KR20200000048A - Compositions for preventing or treating cognitive impairment-related disease comprising chebulanin - Google Patents

Abstract

The present invention relates to a composition for preventing or treating a cognitive impairment-related disease comprising chebulanin. Specifically, the present invention relates to a pharmaceutical composition, a health functional food composition and a feed composition for preventing or treating a cognitive impairment-related disease, and a health functional food for improving learning, cognitive function or memory comprising chebulanin or an acceptable salt thereof as an active ingredient; and a method of treating the cognitive impairment-related disease by using the pharmaceutical composition. The chebulanin prevents damages to cholinergic neurons and thus, can improve deteriorated cognitive function by exhibiting an inhibition effect with respect to acetylcholine esterase to maintain acetylcholine concentration in synapse. Therefore, the chebulanin according to the present invention can be useful in treatment of the cognitive impairment-related disease occurred by the damages to cholinergic neurons, improvement of learning, cognitive function and memory and the like.

Description

Composition for preventing or treating cognitive impairment related disease containing chebulanin {Compositions for preventing or treating cognitive impairment-related disease comprising chebulanin}

The present invention relates to a composition for preventing or treating a disease related to cognitive disorders containing chebulanin, specifically, a pharmaceutical composition for preventing or treating a disease related to cognitive disorders comprising chebulanin or an acceptable salt thereof as an active ingredient; Health functional food composition; Feed composition; Dietary supplements for learning, cognitive function, or memory; And it relates to a method of treating cognitive impairment-related diseases using the pharmaceutical composition.

Cognitive ability encompasses memory ability, space-time grasping ability, judgment ability, language ability, and computational ability, so that everyday life can be performed without the help of others. However, in all cases of brain injury such as rapid death of neurons caused by stroke, trauma, etc., or slow death of neurons, which causes degenerative brain diseases, it immediately leads to irreversible dysfunction of neural networks. Eventually, cognitive decline will lead to forgetfulness or memory disorders, dementia, Alzheimer's disease, etc., and will not be able to maintain previous levels of daily life. The number of cognitive impairment-related patients described above, which causes a decline in the population as well as individual pain, is expected to increase to more than 74.7 million by 2030 (Abate G, 2017, Oxid Med Cell Longev. 2017: 10 ), The development of a therapeutic agent or treatment method thereof is an urgent problem.

Neurodegenerative disorders that cause progressive loss of cognitive function and memory, such as cognitive impairment, have a variety of causes, but one of them is known to be caused by damage to the acetylcholine neurons in the base of the cerebral base. Agonists for the muscarinic acetylcholine receptor that prevents the breakdown of choline and maintains acetylcholine levels at synapses, improving cognitive function, acetylcholine production promoters, and acetylcholine degrading enzymes Depending on various mechanisms of action, such as acetylcholinesterase (AChE) inhibitors, drugs have been developed that can enhance the function of acetylcholine neurons. Indeed, the treatment of Alzheimer's disease currently used in various countries is the most of these inhibitors of acetylcholine degrading enzymes, such as tacrine (donrinezil) and donepezil (donepezil). In addition, rivastigmin and galatamine are used.

In addition, to date, a number of patents related to compositions having efficacy for treating cognitive impairment and improving cognitive ability have been disclosed and registered in Korea. Publication No. 2014-0144785 relates to a composition for enhancing memory and learning ability comprising an extract of citron as an active ingredient; Registration No. 10-1837444 relates to a composition for the prevention, improvement or treatment of cognitive dysfunction, which contains a yellow flower extract as an active ingredient; Registration No. 10-1693615 relates to extracts of gastric glands which exhibit dementia prevention or treatment or cognitive improvement. However, even though such chemicals and natural compositions are on the market, excellent formulations with definite efficacy have not yet been developed. In addition, commercially available drugs cause many side effects such as hepatotoxicity, insomnia, hypertension, vomiting. Therefore, there is an urgent need for the development of agents that can effectively treat diseases related to cognitive impairment with less side effects.

Against this background, the present inventors have made diligent research efforts to develop a material capable of improving memory and treating dementia. As a result, chebulanine has an excellent inhibitory effect on acetylcholine degrading enzymes that induce damage to cholinergic nerves. The invention has been completed.

One object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cognitive impairment-related diseases, including chebulanin (chebulanin) or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a method for treating a cognitive disorder related disease, comprising administering the composition to a subject suspected of a cognitive disorder related disease.

Another object of the present invention to provide a nutraceutical composition for the prevention or improvement of cognitive impairment-related diseases, including chebulanin as an active ingredient.

Still another object of the present invention is to provide a health functional food composition for improving learning, cognitive function, or memory, including chebulanin as an active ingredient.

Yet another object of the present invention is to provide a feed composition for preventing or improving a disease related to cognitive impairment, comprising chebulanin as an active ingredient.

In order to achieve the above object, one embodiment of the present invention provides a pharmaceutical composition for preventing or treating cognitive impairment-related diseases, including chebulanin or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, it was confirmed that chebulanin exhibits an inhibitory effect on acetylcholine degrading enzyme, which is well known as an enzyme closely related to cognitive impairment. Chebulanin may be usefully used for the prevention, improvement or treatment of cognitive impairment-related diseases. It confirmed that there was.

As used herein, the term "chebulanin" refers to a compound having the structure of Formula 1 below. Chebulanin is known to have an effect on arthritis, but it is not known for its memory improvement or treatment effect of cognitive impairment-related diseases, it was first identified by the present inventors.

[Formula 1]

The method of obtaining chebulanin is not particularly limited, and chemically synthesized using a method known in the art, or a commercially available material may be used.

In addition, the compounds may exist in solvated or unsolvated form, and may exist in crystalline or amorphous form, all such physical forms are within the scope of the present invention.

The term "cognitive disorder related disease" in the present invention refers to a disease caused by a decrease in cognitive function (cognitive ability) such as memory ability, space-time grasping ability, judgment ability, language ability, calculation ability, etc. by brain injury. Specific examples may include dementia, Alzheimer's disease or memory impairment, and more specifically, the dementia may be vascular dementia or Alzheimer's dementia, but is not limited thereto. The exact pathogenesis and cause of cognitive impairment is not known, but at present, synaptic plasticity due to brain damage such as basal forebrain, white matter, hippocampus, the amount of NMDA receptor expression, memory related factors, and nerve inflammation It is known that this is the cause of the onset.

Dementia is a condition in which cognitive function is impaired by various causes, and various sub-diseases exist depending on the cause. Specific examples include senile dementia, Alzheimer's disease, vascular dementia, Lewy body dementia, frontal lobe dementia, Parkinson's dementia, and Huntington's dementia.

Alzheimer's disease is the most common degenerative brain disease that causes dementia. It is a disease that gradually develops and progressively worsens cognitive function. Cognitive impairment symptoms include memory loss, decreased language ability, impaired ability to understand space and time, decreased judgment and performance of daily living, gait disorder, and behavioral impairment.

A memory disorder is a pathological condition in which it is difficult or very impossible to remember things or to recall past experiences. Memory disorders include forgetfulness, instantaneous memory loss, short-term memory loss, long-term memory loss, and transient memory disorders.

As used herein, the term "prevention" refers to any action that inhibits or delays a cognitive impairment-related disease by administration of a composition comprising the chebulanine or a pharmaceutically acceptable salt thereof.

As used herein, the term "treatment" refers to any action in which the symptoms of cognitive impairment-related diseases are improved or advantageously modified by administration of a composition comprising the chebulanine or a pharmaceutically acceptable salt thereof.

Prevention or treatment of cognitive impairment-related diseases of the composition may be achieved by acetylcholine degrading enzyme inhibition.

Neurodegenerative disorders that cause progressive loss of cognitive function and memory, such as cognitive impairment, have a variety of causes, but one of them is known to be caused by damage to the acetylcholine neurons in the base of the cerebral base. Agonists, acetylcholine production promoters, and acetylcholine for muscarinic acetylcholine receptors, which have been shown to prevent degradation of choline and improve the reduced cognitive function by maintaining acetylcholine levels at synapses. Depending on various mechanisms of action, such as inhibitors of acetylcholinesterase (AChE), drugs that can enhance the function of acetylcholine neurons have been developed. Indeed, the treatment of Alzheimer's disease currently used in various countries is the most of these inhibitors of acetylcholine degrading enzymes, such as tacrine (donrinezil) and donepezil (donepezil). In addition, rivastigmin and galatamine are used.

In a specific embodiment of the present invention, the acetylcholine degrading enzyme inhibitory activity of chebulanin was measured. As a result, chebulanin showed an inhibitory activity in a concentration-dependent manner, showing an IC ₅₀ of 21.36 μM, showing excellent inhibitory activity even at low concentrations. It was confirmed (FIG. 2).

As used herein, the term “pharmaceutically acceptable salts” refers to salts that can be used pharmaceutically, even among salts in which cations and anions are bound by electrostatic attraction. Salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), aluminum salt, or the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N-dibenzylethylenediamine Salts and the like; Salts with inorganic acids can be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like; Salts with organic acids can be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; Salts with basic amino acids can be salts with arginine, lysine, ornithine and the like; Salts with acidic amino acids can be salts with aspartic acid, glutamic acid and the like.

The pharmaceutical composition of the present invention may include chebulanin or a pharmaceutically acceptable salt thereof in an amount of 0.01 to 80%, specifically 0.01 to 70%, and more specifically 0.01 to 60% by weight, based on the total weight of the composition, but prevention of dementia Or as long as it exhibits a therapeutic effect.

In addition, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient or diluent commonly used in the manufacture of the pharmaceutical composition, the carrier may comprise a non-naturally occuring carrier (carrier) have. Specific examples of the carrier, excipient, and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate or mineral oil may be used, but is not limited thereto.

In addition, the pharmaceutical composition may be a tablet, a pill, a powder, a granule, a capsule, a suspension, a solution, an emulsion, a syrup, a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilizer and a suppository, respectively, according to a conventional method. It may have any one formulation selected from the group consisting of, and may be various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Tablets, pills, powders, granules, capsules and the like may be used for the solid preparation for oral administration, and the solid preparation may be at least one excipient such as starch, calcium carbonate, sucrose or lactose, Gelatin and the like can be used. In addition to the simple excipients, lubricants such as magnesium stearate, talc and the like can be used. As a liquid preparation for oral administration, suspending agents, liquid solutions, emulsions, syrups, etc. may be used.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be used. Can be used. For parenteral administration, sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations or suppositories may be used. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like may be used, but are not limited thereto.

Another aspect of the invention provides a method of treating a cognitive disorder related disease, comprising administering the composition to a subject suspected of a cognitive disorder related disease.

At this time, the definition of the "cognitive disorder related diseases" and "treatment" is as described above.

As used herein, the term "administration" means introducing the pharmaceutical composition to an individual in a suitable manner.

As used herein, the term "individual" refers to all animals, such as rats, mice, and livestock, including humans, who may or may have developed cognitive impairment-related diseases. As a specific example, it may be a mammal including a human.

The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount.

The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level refers to the type and severity of the subject, severity, age, sex, activity of the drug, Sensitivity to drug, time of administration, route of administration and rate of release, duration of treatment, factors including concurrent use of drugs, and other factors well known in the medical arts.

The pharmaceutical composition may be administered as a separate therapeutic agent or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. In addition, single or multiple administrations can be made. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects, which can be easily determined by those skilled in the art.

In addition, the pharmaceutical composition may be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally, or topically) according to a desired method, and the dosage is based on the condition and weight of the patient, and the degree of disease. Depending on the drug form, route of administration, and time, it may be appropriately selected by those skilled in the art. As a specific example, the pharmaceutical composition may generally be administered in an amount of 0.001 to 1000 mg / kg, more specifically 0.05 to 200 mg / kg, most specifically 0.1 to 100 mg / kg once a day or several times. However, the preferred dosage may be appropriately selected by those skilled in the art depending on the condition and weight of the individual, the severity of the disease, the form of the drug, the route of administration and the duration.

Another aspect of the present invention provides a nutraceutical composition for preventing or ameliorating cognitive impairment-related diseases, including chebulanin or a physiologically acceptable salt thereof as an active ingredient.

Another aspect of the present invention provides a nutraceutical composition for learning, cognitive function, or memory improvement, comprising chebulanin or a physiologically acceptable salt thereof as an active ingredient.

At this time, the definition of "chebulanin", "cognitive disorders related diseases" and "prevention" is as described above.

As used herein, the term "learning" refers to the ability or behavior to perceive and change one's own behavior and includes spatial perception, cognition, concentration, and the like.

As used herein, the term "cognitive function" refers to an ability to acquire, maintain, and utilize information, and includes cognitive ability such as memory ability, space-time grasping ability, judgment ability, language ability, and computing ability.

The term "memory" or "memory" of the present invention refers to the ability to acquire new information, learned experience, and knowledge from the surrounding environment, encode and store it in a specific part of the brain, and recall it.

As used herein, the term “physiologically acceptable salts” is a physiologically acceptable and when administered to an organism, the compound to be administered does not normally cause an allergic or similar reaction, such as gastrointestinal disorders, dizziness, or the like. It means that it is commonly used to exhibit the effect.

As used herein, the term "improvement" refers to any action that at least reduces the parameters associated with the condition to be treated with the administration of a composition comprising chebulanin, such as the extent of symptoms.

Chebulanin according to the present invention can exhibit a memory improvement or enhancement effect by inhibiting acetylcholine degrading enzymes known to affect memory disorders, thereby preventing or improving cognitive impairment-related diseases; Or it may be included in the nutraceutical composition for the purpose of improving learning, cognitive function, or memory, the nutraceutical composition can prevent or improve cognitive impairment-related diseases because it is possible to take daily; Or high effects on learning, cognitive function, or memory improvement.

As used herein, the term "health functional food" refers to a food prepared and processed using raw materials or ingredients having functional properties useful for the human body according to Act No. 6767 of the Health Functional Food Act. It means to obtain useful effects on health use such as nutrient regulation or physiological action on structure and function. On the other hand, health food refers to foods that have active health maintenance or promotion effect compared to general foods, and health supplement food means foods for the purpose of health supplement, in some cases, the term functional health food, health food, health supplement food Can be used interchangeably.

Chebulanine of the present invention may be added as it is or used with other food or food ingredients, and may be appropriately used according to conventional methods.

The health functional food composition of the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art. Specifically, the nutraceutical composition may further include a physiologically acceptable carrier, the type of carrier is not particularly limited and may be used as long as it is a carrier commonly used in the art.

In addition, the health functional food composition is a food, such as preservatives, fungicides, antioxidants, colorants, coloring agents, bleaches, seasonings, sweeteners, flavorings, swelling agents, reinforcing agents, emulsifiers, thickeners, coatings, gum herbicides, foam inhibitors, solvents, improvers May include additives. The additive may be selected according to the type of food and used in an appropriate amount.

In addition, the formulation of the health functional food can be prepared without limitation as long as the formulation is recognized as food. The health functional food composition of the present invention can be prepared in a variety of dosage forms, unlike the general medicine because it has the advantage that there is no side effect, such as may occur when taking a long-term use of the food as a raw material and excellent portability, The food of the present invention can be ingested as an adjuvant for enhancing the effect of preventing or ameliorating a cognitive disorder-related disease.

Chebulanin of the present invention can be used for the prevention or amelioration of diseases related to cognitive impairment; Or if it can show the effect of learning, cognitive function, or memory can be included in the dietary supplement composition in various weight percent. Specifically, it may be included as 0.00001 to 100% by weight or 0.01 to 80% by weight relative to the total weight of the dietary supplement composition, but is not limited thereto. In the case of long-term intake for health and hygiene purposes, it may include the content below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

Another embodiment provides a feed composition for preventing or ameliorating a cognitive disorder-related disease, comprising chebulanin or a physiologically acceptable salt thereof as an active ingredient.

In this case, the definitions of "chebulanine", "physiologically acceptable salt", "cognitive disorder related disease", "prevention" and "improvement" are as described above.

As used herein, the term "feed" means any natural or artificial diet, one meal, or the like or any ingredient of the one meal for the animal to eat, ingest, and digest.

The kind of the feed is not particularly limited, and may be used a feed commonly used in the art. Non-limiting examples of the feed may include plant feeds such as cereals, fruits, food processing by-products, algae, fibres, pharmaceutical by-products, oils, starches, gourds or grain by-products; And animal feeds such as proteins, minerals, fats and oils, minerals, fats and oils, single cell proteins, zooplankton or foods. These may be used alone or in combination of two or more thereof.

Feed composition of the present invention can be prepared in various forms known in the art. In addition, it may further include a substance that exhibits various effects such as supplementation of nutrients and prevention of weight loss, enhancement of digestive availability of fiber in the feed, improvement of oil quality, prevention of reproductive disorder and conception, and prevention of high temperature stress in summer. For example, mineral preparations such as sodium bicarbonate, bentonite, magnesium oxide, composite minerals, mineral preparations such as trace minerals such as zinc, copper, cobalt and selenium, keratin, vitamin E, vitamins A, D, E, Vitamins such as nicotinic acid and vitamin B complexes, protective amino acids such as methionine and lyric acid, protective fatty acids such as fatty acid calcium salts, probiotics (lactic acid bacteria), yeast cultures, fungi fermentation products such as fungi and yeasts It may be included as.

Chebulanin of the present invention exhibits an inhibitory effect on acetylcholine degrading enzymes, thereby maintaining the concentration of acetylcholine at the synapse, thereby preventing damage to cholinergic nerves and improving cognitive function. It can be useful for treatment or learning, cognitive function, memory improvement.

1 is a graph showing the inhibitory effect of acetylcholine degrading enzyme and butyrylcholine degrading enzyme of Gaza extract-derived compound.
Figure 2 is a graph showing the inhibitory effect of acetylcholine degrading enzyme for each concentration of chebulanin.
3 is a graph showing the results of NMR analysis for chebulanin.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as limited by these examples.

Example 1 Isolation of Chebulanine

1-1. Gaza Extract Manufacturer

1.8 kg of Terminalia chebula was immersed in methanol for 12 hours at room temperature to obtain a methanol extract. The extract was filtered and lyophilized to give 652.3 g of dried product of the extract.

1-2. Fraction and Compound Separation from Gaza Extract

Solvent fractionation and column chromatography were performed on the dried product of Gaza extract obtained in Example 1-1 to obtain a fraction. The dried product (652.3 g) was diluted with distilled water (4 L), partitioned with n-hexane (3.1 g), CHCl ₃ (4.1 g) and n-BuOH (350.4 g), and then 4 sub-orders from the n-BuOH fraction HP-20 resin (1.6) eluted sequentially with gradient of MeOH: H ₂ O (25:75, 50:50, 75:25, 100: 0, 8 L each) to yield fractions (B1 to B4) kg) applied to CC. The obtained subfractions were separated by further fractionation using an MPLC or HPLC column and the like (LEE, Dong Young, et al., Phytochemistry , 2017; LEE, Dong Young, et al., Bioorganic & medicinal chemistry letters , 2017 Reference). Compounds were separated according to the same method as described above to isolate 48 hydrolysable tannins and 12 polyhydroxytriterpenoid derivatives (Table 1). Chebulanin yielded 70 mg (about 0.01% separation yield).

Experimental Example 1. Analysis of acetylcholine degrading enzyme inhibitory effect of Gaza extract-derived compound

The inhibitory effects of acetylcholine degrading enzyme and butyrylcholine degrading enzyme on the 60 compounds isolated in Example 1-2 were confirmed using a kit based on the Ellman method (Ellman et al., 1961). .

As a result, as shown in Fig. 1 and Table 1, it was confirmed that chebulanin in the Gaza extract-derived compound showed the best inhibition rate of acetylcholine degrading enzyme (47.7 ± 5.8%).

compound Inhibitory activity
(% At 10 μM) IC ₅₀ value
(μM) division name AChE AChE One Gallic acid - NT 2 Methyl gallate - NT 3 4-O-Galloyl-(-)-shikimic acid - NT 4 5-O-Galloyl-(-)-shikimic acid - NT 5 Digallic acid - NT 6 6-O-Galloyl-D-glucose - NT 7 1,3-Di-O-galloyl-β-D-glucose - NT 8 1,6-Di-O-galloyl-β-D-glucose - NT 9 3,6-Di-O-galloyl-D-glucose - NT 10 1,3,6-Tri-O-galloyl-β-D-glucose - NT 11 3,4,6-Tri-O-galloyl-D-glucose - NT 12 1,2,3,6-Tetra-O-galloyl-β-D-glucose - NT 13 1,3,4,6-Tetra-O-galloyl-β-D-glucose - NT 14 1,2,3,4,6-Penta-O-galloyl-β-D-glucose 17.9 ± 4.0 NT 15 Corilagin - NT 16 Tercatain 7.2 ± 0.7 NT 17 Gemin D 0.5 ± 1.2 NT 18 Telimagrandin i 18.8 ± 3.7 NT 19 Punicacortein C 17.0 ± 2.0 NT 20 Punicacortein D 13.8 ± 0.2 NT 21 Punicalagin 7.1 ± 3.9 NT 22 Terflavin A 23.1 ± 6.9 NT 23 Chebulic acid 22.1 ± 6.6 NT 24 11-methyl chebulate 17.3 ± 7.2 NT 25 13-methyl chebulate 22.6 ± 9.4 NT 26 Brevifolincarboxylic acid 19.2 ± 2.7 NT 27 Phyllanemblinin E 16.4 ± 6.4 NT 28 6'-O-Methyl neochebulanin 19.9 ± 2.7 NT 29 1'-O-Methyl neochebulinate 12.8 ± 3.6 NT 30 Dimethyl neochebulinate 28.4 ± 2.2 NT 31 Neochebulagic acid 25.4 ± 9.6 NT 32 6'-O-methyl neochebulagate 35.7 ± 10.4 > 200 33 Dimethyl neochebulagate 32.6 ± 6.6 > 200 34 Dimethyl 4'-epi-neochebulagate 37.9 ± 3.1 > 200 35 Phyllanemblinin F 44.4 ± 5.6 24.02 36 Chebulanin 47.7 ± 5.8 21.36 37 Chebulinic acid - NT 38 Chebulagic acid - NT 39 Methyl chebulagate 9.0 ± 6.0 NT 40 Ellagic acid 5.9 ± 10.3 NT 41 Eschweilenol C 11.3 ± 2.0 NT 42 4-O- (4 "-O-galloyl-α-L-rhamnopyranosyl) ellagic acid 16.2 ± 6.1 NT 43 4-O- (3 ", 4" -Di-O-galloyl-α-L-rhamnopyranosyl) ellagic acid 22.2 ± 6.0 NT 44 4-O- (2 ", 4" -Di-O-galloyl-α-L-rhamnopyranosyl) ellagic acid 17.8 ± 2.5 NT 45

-D-glucose2-O-cinnamoyl-1,6-di-O-galloyl-

-D-glucose - NT 46 1,2-di-O-galloyl-6-O-cinnamoyl-

-D-glucose - NT 47 1,2,3-tri-O-galloyl-6-O-cinnamoyl-β-D-glucose 8.2 ± 2.6 NT 48 1,3,4,6-tetra-O-galloyl-2-O-cinnamoyl-β-D-glucose - NT 49 Arjungenin - NT 50 23-Galloyl arjunic acid - NT 51 Arjunglucoside I 27.4 ± 1.1 NT 52 Quercotriterpenoside I 30.5 ± 6.8 > 200 53 Terminolic acid 29.6 ± 0.2 189.59 54 Arjunolic acid 39.2 ± 7.1 126.63 55 23-Galloyl arjunolic acid 45.3 ± 4.3 67.25 56 Arjunetin (= 24-deoxy sericoside) 42.4 ± 3.2 47.85 57 23-Galloylarjunolic acid 28-O-β-D-glucopyranosyl ester 30.3 ± 4.1 117.17 58 Arjunic acid 31.6 ± 3.5 > 200 59 Arjunglucoside ii 9.9 ± 2.1 NT 60 pinfaenoic acid 28-O-β-D-glucopyranosyl ester 15.1 ± 2.7 NT Donepezil ^c 97.2 ± 0.6 0.099

Experimental Example 2. Analysis of acetylcholine degrading enzyme inhibitory effect by chebulanin concentration

In order to confirm the effect of inhibiting acetylcholine degrading enzyme according to the concentration of chebulanin, the effect of inhibiting acetylcholine degrading enzyme was determined using the same method as Experimental Example 1 for various concentrations of chebulanine.

As a result, as shown in Figure 2, chebulanin showed a concentration-dependent inhibitory effect, IC ₅₀ was 21.36μM was confirmed that the excellent inhibitory effect even at a low concentration.

Therefore, the chebulanin can prevent the damage of cholinergic nerves by maintaining the concentration of acetylcholine at the synapse through the inhibitory effect on acetylcholine degrading enzymes, thereby improving the reduced cognitive function, thereby causing cognitive impairment-related diseases. It can be used for treatment or learning, cognitive function, memory improvement.

Experimental Example 3. Chebulanine NMR Analysis

In order to specifically identify chebulanin separated by Example 1, ¹ H-NMR and ¹³ C-NMR spectral analysis were performed.

As a result, the ¹ H-NMR signal (300 MHz, CD ₃ OD) is δ 7.45 (1H, s , Cheb-H-2 "), 7.13 (1H, s , Gal-H-2 ', 6'), 6.37 (1H, d , J = 2.8 Hz, H-1), 5.22 (1H, m , H-2), 5.10 (1H, dd , J = 1.5, 7.2 Hz, Cheb-H-3 '), 4.82 (1H , m , H-4), 4.81 (1H, m , H-3), 4.78 (1H, m , Cheb-H-2 ') 4.30 (1H, dt , J = 12.4, 6.4 Hz, H-5), 4.04 (2H, m, H-6), 3.81 (1H, ddd , J = 1.0, 4.1, 5.5 Hz, Cheb-H-4 '), 2.15 (2H, m , Cheb-H-5') , ¹³ C-NMR signal (75 MHz, CD ₃ OD) is δ 174.8 (Cheb-C-6 '), 174.6 (Cheb-C-7'), 170.7 (Cheb-C-1 '), 166.6 (Gal- C-7 '), 166.4 (Cheb-C-7 "), 147.1 (Cheb-C-3"), 146.5 (Gal-C-3', 5 '), 141.2 (Cheb-C-5 "), 140.4 (Gal-C-4 '), 140.0 (Cheb-C-4 "), 120.4 (Gal-C-1'), 119.4 (Cheb-C-1"), 117.3 (Cheb-C-2 "), 115.9 (Cheb-C-6 "), 110.4 (Gal-C-2 ', 6'), 92.9 (C-1), 79.4 (C-5), 74.1 (C-2), 72.0 (C-4), 67.0 (Cheb-C-2 '), 63.5 (C-6), 61.6 (C-3), 41.4 (Cheb-C-3'), 39.9 (Cheb-C-4 '), 30.1 (Cheb-C- 5 ').

In addition, as shown in FIG. 3, the analysis of the section in which the main peak of the signal appears, it was confirmed that the structure of chebulanin separated from the compound is consistent with the structure of the known chebulanin of formula (1).

Therefore, it was confirmed that the compound isolated in Example 1 is chebulanin.

Taken together, chebulanin contained in traces of Gaza extract (70mg out of 652.3g) showed superior inhibitory effect of acetylcholine degrading enzyme compared to other compounds derived from Gaza extract, so that chebulanin may have dementia treatment or memory improvement effects. Suggests that you can.

In the present specification, those skilled in the art of the present disclosure can fully recognize and infer the details thereof, and the detailed descriptions thereof have been omitted, and the technical spirit or essential configuration of the present invention may be changed in addition to the specific examples described herein. More variations are possible without departing from the scope of the invention. Therefore, the present invention can be implemented in a manner different from that specifically described and illustrated herein, which can be understood by those skilled in the art.

Claims (11)

Chebulanin (chebulanin) or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutical composition for the prevention or treatment of cognitive disorders related diseases.
According to claim 1, wherein the chebulanin is represented by the following formula (1), pharmaceutical composition.
[Formula 1]

The pharmaceutical composition of claim 1, wherein the cognitive disorder related disease is one or more selected from the group consisting of dementia, Alzheimer's disease and memory disorder.
The pharmaceutical composition of claim 1, wherein the dementia is vascular dementia or Alzheimer's dementia.
The pharmaceutical composition of claim 1, wherein the prevention or treatment of the cognitive disorder-related disease is achieved by an acetylcholine degrading enzyme inhibitory effect.
The pharmaceutical composition of claim 1, wherein the composition comprises 0.01 to 80% by weight of the compound.
The pharmaceutical composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.
A method of treating dementia comprising administering the pharmaceutical composition of any one of claims 1 to 7 to a suspected subject related to a cognitive impairment other than a human.
Chebulanin (chebulanin) or a physiologically acceptable salt thereof as an active ingredient, a health functional food composition for preventing or improving diseases related to cognitive disorders.
Chebulanin (chebulanin) or a physiologically acceptable salt thereof as an active ingredient, a health functional food composition for learning, cognitive function, or memory improvement.
Chebulanin (chebulanin) or a physiologically acceptable salt thereof as an active ingredient, cognitive disorders related diseases prevention or improvement of feed composition.

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