KR100912290B1 - Novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof, preparation method thereof and effective thereof Hangover Relief Composition Containing Ingredients - Google Patents

Abstract

The present invention is a novel 6,8-di (γ, γ-dimethylallyl) -3,5 having an alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) activation and blood alcohol elimination for hangover relief The present invention relates to a novel compound according to the present invention, wherein the present invention relates to a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a method for preparing the same, and a composition for releasing hangover containing the same as an active ingredient. Phosphorus 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof may resolve hangovers and decompose alcohol It increases the activity of alcohol dehydrogenase and acetaldehyde dehydrogenase involved in the acute toxicity, and is safe from the separation from natural products, so it can be useful for liver protection or hangover drink and preparation.

Hemp Ginseng, Hangover Relief, Alcohol Dehydrogenase, Acetaldehyde Dehydrogenase, Flavonoids, 3-Hydroxy-Kenusanone B, Liver Protection

Description

Novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof, preparation method thereof and effective thereof Hangover-relieving composition containing as an ingredient {Novel 6,8-di (γ, γ-demethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxy- flavanone or 黄 acceptable salt etc, preparation method and composition for removing hangover containing the same as an active ingredient}

The present invention provides a novel 6,8-di (γ, γ-dimethylallyl) -3,5,7, which has an alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) activation and blood alcohol elimination for hangover relief. It relates to 2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof, a method for preparing the same and a composition for relieving hangover containing the same as an active ingredient.

In Korea's drinking culture, many people are showing high interest in drugs or beverages that can eliminate hangovers due to heavy drinking and frequent drinking.

A hangover is a headache, diarrhea, anorexia, nausea, vomiting, chills, or cold sweating after drinking alcohol. Objective symptoms include perception, decreased motor performance, hematologic changes, and changes in hormones. The causes of hangovers are known as dehydration, toxicity of alcohols and alcohol metabolites (acetaldehyde, formaldehyde, acetone, etc.), and nutrient deficiencies due to malabsorption (lack of blood sugar, vitamins, minerals). The degree of hangover is very different depending on the individual's genetic variation, environmental conditions (nutrition, exercise, dehydration, health).

After drinking alcohol is absorbed in small amounts in the esophagus and oral mucosa, about 10% in the stomach 90% in the small intestine. Alcohol is metabolized through three pathways. When the concentration of ethanol is low, alcohol dehydrogenase and acetaldehyde dehydrogenase, which are present in the gastrointestinal tract or liver, acts on the endoplasmic reticulum. It is metabolized to acetaldehyde and acetic acid by the existing microsomal ethanol oxidizing system (MEOS), and then through the action of catalase present in the peroxisome, carbon dioxide (CO ₂ ) and Final decomposition into water (H ₂ O). When the proper amount of alcohol is introduced, the metabolic system described above works smoothly and does not cause any symptoms caused by alcohol. However, when a large amount of alcohol is introduced, the balance of the metabolic system is destroyed and thus the homeostasis cannot be maintained. Under these circumstances, the most affected organs are the liver. In the long term, various liver dysfunctions such as fatty liver and cirrhosis occur, and short-term symptoms include headache or double head, loss of concentration, heartburn and indigestion.

In order to relieve hangovers, bean sprouts soup and northern fish soup have been used since ancient times. In particular, bean sprouts contain abundant aspartic acid, which is known to protect the liver by promoting the action of alcohol dehydrogenase and promoting alcohol breakdown, and the early hangover drinks were made and sold with aspartic acid as the main ingredient.

Currently, hangover drinks are available from Jagi, Astragalus, Lotus seed, rice germ, etc. (CJ Co., Ltd.), Dimkyu (Ceun Kun Dang) based on high-purity chitosan, Dawn tree, and rowan extract 808 ( Dozens of papers are sold, and research publications and patents have been filed. In particular, as a result of comparing the functions of each product recently, it can be used for propaganda and advertisement, the change of blood ethanol and acetaldehyde concentration in animals or human body, the activity of enzymes related to blood liver function (ALT, AST, ALP, etc.) Simple clinical studies on changes, hangovers, etc. have been conducted by each company individually. Materials of the earth, neck, fruit extract, persimmon extract, green tea extract, ginseng (red ginseng) extract, etc. are being studied.

Most of the research on hangover is done through animal experiments in Korea. Japan is focusing on the development of materials to relieve hangovers, while the United States and Europe are actively engaged in research on the symptoms of poisoning of ethanol (methanol), toxic agents and toxic mechanisms. In particular, the structure of tetrahydroisoquinoline or tetrahydro-beta-carbolines produced by metabolism of ethanol is similar to that of morphine, resulting in withdrawal symptoms. Induce. This is known to be due to a decrease in ethanol metabolizing enzymes and in part to a decrease in the response of brain neurons. Recently, the metabolism of methanol and formaldehyde in small amount of alcohol (ethanol) has been pointed out as a cause of hangover, and the actual alcohol hangover is reported to be due to alcohol metabolism, acetaldehyde, acetone, etc. It is entering (Moser J, Bagchi D, Akubue PI, Stohs SJ .. Alcohol Alcohol . 28: 287-295, 1993). In Japan, there was a patent claim that fermentation products of rice bran extract contributed to lower acetaldehyde concentration than blood alcohol concentration.In the case of severe hangover symptoms, acetaldehyde concentration was higher than those with low hangover symptoms. There have been few reports, focusing on acetaldehyde as the causative agent of alcohol hangovers.

Looking at the patents on the existing hangover, it is in the form of beverages, health functional foods, chewing gum, etc., and the raw materials used are silk fibroin (Korean Patent No. 0528740), Ogapi, Root, Chinese quince, cherry tree, low head river (Korea) Registered Patent No. 0528388), wormwood, goji berry, health, dermis, lotus root, earth, lettuce, Schisandra chinensis (Korean Registered Patent No. 0512912), astaxanthin, aspartic acid (Korean Registered Patent No. 0520985), persimmon leaf, persimmon (Korean Registered Patent No. 0504351), Dermis, Baekbokyeong, Injin, Galhwa, Kaleun (Korean Registered Patent No. 0500373), Asparagus, Green Tea, Onion, Plum (Korean Registered Patent No. 0496524), Dharm (Korean Registered Patent No. 0462329 No.), soybeans, bean sprouts, grape seeds (Korean Patent No. 0455075), cricket (Korean Patent No. 0453475), active ingredient Hobe nodulinol (Korean Patent No. 0452128), radish Mugwort, 칡, persimmon leaf, three hundred seconds (Republic of Korea Patent No. 0451013), Decusinol (Republic of Korea Patent No. 0448680), Earth, earth tree, hut tree mixture, brown root, Baek Ha Shou, mountain medicine, Peony (Korea Registered Patent No. 0446061), Baekmo-geun, Audi, Tosa, Gallium, Creation, Bokbunja, Snakeberry, Branched grass, Gil-core (Korean Registered Patent No. 0442771), Pine Needles (Republic of Korea Registered Patent No. 0412425), Bark Wood, etc. (Registered in Korea) Patent No. 0403720-22), Brown, Big Thistle Seed, Taurine, Ulgeum (Republic of Korea Registered Patent No. 0392876), Narinjin, Naringenin (Republic of Korea Patent No. 0375047), Alder, Rowan (Republic of Korea Patent No. 0181168) ). Raw materials used in other applied patents include horseshoe mushrooms, green tea catechins, ogapi, palm cactus (baekryoncho), cheonma, roe deer mushrooms, chodugu, propolis, jakhwaksu, falcon, sesame oil and the like. However, until now, the hangover, food, chewing gum and the like have been developed using the above materials, but the effect is almost outstanding.

All aerobic organisms, including humans, survive through energy metabolism using oxygen (O ₂ ). However, when oxygen in the body is subjected to various physical, chemical and biological stresses, harmful substances such as superoxide anion radical (O ₂ −), hydrogen peroxide (H ₂ O ₂ ) and hydroxy radicals (OH) It turns into active oxygen species, causing fatal physiological disorders in the body and, in severe cases, causing disease and losing life.

Although living organisms are thought to have evolved from the self-defense mechanism that removes reactive oxygen species, developing antioxidant mechanisms, the generation of reactive oxygen species that transcends the defenses of tissues is not immune to proteins, DNA, enzymes and T cells. Damage to the system factors cause various diseases. In addition, reactive oxygen species attack perunsaturated fatty acids that are components of cellular membranes, causing peroxidation reactions, and lipid peroxides accumulated in vivo are known to cause aging and various diseases (Halliwell, B., Drugs 42: 569). , 1999;.. Fukuzawa, K and Takaishi, Y., J. Act Dxyg Free Rad . 1:55, 1990; Neuzil, J., Gebicki, JM and Stocker, R., Biochem. J. 293: 601, 1993; Sies, H., ed., Oxidative stress , 1985; Steinberg. D., et al., N. Engl . J. Med . 320: 915. 1989).

Recently, as the theory that aging and geriatric diseases are caused by reactive oxygen species has been recognized, research on the development of antioxidants known as substances capable of regulating reactive oxygen species has been actively conducted, and superoxide dismutase Antioxidants such as oxidase, catalase, and glutathione peroxidase, antioxidant enzymes such as tocopherol, ascorbate, carotenoid, and glutathione Much research has been done on (Chang, SS, et al ., J. Food Sic . 42: 1102, 1977; Hammerschmidt, PA and Pratt, DE, J. Food Sic . 43: 556, 1964), synthetic antioxidants such as 2,6-di-tert-butyl-4-hydroxyanisole (BHA) have been developed. It is used in the food field (Kitahara, K., et al ., Chem Pharm . Bull . 40: 2208, 1992; Hatano, T., Natural Medicines 49: 357, 1995; Masaki, H., et al ., Biol . Pharm . Bull. 18: 162, 1995).

However, consumer avoidance of synthetic antioxidants and carcinogenicity have been reported in animal experiments in which large amounts of synthetic antioxidants have been administered (Branen, AL, JAOCS 52:59, 1975). The use of synthetic antioxidants is increasingly limited. As such, there is an urgent need to develop new natural antioxidants that are both effective and safer.

Echinosophora koreensis It is an outpost of the legumes nectarine. It is also called ant grass, red ginseng tree, cedar tree, and stick of thief. It is distributed in the north of Yang-gu, Gangwon-do, Pyeongannam-do, and Hamgyongnam-do. It is a deciduous shrub in the foothills or roadsides. The plant multiplies under the ground and its branches are dark brown and hairy. Winter snow is covered with fur and invisible. Leaves are pinnate, leaves are 13-25 sheets, leaf surface is white, hairy, long oval shape, blunt, hairy edge. Chin leaves do not fall into thorns. In May, yellow flowers bloom in turn. Inflorescences are 3-5 cm long, hanging from the end of a new branch, with a flower about 15 mm in diameter. Small vesicles are basso, black, with hairs. The calyx is divided into 5 pieces and the rear two are slightly smaller. Contains alkaloids and flavonoids. Current antimicrobial effects (Sohn, H.-Y. et al ., Phytomedicine . 11: 666-672, 2004) and antimicrobial effects on MRSA (Hironori T et al ., J. Ethnopharmacol . 5027-5034, 1996). In addition, the extract showed excellent radical scavenging ability, and increased the activity of alcohol dehydrogenase and acetaldehyde dehydrogenase to promote alcohol metabolism in vivo, thereby reducing blood alcohol concentration and acetaldehyde concentration. Has been disclosed in the extract of Echinosophora japonica having anti-drunken and antioxidant functions.

However, in the case of flavonoid compounds of the isolated material from the Echinacea, various physiological activities have been reported, but there are no reports on the alcohol dehydrogenase and hangover related physiological activities.

Accordingly, the present inventors have isolated a new compound from the cedar, and the compound increases the activity of alcohol dehydrogenase and acetaldehyde dehydrogenase to promote alcohol metabolism in vivo to reduce blood alcohol concentration and acetaldehyde concentration, thereby protecting liver and hangover. The present invention was completed after confirming the effect on elimination.

It is an object of the present invention to provide novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof. There is.

Another object of the present invention is that of the novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof It is to provide a manufacturing method.

Still another object of the present invention is the novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable thereof. It is to provide a liver protection or hangover relief composition containing a salt as an active ingredient.

In order to achieve the above object, the present invention provides a novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutical thereof Provide acceptable salts.

The present invention also provides the preparation of the novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof. Provide a method.

Furthermore, the present invention provides the novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof. Provided is a hepatoprotective or hangover-relieving composition containing as an active ingredient.

According to the present invention, 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof according to the present invention It increases the activity of alcohol dehydrogenase and acetaldehyde dehydrogenase involved in hangover resolution and alcohol decomposition and is acutely toxic and safe from natural products, so it can be useful for liver protection or hangover drink and preparation.

The present invention is a novel 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone represented by the following formula (1) Provide acceptable salts.

The compound of Formula 1 according to the present invention is a compound having the properties of a pale yellow amorphous powder having a formula of C ₂₅ H ₂₇ O ₈ and a molecular weight of 457, and is a natural substance. The compound of Chemical Formula 1 may be preferably used by separating and purifying from cedar.

The present invention is 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone represented by Formula 1 or a pharmaceutically acceptable thereof In addition to salts, it includes all possible solvates, hydrates that can be prepared therefrom.

The 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone of the general formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, acid addition salts formed by pharmaceutically acceptable free acid are useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and iodide. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesul Nate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1- Sulfonates, naphthalene-2-sulfonates or mandelate.

The acid addition salts according to the invention are dissolved in conventional methods, for example, by dissolving a compound of formula 1 in an excess of aqueous acid solution and using the water miscible organic solvent, such as methanol, ethanol, acetone or acetonitrile. It can be prepared by precipitation.

Equivalent amounts of the compound of formula 1 and the acid or alcohol in water may be heated and then the mixture is evaporated to dryness or prepared by suction filtration of the precipitated salt.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound of formula 1 in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding silver salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg, silver nitrate).

In addition, the present invention

Echinosophora koreensis in water, C ₁ To C ₄ lower alcohol or a mixed solvent thereof (step 1);

Fractionating the extract extracted in step 1 with hexane, chloroform and butanol in order to obtain a fraction (step 2);

Performing a C18 reverse phase column chromatography on the butanol fraction of the fraction extracted in step 2 using a mixed solution of methanol / water to obtain a methanol / water fraction (step 3); And

Performing C18 reverse phase column chromatography again using a mixture of acetonitrile and water containing 0.02% trifluoroacetic acid as the eluent using the methanol / water fraction obtained in step 3 to obtain a compound of Chemical Formula 1 (step 4) Provided is a method for preparing 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone of Formula (1).

First, step 1 waters the cedar, C ₁ To C ₄ lower alcohol or a mixed solvent thereof.

The Echinacea can be used without limitation, such as cultivated or commercially available, it is used to wash clean and dry. The extraction method may be a conventional extraction method such as ultrasonic extraction, filtration reflux extraction method.

For example, crushed dried Echinacea starch into a suitable size and put into an extraction container C ₁ To lower alcohol of C ₄ or a mixed solvent thereof, preferably methanol or ethanol, and allowed to stand for a while, followed by filtering with a filter paper to obtain an alcohol extract. At this time, the volume of the alcohol solvent is preferably 5 to 10 times. The extraction time is preferably 2 to 24 hours, most preferably 3 hours. Thereafter, a method such as concentration or lyophilization may be additionally performed.

Next, step 2 is a step of obtaining an extract by sequentially fractionating the extract extracted in step 1 to hexane, chloroform, butanol using a commonly known method.

Next, step 3 is a step of obtaining a methanol / water fraction by performing C18 reverse phase column chromatography of the butanol fraction of the fraction extracted in step 2 using a mixed solution of methanol / water.

In step 3, the methanol / water fraction may be performed while increasing the content of methanol with respect to the mixed solvent of methanol and water as eluent. In order to obtain the methanol / water fraction, the concentration gradient is preferably methanol / water (60:40-> 80:20) for 60 minutes, and the methanol / water (80:20) fraction in the fraction thus obtained is added to the next step. Use it.

Next, in step 4, C18 reverse phase column chromatography is re-run by using a mixture of acetonitrile and water containing 0.02% trifluoroacetic acid as the eluent using the methanol / water fraction obtained in step 3 to obtain a compound of formula 1. Step. In the same step as in step 3 using a mixture of acetonitrile and water containing 0.02% trifluoroacetic acid as an eluent to increase the composition of acetonitrile for 60 minutes from 10% acetonitrile / water to 100% acetonitrile Gradients can separate the compounds of formula 1 according to the invention.

Furthermore, the present invention provides 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a hangover relief or hepatoprotective composition containing.

The compound of formula 1 according to the present invention increases the activity of alcohol dehydrogenase (see FIGS. 1 and 2) and acetaldehyde dehydrogenase (see FIGS. 2 and 3) in a concentration-dependent manner, and is commercially available when administered to experimental animals. In vivo alcohol degrading ability equivalent to the hangover drink was present (see Fig. 3 and Table 4). Through this, the compound of formula 1 according to the present invention promotes alcohol metabolism in vivo, effectively reducing blood alcohol concentration and acetaldehyde concentration, and inhibiting the activity of alcohol dehydrogenase and acetaldehyde dehydrogenase which affect liver metabolism and hangover resolution. Increasingly, since there are no side effects, it can be usefully used as a hangover or liver protection agent and health food.

6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof according to the present invention The composition containing the active ingredient can be used in the form of a general pharmaceutical formulation.

That is, 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone of the formula (1) of the present invention is orally and at the actual clinical administration It can be administered in various parenteral formulations. In addition, when formulated, in addition to the compound of Formula 1, which is an active ingredient, it may be prepared by including one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers may be used in combination with saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components, if necessary, as antioxidants, buffers And other conventional additives such as bacteriostatic agents can be added.

Solid preparations for oral administration may include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, in the compound of Formula 1 Sucrose (Sucrose) or lactose (Lactose), gelatin and the like are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used.

In addition, liquid preparations for oral administration include suspending agents, liquid solutions, emulsions, and syrups, and various excipients, for example, wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents, water and liquid paraffin. This may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers, suppositories. 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 butter, glycerogelatin and the like can be used.

Furthermore, the pharmaceutical compositions of the present invention can be administered parenterally, and parenteral administration is by subcutaneous injection, intravenous injection or intramuscular injection. To formulate into a parenteral formulation, the compound of Formula 1 is mixed in water with a stabilizer or buffer to prepare a solution or suspension, which is formulated in unit dosage forms of ampoules or vials.

In addition, the dosage or dosage of the pharmaceutical composition according to the present invention varies depending on the weight, age, sex, health condition, diet, time of administration, administration method, excretion rate and severity of the patient, If the doctor decides to take 250-3000 mg based on the adult at regular intervals once a day or divided into several times.

Furthermore, the present invention provides 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone of the general formula (1) which shows the effect of preventing and improving pain. And it provides a food composition for the prevention and amelioration of pain, including a food acceptable additive.

The food composition of the present invention may be added to health food for the purpose of preventing and treating pain. When using the compound of Formula 1 of the present invention as an additive, the compound of Formula 1 may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be suitably determined depending on the purpose of use (prevention, health or therapeutic treatment). In general, in the preparation of food or beverage, the compound of formula 1 of the present invention is added in an amount of 1 to 20% by weight, preferably 5 to 10% by weight based on the raw materials. However, in the case of long-term intake for health and hygiene or health control, the amount may be below the above range, and the active ingredient may be used in an amount above the above range because there is no problem in terms of safety. .

There is no particular limitation on the kind of food. Examples of foods to which the substance may be added include beverages, gums, vitamin complexes, or health supplements, and include all health foods in the conventional sense.

The beverage composition of the present invention may contain various flavors, natural carbohydrates, and the like as additional components, as in general beverages. The above-mentioned natural carbohydrates are glucose, monosaccharides such as fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol and erythritol. As the sweetening agent, natural sweetening agents such as tautin and stevia extract, synthetic sweetening agents such as saccharin and aspartame, and the like can be used. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 g, preferably about 0.02 to 0.03 g per 100 ml of the composition of the present invention.

In addition, the compositions of the present invention include various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohols, And a carbonation agent used for the carbonated beverage. In addition, the composition of the present invention may contain a flesh for preparing natural fruit juice, fruit juice beverage and vegetable beverage. These components can be used independently or in combination. The proportion of such additives is not critical but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited thereto.

< Example  1> new 6,8-di (γ, γ- Dimethylallyl ) -3,5,7,2 ', 4', 6'- Of hexahydroxyflavanone  Produce

<1-1> From cedar  6,8-di (γ, γ- Dimethylallyl ) -3,5,7,2 ', 4', 6'- Hexahydroxy Extraction, Separation and Purification of Siflavanone

6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone according to the present invention was extracted, isolated and purified from Echinacea as follows. .

1.4 kg of dried Echinacea outpost (collected from Gangwon-do, Korea) was placed in an extraction bag, immersed in 10% of 100% methanol, extracted under reflux for 3 hours, cooled to room temperature, and filtered through a filter paper. The extract was concentrated using a concentrator at 50 ° C. under reduced pressure until the solution evaporated completely to obtain 120 g of alcohol extract.

The alcohol extract was suspended in water, and then partitioned into hexane, chloroform and butanol in order to obtain fractions of 12.5 g, 36.4 g, 5.3 g and 30.5 g, respectively, to obtain 23.0 g of the remaining water fraction.

Then, C18 reversed phase chromatography was performed on 28 g of butanol fraction using a mixture of methanol and water, changing the ratio of methanol and water in a 60:40 to 80:20 volume ratio for 60 minutes. Then, acetonitrile for 60 minutes from 10% acetonitrile / water to 100% acetonitrile using a mixed solution of acetonitrile and water containing 0.02% trifluoroacetic acid with respect to the methanol / water (80:20) fraction was used as the eluent. 100 mg of pure compound was obtained through high performance liquid chromatography separation using a C18 reversed phase column with a concentration gradient to increase the composition of.

<1-2> Structural Analysis of Isolated Compound

In order to analyze the structure of the compound separated in the above <1-1>, the molecular weight and molecular formula of the compound were determined by performing NMR analysis and high resolution mass spectrometry as follows.

Molecular weights and molecular formulas were determined using MS measurements using the Agilent 1100 Fast Fluid Chromatography-Mass Spectrometer (HPLC-ESI-MS) and ¹ H, ¹³ C-NMR spectra using a Nuclear Magnetic Resonator (Varian 500 MHz NMR). The structures were determined by comprehensive analysis of these spectra.

The analysis results are shown in Table 1.

 Constellation  Light yellow amorphous powder  Molecular formula C ₂₅ H ₂₇ O ₈  Molecular Weight m / z 457 [M + H] ⁺  NMR Results ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 1.48 (3H, s, H3-5 '''), 1.55 (3H, s, H3-4'''), 1.61 (3H, s, H3- 4 "), 1.70 (3H, s, H3-5"), 3.05 (1H, br dd, J = 14.5, 7.0 Hz, H-1 '''a), 3.09 (1H, br dd, J = 14.5, 7.0 Hz, H-1 '''b), 3.22 and 3.28 (1H, br dd, J = 14.5, 7.0 Hz, H-1 "a and H-1" b), 5.03 (1H, br t, J, respectively) = 7.0 Hz, H-2 '''), 5.09 (1H, brt, J = 7.0 Hz, H-2 "), 5.20 (1H, dd, J = 12.0, 6.0 Hz, H-3), 5.38 ( 1H, d, J = 12.0 Hz, H-2), 5.47 (1H, d, J = 6.0 Hz, 3-OH), 5.80 (2H, s, H-3 'and H-5'), 9.12 (1H , s, 4'-OH), 9.26 (2H, s, 2'-OH and 6'-OH), 9.49 (1H, s, 7-OH), 12.29 (1H, s, 5-OH) ¹³ C NMR (125 MHz, DMSO-d ₆ ): `` 18.1 (C-5 '''), 18.4 (C-5 "), 21.6 (C-1"), 22.1 (C-1'''), 26.2 ( ^{C-4 ''') a} , 26.3 (C-4 ") a, 69.8 (C-3), 76.5 (C-2), 95.1 (C-3' and C-5 '), 101.2 ( C-4a ), 102.0 (C-1 '), 107.6 (C-8), 108.2 (C-6), 123.2 (C-2'''), 123.6 (C-2 "), 131.0 (C-3"), 131.1 (C-3 '''), 159.0 (C-5), 159.2 (C-4') ^b , 159.3 (C-2 'and C-6') ^b , 159.4 (C-8a), 161.9 (C -7), 201.0 (C-4); a, b exchangeable signals.

As shown in Table 1, the compound isolated and purified in <1-1> was determined as in Chemical Formula 1, and 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ' It was identified as, 4 ', 6'-hexahydroxyflavanone and was named 3-hydroxy-kinusanone B.

< Experimental Example  1> alcohol dehydrogenase ( ADH ) Activity measurement

The enzyme source was dissolved 26.4 mg of freeze-dried rat liver homogenate (MOLTOX Co., USA) in 8 ml of 0.1% bovine serum albumin (BSA) solution with a final concentration of 3.3 mg / ml. It filtered and used with the 0.45 micrometer syringe filter. Alcohol dehydrogenase activity was measured using the rate of NADH production as absorbance at 340 nm. The composition of the reaction solution was 1 ml of distilled water, 0.75 ml of 1 M tris-HCl (pH 8.8), 0.3 ml of 20 nM NAD +, 0.3 ml of ethanol, and a sample (1, 30, 100 µg / ml) according to the present invention. ) And a mixture of 0.15 ml of enzyme source in a cuvette (cuvette) and adjusted to 3 ml in total, followed by a total reaction at 30 ° C. for 5 minutes, and then the change in absorbance at 340 nm for 5 minutes. At this time, the sample was not added as a control. Alcohol dehydrogenase activity of the samples was determined as relative activity (%) relative to the control. The measurement results are shown in FIGS. 1 and 2.

division Alcohol dehydrogenase activity (%) Control 100 Example (1 μg / ml) 101 Example (30 μg / ml) 133 Example (100 μg / ml) 207

As shown in Figure 1 and Table 2, the compound of formula 1 according to the present invention effectively increases the activity of the alcohol dehydrogenase, and it is found that the increase rate of the alcohol dehydrogenase activity increases as the concentration of the added compound is increased. Can be.

Therefore, the compound of Formula 1 according to the present invention can be usefully used for hangover elimination because it reduces the hangover by increasing the activity of alcohol dehydrogenase.

Experimental Example 2 Measurement of Acetaldehyde Dehydrogenase (ALDH) Activity

The enzyme source was dissolved 26.4 mg of freeze-dried rat liver homogenate (MOLTOX Co., USA) in 8 ml of 0.1% bovine serum albumin (BSA) solution with a final concentration of 3.3 mg / ml. It was used by filtration with a 0.45 μm syringe filter. Acetaldehyde dehydrogenase activity was measured using the rate of NADH production at an absorbance of 340 nm. The composition of the reaction solution was 2.1 ml of distilled water; 0.3 ml of 1.0 M Tris-HCl buffer (pH 8.0), 20 mM NAD ⁺ 0.1 ml, 1.0 ml of 1.0 M acetaldehyde; 0.1 ml 3.0 M KCl; 0.1 ml 0.33 M 2-mercaptoethanol; A reaction mixture of 0.1 ml of a sample (1, 20, 50 μg / ml of the compound of Formula 1 according to the present invention) and 0.1 ml of enzyme source were put into a cuvette and adjusted to a total of 3 ml. After the change of absorbance was measured at 340 nm for 5 minutes. At this time, the sample was not added as a control. Acetaldehyde dehydrogenase activity of the samples was measured as relative activity (%) relative to the control. The measurement results are shown in FIG. 2 and Table 3.

division Acetaldehyde dehydrogenase activity (%) Control 100 Example (1 μg / ml) 234 Example (20 μg / ml) 238 Example (50 μg / ml) 253

As shown in Figure 2 and Table 3, the compound of formula 1 according to the present invention effectively increases the activity of acetaldehyde dehydrogenase, and the increase rate of acetaldehyde dehydrogenase activity increases as the concentration of the added compound is increased. It can be seen that.

Therefore, the compound of formula 1 according to the present invention can be usefully used for hangover elimination because it reduces the hangover by increasing the activity of acetaldehyde dehydrogenase.

< Experimental Example  3> Acute Toxicity of Oral Administration in Mice

In order to measure the toxicity of the compound of Formula 1 according to the present invention isolated from Echinosophora japonica in the above example, an acute toxicity test was performed using an experimental animal as follows.

ICR mice weighing 22-25 g were used as experimental animals. The samples were used for pre-breeding for 1 week after free intake of solid samples and tap water. After 18 hours of fasting, 3-hydroxy-kenusanone B of the present invention was prepared orally in 0.7% CMC (Carboxy methyl cellulose) solution at a constant concentration. Thereafter, the mice were killed for 2 weeks by the toxicity of the samples. Experimental results showed that even at a dose of 2000 mg / kg, there is no acute toxicity by 3-hydroxy-kenusanone B according to the present invention, and the minimum lethal dose (LD ₅₀ ) for oral administration is determined to be a safe substance of more than 2000 mg / kg. It became.

< Test Example  4> Ethanol resolution measurement

Experimental animals used magnetic SD (Sprague Dawley) rats weighing 175 ~ 195 g, was used for the test after one week of pre-breeding to allow free intake of solid samples and tap water. After 18 hours of fasting, water was administered as a control group, and the hangover antibacterial beverage commercially available as a comparative group of Example 1 according to the present invention as a test group was added to a 0.7% Carboxy methyl cellulose (CMC) solution at a concentration of 10 mg / ml. It was prepared and administered orally. After 30 minutes, the blood was collected from the heart at 1, 3 and 5 hours after oral administration of alcohol in an amount of 3 g / kg. The collected blood was mixed with perchloric acid in the same amount, centrifuged at 3,000 rpm for 10 minutes, and the supernatant was mixed with 0.5 volume of buffer solution I and left at 4 ° C. for 30 minutes. After removing the protein by centrifugation at 3,000 rpm for 10 minutes, the concentration of ethanol was measured using an ethanol measurement kit (Roche, USA) and shown in Figure 3 and Table 4.

division Blood concentration (%) 1 hours 3 hours 5 hours Control 0.051 0.040 0.041 ethanol 0.305 0.270 0.178 Comparison 0.254 0.161 0.131 Example (Compound of Formula 1) 0.240 0.192 0.127

As shown in Figure 3 and Table 4, the compound of formula 1 (3-hydroxy-kinusanone B) according to the present invention shows that the effect of reducing blood alcohol concentration is equivalent to or more than the commercial hangover beverage Able to know.

Therefore, the compound of Formula 1 according to the present invention can be usefully used for hangover elimination because it reduces the hangover by reducing the blood alcohol concentration.

< Formulation example  1> Preparation of Pharmaceutical Formulations

<1-1> Powder  Produce

2 g of a compound of formula 1

1 g lactose

After mixing the above components, the airtight cloth was filled to prepare a powder.

<1-2> Preparation of Tablet

100 mg of compound of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

<1-3> Preparation of Capsule

100 mg of compound of Formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg magnesium stearate

After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.

<1-4> Preparation of Injection Solution

10 μg / ml of the compound of Formula 1

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

The compound of formula 1 was dissolved in an appropriate volume of sodium chloride BP for injection, and the pH of the resulting solution was adjusted to pH 3.5 with dilute hydrochloric acid BP, and the volume was adjusted with sodium chloride BP for injection and thoroughly mixed. The solution was filled into a 5 ml Type I ampoule made of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclaving at 120 ° C. for at least 15 minutes to prepare an injection solution.

< Formulation example  2> Manufacture of food

<2-1> Preparation of Cooking Seasoning

10 to 15 parts by weight of the compound of formula 1 according to the present invention was prepared by participating in 100 parts by weight of cooking seasoning for hangover.

<2-2> Preparation of Flour Food

0.5 to 5 parts by weight of the compound of Formula 1 according to the present invention was added to 100 parts by weight of wheat flour, and the mixture was used to prepare bread, cake, cookies, crackers, and noodles to prepare foods for health promotion.

<2-3> soup  And juicy ( gravies Manufacturing

0.1 to 5 parts by weight of the compound of formula 1 according to the present invention was added to 100 parts by weight of soup and juice to prepare meat products for health promotion, soup and noodles of noodles.

<2-4> dairy products ( dairy products Manufacturing

5 to 10 parts by weight of the compound of Formula 1 according to the present invention was added to 100 parts by weight of milk, and various dairy products such as butter and ice cream were prepared using the milk.

<2-5> Linear  Produce

Brown rice, barley, glutinous rice, and yulmu were alphad by a known method, and then dried and roasted.

Black beans, black sesame seeds, and perilla were also steamed and dried by a known method, and then powdered into powder having a particle size of 60 mesh.

The compound of Chemical Formula 1 according to the present invention was dried under reduced pressure and concentrated in a vacuum concentrator, dried by spraying and a hot air dryer, and ground to a particle size of 60 mesh by a grinder to obtain a dry powder.

Cereals, seeds and the compound of the formula 1 according to the present invention prepared by combining in the following ratio.

Cereals (30 parts by weight brown rice, 15 parts by weight brittle, 20 parts by weight of barley),

Seeds (7 parts by weight perilla, 8 parts by weight black beans, 7 parts by weight black sesame seeds),

Compound of formula 1 (3 parts by weight),

Ganoderma lucidum (0.5 parts by weight),

Sulfur (0.5 part by weight).

< Formulation example  3> Manufacture of beverage

<3-1> Preparation of Carbonated Drink

5 to 10 parts by weight of sugar, 0.05 to 0.3 parts by weight of citric acid, 0.005 to 0.02 parts by weight of caramel, 0.1 to 1 parts by weight of vitamin C, and 1 to 5 parts by weight of the compound of formula 1 are mixed and 79 to 94 parts by weight of purified water Mixed to make a syrup, the syrup was sterilized at 85 to 98 ° C. for 20 to 180 seconds, mixed with cooling water at a ratio of 1: 4, and 0.5 to 0.82 parts by weight of carbon dioxide was added to contain the compound of Chemical Formula 1 of the present invention. A carbonated beverage was prepared.

<3-2> Preparation of functional drink for hangover

0.1 parts by weight of vitamin, 5.8 parts by weight fructose, 3.8 parts by weight of white sugar, 0.12 parts by weight of citric acid, 0.03 parts by weight of malic acid, 0.04 parts by weight of sodium citrate and 0.02 parts by weight of gardenia blue pigment Completely dissolved in metered water. The dissolved beverage was adjusted with purified water so that the total amount was 100 parts by weight.

<3-3> Preparation of health drinks

10 parts by weight of the compound of Formula 1 and 10 parts by weight of a compound such as 0.5 parts by weight of liquid fructose, 2 parts by weight of oligosaccharide, 2 parts by weight of sugar, 75 parts by weight of water and 75 parts by weight of water are homogeneously mixed and then sterilized immediately. Healthy drinks were prepared by packaging in small back containers.

<3-4> Preparation of Vegetable Juice

5 g of the compound of Formula 1 of the present invention was added to 1 L of tomato or carrot juice to prepare a vegetable juice for health promotion.

<3-5> Preparation of Fruit Juice

1 g of the compound of Formula 1 was added to 1 L of apple or grape juice to prepare a fruit juice for health promotion.

1 is a graph showing a change in the activity of alcohol dehydrogenase for the administration of the compound of formula 1 according to an embodiment of the present invention.

Figure 2 is a graph showing the change in activity of acetaldehyde dehydrogenase for the administration of the compound of formula 1 according to an embodiment of the present invention.

Figure 3 is a graph showing the blood alcohol concentration for the administration of the compound of formula 1 according to an embodiment of the present invention.

Claims (12)

6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone represented by Formula 1 below or a pharmaceutically acceptable salt thereof. <Formula 1>

Echinosophora koreensis in water, C ₁ To C ₄ lower alcohol or a mixed solvent thereof (step 1); Fractionating the extract extracted in step 1 with hexane, chloroform and butanol in order to obtain a fraction (step 2); Performing a C18 reverse phase column chromatography on the butanol fraction of the fraction extracted in step 2 using a mixed solution of methanol / water to obtain a methanol / water fraction (step 3); And Performing C18 reverse phase column chromatography again using a mixture of acetonitrile and water containing 0.02% trifluoroacetic acid as the eluent using the methanol / water fraction obtained in step 3 to obtain a compound of Chemical Formula 1 (step 4) A method for producing 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone according to claim 1. The 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'- of claim 1, wherein the lower alcohol is methanol or ethanol. Method for preparing hexahydroxyflavanone. The method according to claim 2, wherein step 3 is carried out by concentration gradient of methanol / water mixture in a volume ratio of 60:40-> 80:20 for 60 minutes, wherein the 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone. The 6,8-di (γ, γ-dimethylallyl) -3,5 of claim 1, wherein the methanol / water fraction obtained in step 3 is a methanol / water (80:20) fraction. Process for the preparation of, 7,2 ', 4', 6'-hexahydroxyflavanone. The method according to claim 2, wherein the mixed solution of acetonitrile / water of step 4 is concentrated in a volume ratio of 10:90-> 100: 0 in a volume ratio for 60 minutes to perform the 6,8-di (γ) of claim 1 , γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone. 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof as an active ingredient Hangover cure composition. 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof as an active ingredient Alcoholic liver protection composition. The method according to claim 7 or 8, wherein 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone is selected from alcohol dehydrogenase. A composition characterized by increasing activity. The method according to claim 7 or 8, wherein 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone is acetaldehyde dehydrogenase A composition characterized by increasing the activity of. 6,8-di (γ, γ-dimethylallyl) -3,5,7,2 ', 4', 6'-hexahydroxyflavanone or a pharmaceutically acceptable salt thereof as an active ingredient Healthy food to relieve hangover. The method of claim 11, wherein the health food is a hangover, health food for hangover, characterized in that the beverage, gum, vitamin complexes or health supplements.

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