in the number of neurons. In contrast, the KDS12025-treated group did not exhibit collagen or glial barriers, and the number of neurons was maintained.

[0136] As shown in Figure 3, it was confirmed that the size of the wound was significantly smaller in the KDS12025 treatment group compared to the untreated group.

[0137]

[0138] Experimental Example 2. Confirmation of KDS12025's ability to restore motor skills in a mouse model.

[0139] Additionally, a behavioral assessment was conducted to determine the ability of the compound to restore motor ability according to one specific example. Induction of ischemic stroke using two methods (cortical and subcortical ischemic stroke models) and administration of KDS12025 were performed in the same manner as in Experimental Example 1.

[0140] Behavioral evaluation was performed using the cylinder test and the single pellet reaching test.

[0141] The cylinder test measures spatial sense and motor-based exploratory ability. Mice were placed in a cylinder measuring 14 cm in diameter and 20 cm in height, and the number of times the mice stood up and touched the cylinder with their forepaws was observed for 5 minutes. During this time, the total number of times the mice touched the cylinder wall and the number of times the paws in the lesioned area touched the cylinder wall were measured. Measurements were performed six times in total on days 1, 3, 7, 14, 21, and 28 after ischemic stroke induction, and the results are shown in the graph in Figure 4.

[0142] The food access assessment is a method for measuring fine motor function in the palm of a mouse. Mice are placed in a custom-designed test box, a single pellet of food that can be grasped with one hand is placed in the center, and the success rate at which the mouse reaches for the food is quantified. First, for 14 days before stroke induction, mice are trained to use only their left hand, and baseline function is measured. Food is presented 10 times, and each opportunity is scored from 0 to 5, resulting in a total score of 50. Only mice scoring 48-50 before stroke surgery are included in the experiment. After surgery, mice waited 7 days to create a chronic model, and measurements were taken at 7, 8, 9, 10, 12, 15, 18, and 20 days after surgery. The results are presented in Figures 4 and 5.

[0143] Figure 4 is an image of a cylinder evaluation method and results.

[0144] Figure 5 is an image of the evaluation method and results of the single pellet reaching test.

[0145] As shown in Fig. 4, the number of times the cylinder wall was touched significantly decreased in the KDS12025 untreated group after ischemic stroke modeling, and this behavior was maintained for up to 28 days. On the other hand, the number of times the cylinder wall was touched significantly increased in the KDS12025 treated group, and this significantly increased even when the cylinder wall was touched using the paw at the lesion site. In addition, as shown in Fig. 5, the score for taking food significantly decreased in the KDS12025 untreated group after subcortical ischemic stroke modeling, and it was confirmed that the decline in motor function due to stroke was recovered when KDS12025 and rehabilitation were performed.

[0146]

[0147] Experimental Example 3. Confirmation of Lesion Recovery by KDS12025 in a Monkey Model

[0148] An experiment was conducted to determine the lesion recovery pattern in monkeys with induced ischemic stroke when a compound was administered according to one specific example.

[0149] First, three cynomolgus macaques were prepared and perfused with Rose Bengal (15 mg / ml) solution as in the mouse, and the brain was exposed through craniotomy, and ischemic stroke was induced using a 532 nm laser. From the first day of stroke induction, KDS12025 was intubated using an E tube at a concentration of 0.1 mg / kg once or 0.03 mg / kg three times (once daily for 3 days). MRI was performed before, 1 day, 7 days, and 14 days after ischemic stroke modeling, and the results of quantitative analysis of the T2 signal of the acquired MRI and the damaged area obtained through the T2 signal are shown in Figure 7, and the results of reconstruction of the axonal organization using diffusion tensor imaging (DTI) extracted from the MRI image and its quantitative analysis are shown in Figure 8.

[0150] As shown in Figures 7 and 8, lesions developed in all three animals after surgery, and in the animal that was not administered the drug, a distinct lesion was observed in the penumbra 14 days later, but the two animals in the drug-treated group showed signs of recovery.

[0151]

[0152] Experimental Example 4. Confirmation of KDS12025's ability to restore motor skills in a monkey model.

[0153] Additionally, a behavioral assessment was conducted to determine the ability of the compound to restore motor skills according to one specific example. Induction of ischemic stroke and administration of KDS12025 were performed in the same manner as in Experimental Example 1.

[0154] Behavioral assessment was performed using the single fruit reaching test. Before the test, the monkeys were habituated to the monkey chair to acclimate them to the experimental conditions. After acclimation, they were trained to use their right arm to reach for fruits presented by the experimenter on the board with their fingers, while their left arm was fixed. All experimental procedures were videotaped, and the use of fingers and palms, the frequency of fruit grasping, and the time taken to reach and retrieve the fruit were quantitatively analyzed. The test was conducted before ischemic stroke modeling and on days 0, 5, 10, and 15 after the induction. The results of a quantitative analysis of the number of successful fruit presentations and the time taken to reach and retrieve the fruit are shown in Figure 9.

[0155] As shown in Fig. 9, the results of the motor function test showed that the individual that was not administered the drug according to one specific example was unable to use its hands at all, but the two drug-treated individuals were observed to have recovered their hand motor ability to a normal level after 5 days, as confirmed through quantification of the number of times they picked up and brought the fruit to their mouth (left) and the number of times they successfully picked up and ate all presented fruits (right).

[0156]

[0157] In summary, compounds specific to the daily pattern significantly reduced the size of wounds and infarctions following ischemic cerebrovascular disease and restored motor function to normal. This suggests that compounds specific to the daily pattern have potential as therapeutic agents for ischemic cerebrovascular disease, particularly for its sequelae.

[0158]

[0159] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. A pharmaceutical composition for preventing, improving or treating ischemic cerebrovascular disease or its sequelae, comprising an aminoaromatic compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] In the above chemical formula 1, Ar is C6-C 20 Arylene, and the arylene of the above Ar is C1-C 10 Alkyl, C1-C 10 Alkoxy, amino, mono- or di-C1-C 10 Alkylamino, haloC1-C 10 Alkyl, haloC1-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 It is alkyl; R 3 is halogen, C1-C 10 Alkoxy, haloC1-C 10 Alkyl or haloC1-C 10 It is alkoxy; n is an integer of 1 or 2; Only R 3 If is a halogen, n is an integer greater than 1.

2. In claim 1, A pharmaceutical composition wherein the aminoaromatic compound represented by the above chemical formula 1 is an aminoaromatic compound represented by the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, R 1 and R 2 are each independently hydrogen or C1-C7 alkyl; R 3 is C1-C7alkoxy or haloC1-C7alkyl; 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.

3. In claim 2, the R 3 A pharmaceutical composition wherein R' is C1-C7 alkoxy and R' is hydroxy.

4. In claim 1, A pharmaceutical composition wherein the aminoaromatic compound represented by the above chemical formula 1 is one selected from the group consisting of the following chemical formulas 3 to 6: [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] .

5. In claim 1, A pharmaceutical composition, wherein the above ischemic cerebrovascular disease is any one selected from the group consisting of stroke, cerebral infarction, cerebral thrombosis, cerebral embolism, lacunar cerebral infarction, transient ischemic attack, cerebral vascular occlusion, moyamoya disease, small infarction, and leukodermatitis.

6. In claim 1, A pharmaceutical composition wherein the above-mentioned side effect is a motor disorder.

7. In claim 1, A pharmaceutical composition, wherein the composition reduces the size of an infraction.

8. Health functional food for preventing or improving ischemic cerebrovascular disease or its sequelae, containing as an active ingredient an aminoaromatic compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] 9. In claim 8, A health functional food wherein the aminoaromatic compound represented by the above chemical formula 1 is one selected from the group consisting of the following chemical formulas 3 to 6: [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] .

10. A method for preventing, improving or treating ischemic cerebrovascular disease or its sequelae, comprising administering to a subject in need thereof an effective amount of an aminoaromatic compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, Ar is C6-C 20 Arylene, and the arylene of the above Ar is C1-C 10 Alkyl, C1-C 10 Alkoxy, amino, mono- or di-C1-C 10 Alkylamino, haloC1-C 10 Alkyl, haloC1-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 It is alkyl; R 3 is halogen, C1-C 10 Alkoxy, haloC1-C 10 Alkyl or haloC1-C 10 It is alkoxy; n is an integer of 1 or 2; Only R 3 If is a halogen, n is an integer greater than 1.

11. Use of an aminoaromatic compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical preparation for preventing, improving or treating ischemic cerebrovascular disease or its sequelae: [Chemical Formula 1] In the above chemical formula 1, Ar is C6-C 20 Arylene, and the arylene of the above Ar is C1-C 10 Alkyl, C1-C 10 Alkoxy, amino, mono- or di-C1-C 10 Alkylamino, haloC1-C 10 Alkyl, haloC1-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 It is alkyl; R 3 is halogen, C1-C 10 Alkoxy, haloC1-C 10 Alkyl or haloC1-C 10 It is alkoxy; n is an integer of 1 or 2; Only R 3 If is a halogen, n is an integer greater than 1.

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