KR20120103317A - Composition comprising an extract of coriandrum sativum l. seed or linalool isolated therefrom having acyl coa:cholesterol acyltransferase inhibitory activity - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing coriander seed extract or linalool is provided to effectively suppress ACAT activation and to prevent and treat ACAT-mediated diseases. CONSTITUTION: A composition suppressing acyl coA:cholesterol acyl transferase(ACTA) activation contains coriander seed extract and non-polar organic solvent fraction thereof, linalool of chemical formula 1 or a pharmaceutically acceptable salt thereof. The extract is prepared by water, organic solvent, or a mixture solvent thereof. The organic solvent includes methanol, ethanol, isopropanol, butanol, ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N,N-dimethylformamide(DMF), dimethyl sulfoxide(DMSO), 1,3-butylene glycol, propylene glycol, or a mixture thereof.

Description

Composition comprising an extract of Coriandrum sativum L. seed or linalool isolated there from having Acyl CoA: cholesterol acyltransferase inhibitory activity }

The present invention relates to a composition for inhibiting acyl CoA: cholesterol acyltransferase (ACAT) activity, including a coriander ( Coriandrum sativum L) seed extract or a monoterpene (monoterpene) compound isolated therefrom. Specifically, the present invention provides an ACAT-mediated disease comprising coriander seed extract having ACAT inhibitory activity, a nonpolar organic solvent fraction thereof, linalool isolated therefrom or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to a pharmaceutical composition for prophylaxis and treatment.

Acyl CoA: cholesterol acyltransferase (ACAT) catalyzes the acylation of cholesterol to absorb cholesterol in the small intestine, synthesize very low density lipoprotein (VLDL) in the liver, and store it in adipocytes and blood vessel walls It is known to be an enzyme involved in the accumulation of type cholesterol. ACAT inhibitors that inhibit the activity of the enzyme have been reported to be effective in the prevention and treatment of hyperlipidemia (Sliskovic DR and AD White, 1991, Trends in Pharmacol. Sci . 12: 194-199), particularly in the mechanism of atherosclerosis. The development of ACAT inhibitors is recommended as part of the development of therapeutic agents for hyperlipidemia with new mechanisms of action that are directly involved.

The ACAT inhibitors known to date are mainly chemical synthetic products, mainly composed of synthetic compounds of urea, amide, and phenolic system. In order to develop ACAT inhibitors having a new structure in terms of stability, studies on natural resources are actively conducted. have. As part of this study, purpactin (Tomoda H, et al., 1991, J. Antibiotics 44: 136-143), epi-cohliquinone A (Japanese Patent Laid-Open No. 4-334383) ), Acatelin (Naganuma S, et al., 1992, J. Antibiotics 45: 1216-1221), helmintosporol (Park JK, et al., 1993, J. Antibiotics 46: 1303-1305). ), Lateritin (Hasumi K, et al., J. Antibiotics 46: 1782-1787], gypsetin (Shinohara C, et al., 1994, J. Antibiotics 47: 163-167), enniatin (enniatins) (Nishida H, et al., 1992, J. Antibiotics 45: 1207-1214), glisoprenins (Tomoda, H, et al., 1992, J. Antibiotics , 45: 1202-1206), pyripyrophene (pyripyropenes) (Omura S, et al., 1993, J. Antibiotics 46: 1168-1169; Kim YK, et al., 1994, J. Antibiotics 47: 154-162), terpendols (Huang XH, et al., 1995, J. Antibiotics 48: 1-4], AS-183 (Kuroda K, et al., 1993, J. Antibiotics 46: 1196-1202), AS-186 (Kuroda K, et al., 1994, J. Antibiotics 47: 16-22 ), GERI-BP-001 ( Jeong TS, et al., 1995, J. Antibiotics 48: 751-756), GERI-BP-002 (Kim YK, et al., 1996, J. Antibiotics 49: 31-36), Magnonol (Kwon, BM, Et al., 1997, Planta Medica, 63: 550-551), schzandrin (Kwon, BM, et al., 1999, Planta Medica, 65: 74-76), panaxidol (Kwon, BM, et al. , 1999, Biooganic & Medicinal Chemistry Letters, 9: 1375-1378), guineensine (Lee SW, et al., 2004, Planta Med. 70, 678-679), panaxinone A (Rho MC, et al. , 2005, J. Agric. Food Chem. 53 (4): 919-922), avasimibe (Pfizer), etc. It was developed as an ACAT inhibitor.

The mechanism of action of ACAT occurs largely in three parts of the intestinal, liver and vascular wall cells of the body. First, in the intestine, ACAT converts ingested cholesterol into the form of esters to facilitate its absorption into the intestine. Second, cholesterol that is absorbed from the outside or biosynthesized in the body is accumulated in a carrier called very low-density lipoprotein (VLDL) in the liver and then supplied to each organ of the body through blood vessels. The conversion allows for the accumulation of cholesterol in the carrier. Third, in the cells that make up the arterial vessel wall, ACAT converts cholesterol into its ester form to promote the accumulation of cholesterol in the cell, which is a direct cause of atherosclerosis. In addition, since foam cells contain a large amount of cholesteryl ester derived from cholesterol by ACAT activity, the formation of foam cells derived from macrophages and smooth muscle cells is very important from an experimental and clinical aspect. Since the proliferation of foam cells in the vessel wall is directly related to the increase in ACAT activity, the development of an ACAT inhibitor as a potent antiarterial agent is highly desirable.

Thus, drugs that inhibit the activity of ACAT may reduce the amount of cholesterol entering the body by inhibiting the absorption of intestinal cholesterol, and may inhibit the release of cholesterol into the blood vessels in the liver, thereby lowering blood cholesterol levels. In addition, it is expected that arteriosclerosis can be directly prevented by preventing the accumulation of cholesterol in blood vessel wall cells.

As a direct link between ACAT and cholesterol metabolism has been identified, ACAT has been studied as a target for the treatment of diseases caused by cholesterol metabolism regulation. Based on the fact that the cholesterol level in the blood is reduced by selective inhibition of ACAT activity, it is possible to effectively treat cerebrovascular diseases, cardiovascular diseases, and peripheral vascular diseases induced by high fat levels in blood vessels. For example, ACAT inhibitors include hypercholesterolemia (Raal FJ et al., 2003, Atherosclerosis 171 (2): 273-279), hyperlipidemia (kusunoki J, 2000, Arterioscler Thromb Vasc Biol. 20 (1): 171-178), atherosclerosis (Heinonen TM, 2002, Curr Atheroscler Rep. 4 (1): 65-70), arteriosclerosis (Heinonen TM, 2002, Expert Opin Investig Drugs . 11 (11) ): 1519-1527), coronary arteriosclerosis (Meynier A, 2002, Br J Nutr. 87 (5): 447-458), aortic aneurysm (Hiatt WR et al., 2004, Vasc Med. 9 (4): 271-277) and the like. In addition, inhibition of ACAT activity inhibits the production of amyloid-beta, which forms plaques in Alzheimer's disease, and therefore treatment of Alzheimer's with ACAT inhibitors has been proposed (Hutter-Paier B et al. , 2004, Neurom. 44 (2). ): 227-238; Puglielli L et al., 2004, J Mol Neurosci. 24 (1): 93-96). Therefore, the use of selective inhibitors of ACAT activity is expected to prevent or treat the disease as well as the symptoms or complications caused by it.

On the other hand, Coriander ( Coriandrum sativum L) is an edible plant belonging to an umbel tree, also called a lake basin and bedbugs. A naturalized plant native to the eastern Mediterranean, it is used as a fragrance to make sauces in Europe. In oriental medicine, the fruit is called a good drinker, and it is written as a widow or expectorant. Coriander leaves are partially used and almost use seeds, which can be harvested in May as leaves are harvested. The leaves can be harvested 30 to 40 days after sowing. Seeds are ripe when the seeds are yellowish brown in color, and are usually harvested in July and August when sown in April. Coriander prevents rancidity of animal lipids and is used as a preservative because it is antimicrobial. Seed essential oil is used as a fragrance. The research on cilantro has been mainly focused on cultivation of cilantro, yield, active ingredient of cilantro, volatile components of essential oil, and its use as food, but the correlation between cilantro and ACAT activity has not been reported until now. none.

Accordingly, the present inventors have searched for a new safe and effective ACAT inhibitor from natural resources, and found that coriander seed extract and purified linaool selectively inhibited the activity of ACAT. The present invention was completed by confirming that coriander seed extract can be effectively used for the prevention or treatment of ACAT-mediated diseases.

Accordingly, an object of the present invention is an acyl coco: cholesterol acyltransferase (ACAT) comprising a coriander seed extract, a nonpolar organic solvent fraction thereof, a linalool compound isolated therefrom or a pharmaceutically acceptable salt thereof. It is to provide a composition for inhibiting activity.

Another object of the present invention is to provide a method for preparing a coriander seed extract having ACAT inhibitory activity from coriander seed.

It is still another object of the present invention to provide a method for separating a linarool compound having an ACAT inhibitory activity from coriander seed or a pharmaceutically acceptable salt thereof.

Another object of the present invention is a pharmaceutical for preventing or treating ACAT-mediated diseases comprising coriander seed extract, nonpolar organic solvent fractions thereof, linarol compounds isolated therefrom or pharmaceutically acceptable salts thereof as an active ingredient. It is to provide a composition.

Another object of the present invention is to provide a dietary supplement for improving or preventing ACAT-mediated diseases, including coriander seed extract, nonpolar organic solvent fractions thereof, linarol compounds isolated therefrom or pharmaceutically acceptable salts thereof. It is.

In one embodiment, the present invention provides a coriander seed extract having an acyl coay: cholesterol acyltransferase (ACAT) inhibitory activity, a nonpolar organic solvent fraction thereof, a linaol compound isolated therefrom, or a pharmaceutically acceptable salt thereof. It relates to a composition for inhibiting ACAT activity comprising.

The present invention provides for the first time that coriander seed extract, a nonpolar organic solvent fraction thereof, a linarool compound isolated therefrom or a pharmaceutically acceptable salt thereof selectively inhibits the activity of acyl coco: cholesterol acyltransferase (ACAT). It is clear that this invention proposes a novel use as an ACAT inhibitor, which has the characteristics of the invention.

As used herein, the term "acyl CoA: cholesterol acyltransferase (ACAT)" catalyzes the formation of cholesteryl esters from cholesterol and fatty acyl coenzyme A. Refers to an enzyme.

As used herein, the term "acyl coay: cholesterol acyltransferase (ACAT) activity inhibition" refers to blocking the catalytic reaction of the enzyme forming cholesteryl ester from cholesterol and fatty acyl coenzyme A or reducing the efficiency of the catalysis. Means that. Enzymatic reaction catalyzed by ACAT is essential for the absorption of cholesterol in the small intestine, the synthesis and secretion of apolipoprotein B (apoB) containing lipoproteins, and the intracellular storage of cholesterol, thus inhibiting cholesterol absorption in foods. And reduce liver cholesterol levels, thereby reducing cholesterol levels in the blood.

To this end, the present invention, as one embodiment, provides a method for producing a coriander seed extract having ACAT inhibitory activity from coriander seed.

Coriander seed extract of the present invention shall include any one of all extracts, fractions and purified products obtained in each step of extraction, fractionation and purification, dilution or concentrate thereof or dried products thereof. Preferably, hot water or ethanol extract of coriander seed, more preferably, an n-hexane: ethyl acetate fraction of ethanol extract is used.

Coriander seed extract according to the present invention can be obtained by extracting with water, an organic solvent or a mixed solvent thereof, and preferably, coriander seed, which has been dried and pulverized for a predetermined time, as described in the art for cold needle extraction, heat extraction, and ultrasonic waves. Extraction can be performed by various extraction methods such as reflux cooling extraction. The extraction method is not particularly limited and may be extracted by room temperature or warming under conditions in which the active ingredient is not destroyed or the destruction thereof is minimized. From the extract of the coriander seed extracted therefrom, a highly active nonpolar organic solvent fraction can be obtained and further separated by chromatography or the like to isolate the linarool compound having ACAT inhibitory activity according to the present invention.

Accordingly, the present invention, as another embodiment, provides a method for separating a linarool compound having a ACAT inhibitory activity from coriander seed or a pharmaceutically acceptable salt thereof.

Specifically, the method for separating linaool from coriander seed according to the present invention,

1) extracting coriander seed with water, an organic solvent or a mixed solvent thereof to obtain coriander seed extract;

2) fractionating the coriander seed extract obtained in step 1) with a nonpolar organic solvent to obtain a nonpolar organic solvent fraction; And

3) The non-polar organic solvent fraction obtained in step 2) may be purified by chromatography to separate the linarol compound.

Step 1) is a step of extracting coriander seed with water, an organic solvent or a mixed solvent thereof to obtain a coriander seed extract. The coriander seed can be used without limitation, such as cultivated or commercially available, it is used to wash clean and dry. Organic solvents suitable for the present invention include methanol, ethanol, isopropanol, butanol, ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N, N-dimethylformamide (DMF), dimethyl Sulfoxide (DMSO), 1,3-butylene glycol, propylene glycol, or a mixed solvent thereof, and preferably C1 to C4 lower alcohols such as methanol and ethanol, and more preferably ethanol. .

In a preferred embodiment of the present invention, the coriander seeds are washed, dried and ground into a grinder and then powdered, followed by ethanol in a volume of 2 to 5 times the weight of dried coriander seeds at about 15 to 30 ° C. for about 3 to 10 days. After extracting using hot water extraction, cold needle extraction, reflux cooling extraction or ultrasonic extraction, the supernatant is recovered by vacuum filtration. This extraction process may be repeated several times, preferably two times to collect the supernatant, which may be concentrated under reduced pressure or lyophilized to obtain a coriander seed extract.

Step 2) is a step of suspending by adding water to the coriander seed extract obtained in step 1), and sequentially fractionated using a non-polar organic solvent to obtain a non-polar organic solvent fraction. At this time, a conventional fractional extraction method can be used, and preferably a fractionation funnel can be used. Non-polar organic solvents suitable for the present invention include hexane, ether, dichloromethane, chloroform, ethyl acetate, or a mixed solvent thereof, and may be preferably fractionated using hexane and ethyl acetate.

Step 3) is a step of separating the linaol compound of Chemical Formula 1 by purifying the coarse seed nonpolar organic solvent fraction obtained in step 2) by chromatography. In the present invention, the active ingredient can be separated by performing chromatography one or more times on the non-polar organic solvent fraction of coriander, and the chromatography column and the developing solvent can be variously controlled.

In a preferred embodiment of the present invention, 300 ml of ethanol was added to 100 g of powdered coriander, followed by stationary extraction at room temperature for 7 days, followed by filtration and concentration under reduced pressure to obtain 2.1 g of coriander seed extract. The extract was partitioned sequentially with n-hexane and ethyl acetate to obtain 150 mg of a non-polar organic solvent fraction showing ACAT inhibitory activity. After concentration under reduced pressure, silica gel column chromatography (n-hexane: ethyl acetate = concentration gradient from 100: 1 to 1: 1) and normal column chromatography (normal-phase column chromatography, silica gel, n-hexane: ethyl acetate) Was performed sequentially to obtain an active fraction. The active fraction obtained was then purified by high performance liquid chromatography (HPLC; YMC ODS 5 μm; 250 × 4.6 mm). At this time, 0.7 ml of acetonitrile: water (1: 1) was flowed into the elution solvent per minute, and a detection system was used as a full-wave detection system. The fraction eluted at 14 minutes was recovered to obtain an active substance. The same amount of ethyl acetate was added to the fraction to separate the organic solvent soluble layer, and then anhydrous sodium sulfate was added thereto to remove water, the same amount of diethyl ether was added, and the solvent was removed under nitrogen gas at low temperature to remove 20.1 mg. Active compound was isolated.

The active compound separated by the above method was analyzed by electron shock mass spectrometry, hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum, etc., and the compound was monoterpene (monoterpene) -based compound having a structural formula of Formula 1 It was found to be linalool.

As a result of measuring the ACAT inhibitory activity of linarool according to the present invention, it was confirmed that linarool has an IC ₅₀ value of 0.78 μM, which is the highest ACAT inhibitory activity among plant-derived ACAT inhibitors reported so far. Therefore, it can be seen that the coriander seed extract containing linaool and its nonpolar organic solvent fraction also have an ACAT inhibitory activity corresponding to linaol.

Linarool compound of the present invention is not an artificially synthesized compound, but is isolated and purified from natural extracts, so it is safe, toxic, and has no side effects.

The term "linalool" in the present invention is a monoterpene-based compound which exists in nature and is an aromatic compound found in various herb plants, such as herb species of the genus Coriandrum sativum L. Such linarool may be extracted, separated, purified using methods known in the art, such as solvent extraction, distillation, and steam distillation, in the plants, or purchased commercially purified products as a single substance. Can also be used. Linarool may also be prepared by chemical synthesis by methods known in the art. Linarool in the present invention is isolated and purified from the coriander seed extract, characterized in that it has an ACAT inhibitory activity. Prior to the present invention, no ACAT inhibitory activity of linarool has been reported.

Linarool compounds according to the invention may also form pharmaceutically acceptable salts. As used herein, the term "pharmaceutically acceptable salts" refers to salts derived from inorganic acids, organic acids and bases of pharmacologically or physiologically acceptable linaool. Linarool compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and includes all salts, hydrates and solvates prepared by conventional methods.

Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. Acid addition salts are prepared by conventional methods, for example, by dissolving a compound in an excess of aqueous acid solution and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equivalent molar amounts of the compound and acid or alcohol (eg, glycol monomethylether) in water can be heated and the mixture can then be evaporated to dryness or the precipitated salts can be suction filtered. In this case, organic acids and inorganic acids may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like may be used as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic 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. Can be, and not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and then evaporating and drying the filtrate. In this case, as the metal salt, it is particularly suitable to prepare sodium, potassium or calcium salts, but is not limited thereto. Corresponding silver salts may also be obtained by reacting alkali or alkaline earth metal salts with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of linarool compounds represented by Formula 1 include salts of acidic or basic groups which may be present in compounds of Formula 1 unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of the hydroxy group, and other pharmaceutically acceptable salts of the amino group include hydrobromide, sulfate, hydrogen sulphate, phosphate, Hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts; It can be prepared through the manufacturing method.

In another embodiment, the present invention is for the prevention or treatment of ACAT-mediated diseases comprising coriander seed extract, nonpolar organic solvent fractions thereof, linarol compounds isolated therefrom or pharmaceutically acceptable salts thereof as an active ingredient. It relates to a pharmaceutical composition.

The pharmaceutical composition according to the present invention contains a coriander seed extract having an ACAT inhibitory activity, a nonpolar organic solvent fraction thereof, a linaol compound isolated therefrom or a pharmaceutically acceptable salt thereof as an active ingredient, and thus the ACAT-mediated disease It can be usefully used for prevention or treatment.

As a direct link between ACAT and cholesterol metabolism has been revealed, ACAT has become a target for the treatment of diseases caused by cholesterol metabolism regulation. Selective inhibition of ACAT activity can effectively treat cerebral vascular diseases, cardiovascular diseases, and peripheral vascular diseases induced by high fat levels in blood vessels. For example, ACAT inhibitors can be used to prevent hypercholesterolemia, hyperlipidemia, atherosclerosis, atherosclerosis, coronary arteriosclerosis, and aortic aneurysm, etc. Can be used for treatment. In addition, inhibition of ACAT activity inhibits the production of amyloid-beta, which forms plaques in Alzheimer's disease, thereby treating Alzheimer's disease. Such selective inhibitors of ACAT activity are expected to prevent or treat the disease as well as the symptoms or complications caused by it.

Thus, the term "ACAT-mediated disease" in the present invention means a disease mediated by excessive catalysis of ACAT enzymes that form cholesteryl esters from cholesterol and fatty acyl coenzyme A. Examples of such diseases include hypercholesterolemia, hyperlipidemia, arteriosclerosis, atherosclerosis, coronary atherosclerosis, aortic aneurysm, Alzheimer's disease, obesity, atherosclerosis, vascular restenosis, and obstruction, but the inhibition through the activity of ACAT Any disease that can be suppressed or delayed or the symptoms of the disease can be improved or advantageously changed is included in the scope of the present invention without any limitation.

As used herein, the term "prevention" refers to the administration of a pharmaceutical composition comprising a coriander seed extract according to the present invention, a nonpolar organic solvent fraction thereof, a linarol compound isolated therefrom or a pharmaceutically acceptable salt thereof as an active ingredient. By any action that inhibits or delays the development of ACAT-mediated disease.

As used herein, the term "treatment" refers to the administration of a pharmaceutical composition comprising a coriander seed extract according to the present invention, a nonpolar organic solvent fraction thereof, a linarol compound isolated therefrom or a pharmaceutically acceptable salt thereof as an active ingredient. Any action that improves or beneficially changes the symptoms of an ACAT-mediated disease.

The pharmaceutical composition according to the present invention may include pharmaceutically effective amounts of coriander seed extract, nonpolar organic solvent fractions thereof, linarol compounds isolated therefrom, or pharmaceutically acceptable salts thereof alone or in one or more pharmaceutically acceptable salts. Acceptable carriers, excipients or diluents.

As used herein, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level refers to a patient's sexually transmitted disease, age, type of disease, severity, It can be determined according to the activity of the drug, sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of treatment, factors including the concurrent drug and other factors well known in the medical field. The pharmaceutical compositions of the present invention may be administered as individual therapeutic agents or in combination with other therapeutic agents and may be administered sequentially or simultaneously with conventional therapeutic agents. In addition, the pharmaceutical compositions of the present invention may be administered in a single or multiple doses. 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, and can be easily determined by those skilled in the art. Specifically, the pharmaceutical composition of the present invention is preferably oral administration or intravenous administration.

Examples of pharmaceutically acceptable carriers, excipients and diluents that may be used in the pharmaceutical compositions of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate , Gelatin, calcium phosphate, calcium silicate, calcium carbonate, cellulose, methyl cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxy benzoate, talc, magnesium stearate, mineral oil and the like.

The pharmaceutical composition of the present invention may be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral dosage forms, external preparations, suppositories, and sterile injectable solutions according to conventional methods. . When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one of the coriander seed extract, the linarol compound isolated therefrom, or a pharmaceutically acceptable salt thereof. The above excipients are prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solvents, emulsions, and syrups.In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. Can be. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. As the non-aqueous solvent and suspending agent, 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.

Preferred dosages of the coriander seed extract of the present invention, nonpolar organic solvent fractions thereof, linarol compounds isolated therefrom or pharmaceutically acceptable salts thereof are determined by the condition and weight of the patient, the extent of the disease, the form of the drug, the route and duration of the patient. Depending on, it can be appropriately selected by those skilled in the art. However, for the desired effect, the coriander seed extract of the present invention is preferably administered at 50 to 1000 mg / kg per day, preferably at 100 to 500 mg / kg, and the linarool compound is 1 to 10 mg per day. / kg, preferably from 1 to 5 mg / kg. Administration may be administered once a day or may be divided several times.

In another embodiment, the present invention provides ACAT-mediated treatment by administering to a patient in need thereof a pharmaceutical composition comprising a coriander seed extract, a linarool compound isolated therefrom or a pharmaceutically acceptable salt thereof as an active ingredient. A method for preventing or treating a disease.

As used herein, the term "patient" refers to humans, horses, sheep, pigs, goats, camels, nutrition, and humans with diseases whose symptoms may be improved by administration of a pharmaceutical composition according to the invention that inhibits ACAT activity in cells. Means animals such as dogs. ACAT-mediated diseases such as hypercholesterolemia, hyperlipidemia, arteries by administering to a patient a pharmaceutical composition comprising a coriander seed extract having ACAT inhibitory activity, a linarol compound isolated therefrom or a pharmaceutically acceptable salt thereof Sclerosis, atherosclerosis, coronary atherosclerosis, aortic aneurysms, Alzheimer's disease, obesity, atherosclerosis can be effectively prevented and treated.

As used herein, the term "administration" means introducing a predetermined substance into a patient in any suitable manner, and the route of administration of the pharmaceutical composition according to the invention is oral or via any general route as long as it can reach the desired tissue. Parenteral administration. In addition, the pharmaceutical composition according to the present invention may be administered by any device in which the active ingredient can move to the target cell.

As another aspect, the present invention provides a dietary supplement for improving or preventing ACAT-mediated diseases, including coriander seed extract, nonpolar organic solvent fractions thereof, linarol compounds isolated therefrom or pharmaceutically acceptable salts thereof To provide.

Specifically, the coriander seed extract according to the present invention, the linarool compound isolated therefrom or a pharmaceutically acceptable salt thereof may be added to food or beverage for the purpose of improving or preventing ACAT-mediated diseases. Is not particularly limited, for example, various foods such as sweets, breads, noodles and the like, drinks, such as water, soft drinks, fruit drinks, gum, tea, vitamin complexes, seasonings, health functional foods and the like. At this time, the amount of the extract or compound in the food or beverage is generally in the case of the dietary supplement composition of the present invention can be added to 0.01 to 15% by weight, preferably 0.1 to 5% by weight of the total food weight and the health beverage composition It can be added in a ratio of 0.01 to 5.0 g, preferably 0.01 to 1.0 g based on 100 ml. Since the health functional food of this invention obtained in this way contains the composition of this invention, it is a food which can fully utilize the health prevention and therapeutic effect which the extract or compound which concerns on this invention has.

The health beverage composition of the present invention is not particularly limited to the liquid component except for containing the extract or the compound as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages. . The above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like: disaccharides such as maltose and sucrose; Polysaccharides such as dextrin, cyclodextrin, and the like; And sugar alcohols such as xylitol, sorbitol, erythritol, and the like. As flavoring agents other than those mentioned above, natural flavoring agents (tauumakin, stevia extract, etc.), and synthetic flavoring agents (saccharin, aspartan, etc.) can be advantageously used. The proportion of said natural carbohydrate is generally from about 0.1 mg to 2.0 g, preferably from about 0.1 mg to 1.0 g per 100 ml of the composition of the present invention.

 The health functional food of the present invention is a step of adding the above-mentioned extract or compound of the present invention during the manufacturing process of the base food or by adding the above-mentioned extract or compound of the present invention after the preparation of the base food. It can be obtained easily by adding. At this time, a taste and odor correction agent may be added as needed.

In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid And salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. In addition, the health functional food of the present invention may contain natural fruit juice and fruit flesh for the production of fruit juice drinks and vegetable drinks. Such components may be used independently or in combination. The proportion of such additives is generally selected within the range of about 20 parts by weight or less per 100 parts by weight of the health functional food of the present invention.

As described above, the coriander seed extract according to the present invention, the nonpolar organic solvent fraction thereof, the linarol compound isolated from the pharmaceutically acceptable salt thereof is the activity of acyl coay: cholesterol acyltransferase (ACAT) Can effectively be used for the prevention and treatment of ACAT-mediated diseases such as hypercholesterolemia, hyperlipidemia, atherosclerosis, atherosclerosis, coronary atherosclerosis, aortic aneurysms, Alzheimer's disease, obesity, atherosclerosis and the like.

Figure 1 shows the mass spectrometry spectrum (EI-Mass) of the linarol compound represented by the formula (1) according to the present invention.
Figure 2 shows the hydrogen nuclear magnetic resonance spectrum (CDCl ₃ , 300 MHz) of the linarol compound represented by the formula (1) according to the present invention.
Figure 3 shows the carbon nuclear magnetic resonance spectrum (CDCl ₃ , 75 MHz) of the linarol compound represented by the formula (1) according to the present invention.
Figure 4 shows the ACAT inhibitory activity of the linarol compound represented by the formula (1) according to the present invention.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

Example 1 Isolation and Purification of Active Substances Having Acyl Coay: Cholesterol Acyltransferase Inhibitory Activity from Coriander Seeds

Coriander seeds (purchased at Daejeon Herb Market) were washed with water, dried in the shade and powdered with a bladed grinder. To 100 g of coriander seed powdered to a particle size of 50 to 300 mesh, 300 mL of ethanol (based on the weight of dried coriander seed) was added, and the mixture was left still for 7 days at room temperature, filtered and concentrated under reduced pressure to obtain 2.1 g of coriander seed extract.

In order to isolate and purify the active material from the coriander seed extract, the ACAT inhibitory activity was measured according to the following method by separating each fraction using n-hexane and ethyl acetate as a non-polar organic solvent. A fraction of each fraction was dried to prepare a sample at 1 mg / ml, and the ACAT inhibitory activity was measured. As a result, the best ACAT inhibitory activity was confirmed in the ethyl acetate fraction, and a 150 mg nonpolar organic solvent fraction was obtained therefrom. The non-polar organic solvent fractions obtained above were concentrated under reduced pressure, and then subjected to silica gel column chromatography using a concentration gradient solvent system composed of n-hexane: ethyl acetate = (100/1 → 1/1) to activate the silica gel column chromatography. Fractions were separated. The ACAT inhibitory activity of the separated active fractions was measured, and the fractions having the highest inhibitory activity were recovered, and this was then subjected to normal-phase column chromatography using n-hexane: ethyl acetate as the elution solvent. silica gel) was applied to isolate the active fraction. The ACAT inhibitory activity of the separated active fractions was measured, and the fifth to eighth fractions showing the highest inhibitory activity were subjected to high performance liquid chromatography (HPMC; YMC ODS 5 μm; 250 × 4.6 mm). Separated. At this time, 0.7 ml of acetonitrile: water (1: 1) was flowed out per minute as an eluting solvent. The detection of the active substance was performed at UV 276 nm using a full-wave field detector, and the ACAT inhibitory substance was eluted at 14 min in the fifth fraction. The same amount of ethyl acetate was added to the fraction to separate the organic solvent soluble layer, and then anhydrous sodium sulfate was added thereto to remove water, the same amount of diethyl ether was added, and the solvent was removed under nitrogen gas at low temperature to remove 20.1 mg. Active compound was isolated.

Example 2 Structure Determination of Active Material

The physicochemical properties of the compound having ACAT inhibitory activity isolated and purified in Example 1 were analyzed as follows. First, the molecular weight of the compound is measured using an electrospray ionization mass spectrometry (Fisons VG Quattro 400 mass spectrometer, USA), and the structure of the compound is analyzed by nuclear magnetic resonance (NMR). It was. In the NMR experiment, each sample was dissolved in CDCl ₃ to measure hydrogen and carbon nuclear magnetic resonance spectra in a 5 mm NMR tube, and the peak of each solvent was determined based on tetramethylsilane peak.

As a result of analyzing the molecular weight, molecular formula and mass, the molecular weight of the compound was found to be 154.22, and high resolution mass spectrometry confirmed that the compound had a molecular formula represented by C ₁₀ H ₁₈ O. Referring to the physicochemical properties, 18 hydrogens in the hydrogen nuclear magnetic resonance spectra of the compound dissolved in CDCl ₃ were analyzed to be 1.33 ppm (3H, s), 1.70 ppm (3H, s), 1.82 ppm (3H, s), 5.20 ppm (1H, dd), 5.89 ppm (1H, dd), 5.16 ppm (1H, dd), 5.41 ppm (1H, dd), 3.65 ppm (1OH, s). In addition, 10 carbons in the carbon nuclear magnetic resonance spectrum are 23.2 ppm (C-1), 23.2 ppm (C-2), 21.2 ppm (C-5), 28.1 ppm (C-3), 28.6 ppm (C-8) ), 40.3 ppm (C-4), 42.4 ppm (C-6), 74.6 ppm (C-7), 112.6 ppm (C-10), and 144.3 ppm (C-9). As a result of inferring the structure of the active substance through the above results, the compound having ACAT inhibitory activity isolated and purified from coriander seed was identified as linalool, a monoterpene compound.

Example 3 Acyl Coay: Cholesterol Acyl Transferase Inhibitory Activity of the Active Substance

In order to measure the ACAT inhibitory activity of linaol identified in Example 2, the experiment was performed as follows.

<3-1> Preparation of Enzyme Source

First, the ACAT enzyme source was prepared as follows. Liver from male Sprague-Dawley rats (weight 250-300 g) was extracted and microsome buffer A (0.25 M sucrose, 1 mM EDTA, 0.01 M Tris-HCl, pH 7.4), appropriately chopped with scissors and homogenized with a teflon-glass homogenizer. The homogenate was centrifuged at 14,000 × g for 15 minutes to recover the supernatant, and the supernatant was further centrifuged at 100,000 × g for 1 hour. In order to isolate ACAT containing microsomes, the centrifuged precipitate was added to Microsomal Buffer B (0.25 M sucrose, 0.01 M Tris-HCl, pH 7.4) and centrifuged again at 100,000 × g for 1 hour. In the test, microsomal buffer B was added to the precipitate centrifuged to disperse the precipitate for uniform protein concentration, and protein concentration was determined according to the Lowry method using BSA (bovine serum albumin) as a protein standard. Decided. The enzyme source was then diluted with microsomal buffer B to adjust the protein concentration to 10 mg / ml, then dispensed into 1 ml vials and stored at -70 ° C for use in the test.

<3-2> Determination of enzyme inhibitory activity

The ACAT inhibitory activity of linaool was measured using the enzyme source prepared as described above. ACAT activity was measured by slightly modifying the method described in the literature using [1- ¹⁴ C] oleoyl-coei as substrate (Kim YK, et al., 1996, J. Antibiotics 49: 31-36).

10.0 μl of the Linaolol compound isolated and purified in Example 1, 4.0 μl of the microsomal enzyme solution prepared in Example 3-1, assay buffer (0.5 M KH ₂ PO ₄ , 10 mM DTT, pH 7.4; Sigma) 20.0 μl, fat-free BSA (stock solution 40 mg / ml; Sigma) 15.0 μl, cholesterol (stock solution 20 mg / ml; Sigma) 2.0 μl and distilled water 41.0 μl were mixed to prepare a reaction solution. Pre-react for 15 minutes at 37 ° C. 8 μl of [1- ¹⁴ C] oleoyl-coei (0.05 μCi, final concentration: 10 μM) was added to the reaction solution, and the reaction was carried out at 7 ° C. for 25 minutes to carry out enzyme main reaction, followed by isopropanol: heptane mixture. 1 ml (4: 1 (v / v)) was added to stop the reaction. To this was added 400 μl of 600 μl heptane and 5 times diluted assay buffer (0.5 M KH ₂ PO ₄ , 10 mM DTT, pH 7.4; Sigma) and the mixture was vigorously mixed by vortexer, followed by 300 The organic solvent was separated by centrifugation at xg for 5 minutes. 100 μl of the supernatant obtained by centrifugation was placed in a scintillation bottle, and 3 ml of scintillation cocktail (Lipoluma) was added thereto, followed by mixing well. Radioactivity of the mixture was measured with a 1450 Microbeta liquid scintillation counter (Wallacoy). At this time, the blank test was performed under ice cooling, and obovatol was used as a positive control.

ACAT activity inhibition was determined by measuring the amount of the product generated from the radioactively labeled substrate and the enzyme after the reaction by using a radiometer, and then calculated by the following equation (1).

[Equation 1]

% Inhibition of ACAT activity = 100 × [1-CPM (T) -CPM (C2) / CPM (C1) -CPM (B)]

CPM (T): CPM (counts per minute) when sample and enzyme are added

CPM (C1): CPM when only enzyme is added without sample

CPM (C2): CPM when only sample is added without enzyme

CPM (B): CPM without adding both sample and enzyme

sample Treatment concentration (μM) DPM Average Inhibitory Activity (%) IC ₅₀ ([mu] M) (+) 5973 5692 5833 0.0 0.78 Linarool 30 826 836 831 98.8 10 1202 1259 1231 90.9 3 1398 1403 1401 87.5 One 2945 2486 2716 61.6 0.3 4459 4484 4472 26.9 0.1 5488 5525 5507 6.4 0.03 5565 5476 5521 6.2 0.01 5639 5521 5580 5.0

As a result, as shown in Table 1, linarool of the present invention is 6.1% at 1 μM concentration, 87.5% at 3 μM concentration, 90.9% at 10 μM concentration, and 98.8 at 30 μM concentration ACAT inhibitory activity was shown in%, and its IC ₅₀ value was found to be 0.78 μM. Linarool according to the present invention showed an ACAT inhibitory activity in a concentration-dependent manner, and showed the highest inhibitory activity among plant-derived ACAT inhibitors.

Therefore, the linarol compound according to the present invention, coriander seed extract and non-polar organic solvent fractions thereof comprising the same can be used for various diseases caused by excessive activity of ACAT, namely hypercholesterolemia, hyperlipidemia, arteriosclerosis, atherosclerosis, It was confirmed that it can be effectively used for the prevention and treatment of coronary atherosclerosis, aortic aneurysm, Alzheimer's disease, obesity, atherosclerosis.

Example 4 Oral Acute Toxicity Test

In order to determine the acute toxicity of the coriander seed extract and linaol compound isolated therefrom according to the present invention, the following experiment was performed using a mouse.

Four-week-old specific pathogens-free ICR mice, with 12 females and 12 males (3 males and 3 females each) at 22 ± 3 ° C, 55 ± 10% humidity, and 12L / 12D illumination conditions. It was bred in the animal laboratory of. Mice were allowed to acclimate for about a week before being used for the experiment. Feed for experimental animals (for Cheil Jedang Co., Ltd., mice and rats) and drinking water were supplied after sterilization and ingested freely.

The coriander seed extract prepared in Example 1 and the linaol compound isolated therefrom were prepared at a concentration of 50 mg / ml using 0.5% Tween 80, and then 0.04 ml (100 mg / kg) per 20 g of mouse body weight, 0.2 ml (500 mg / kg) or 0.4 ml (1,000 mg / kg) was administered orally. Samples were administered orally once and observed for adverse events or lethality for 7 days after administration. On the day of dosing, changes in general symptoms and the presence or absence of dead animals were observed at least 1 hour, 4 hours, 8 hours, and 12 hours after the administration, and at least once in the morning and afternoon every day from the day after the administration.

In addition, after dissecting and dissecting the animal on the 7th day of administration, the internal organs were visually inspected, and the change in body weight was measured at intervals of 1 day from the day of the administration to determine the weight change of the animal by administration of the extract and the compound of the present invention. Observed.

As a result, no significant clinical symptoms were observed in all mice treated with the test substance, no mice died, and no toxic changes were observed in weight changes, blood tests, blood biochemical tests, and autopsy findings. .

Therefore, the coriander seed extract and linaol compound isolated therefrom did not show toxicity change up to 1,000 mg / kg in all mice, and the minimum lethal dose (LD ₅₀ ) of at least 1,000 mg / kg or more was safe. It was judged to be a substance.

Examples of preparations for the compositions of the present invention are illustrated below.

Preparation Example 1 Preparation of Pharmaceutical Formulation

Pharmaceutical preparations comprising a coriander seed extract, a nonpolar organic solvent fraction thereof according to the present invention, or a linarool compound isolated therefrom as an active ingredient were prepared as follows.

<1-1> Preparation of powder

Coriander seed extract, its nonpolar organic solvent fraction, or 2 g of linarool

1 g lactose

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

<1-2> Preparation of Tablet

Coriander seed extract, its nonpolar organic solvent fraction, or linarool 100 mg

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 tablet production method.

&Lt; 1-3 > Preparation of capsules

Coriander seed extract, its nonpolar organic solvent fraction, or linarool 100 mg

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 capsule preparation method.

<1-4> Preparation of Injection Solution

Coriander seed extract, nonpolar organic solvent fractions thereof, or 10 μg / ml linarool

Dilute hydrochloric acid BP until pH 3.5

Injectable sodium chloride BP up to 1 ml

Dissolve the coriander seed extract, its nonpolar organic solvent fraction, or the linarol compound isolated therefrom in an appropriate volume of sodium chloride BP for injection, and adjust the pH of the resulting solution to pH 3.5 using dilute hydrochloric acid BP. Afterwards, the volume was adjusted using sodium chloride BP for injection and mixed well. The solution was filled into a 5 ml Type I ampoule of clear glass, encapsulated under an upper grid of air by dissolving the glass, and sterilized by autoclave at 120 ° C. for at least 15 minutes to prepare an injection solution.

Preparation Example 2 Preparation of Food

Food products containing the coriander seed extract, nonpolar organic solvent fractions thereof, or linarool compounds isolated therefrom according to the present invention were prepared as follows.

<2-1> Production of flour food

0.1 to 10.0 parts by weight of coriander seed extract, nonpolar organic solvent fraction thereof or linaol compound isolated therefrom is added to flour, and bread, cake, cookies, crackers and noodles are prepared in a conventional manner using this mixture. To prepare a food for health promotion.

<2-2> Preparation of Soups and Gravys

Coriander seed extract according to the present invention, non-polar organic solvent fractions thereof, or 0.1 to 1.0 parts by weight of linaol compounds isolated therefrom are added to soups and broth to prepare meat products for health promotion, soups and broths in a conventional manner. It was.

<2-3> Preparation of Ground Beef

10 parts by weight of the coriander seed extract according to the present invention, a nonpolar organic solvent fraction thereof, or a linarol compound isolated therefrom was added to the ground beef to prepare a ground beef for health promotion in a conventional manner.

<2-4> Production of Dairy Products

Coriander seed extract according to the present invention, non-polar organic solvent fractions thereof, or 0.1 to 1.0 parts by weight of linaol compounds isolated therefrom are added to milk, and various dairy products such as butter and ice cream are prepared in a conventional manner using the milk. It was.

<2-5> Preparation of Wire

Brown rice, barley, glutinous rice, and yulmu were dried by a known method and dried, and the mixture was granulated to a powder having a particle size of 60 mesh. Black soybeans, black sesame seeds, and perilla seeds were steamed and dried by a conventional method, and then they were prepared into powder having a particle size of 60 mesh by a pulverizer. Coriander seed extract according to the present invention or the linarol compound separated therefrom was decompressed and concentrated in a vacuum concentrator, dried by spraying and drying with a hot air dryer, and then pulverized with a particle size of 60 mesh to obtain a dry powder.

Cereals, seeds and the coriander seed extract according to the present invention or a dry powder of the linarol compound isolated therefrom was prepared in a conventional manner by blending in the following ratios.

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

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

Coriander seed extract, its nonpolar organic solvent fraction or dry powder of linarool (1 part by weight)

Manor (0.5 parts by weight)

(0.5 parts by weight)

Preparation Example 3 Preparation of Beverage

A beverage comprising a coriander seed extract according to the present invention, a nonpolar organic solvent fraction thereof, or a linarool compound isolated therefrom was prepared as follows.

<3-1> Preparation of health drink

Substances such as liquid fructose (0.5%), oligosaccharides (2%), sugars (2%), salts (0.5%), water (75%) and coriander seed extracts according to the present invention, nonpolar organic solvent fractions thereof, or After separating the linarol compound homogeneously and sterilizing it instantaneously, it was packaged in a small packaging container such as a glass bottle, a plastic bottle to prepare a health beverage.

<3-2> Preparation of Vegetable Juice

0.5 g of coriander seed extract, a non-polar organic solvent fraction thereof, or a linaol compound isolated therefrom was added to 1,000 ml of a vegetable juice such as tomato or carrot to prepare vegetable juice for health promotion in a conventional manner.

<3-3> Preparation of Fruit Juice

Coriander seed extract according to the present invention, a non-polar organic solvent fraction thereof or 0.1 g of linaol compounds isolated therefrom was added to 1,000 ml of fruit juice such as apples or grapes to prepare fruit juice for health promotion in a conventional manner.

Claims (17)

A composition for inhibiting acyl coay: cholesterol acyltransferase (ACAT) activity comprising a coriander seed extract, a nonpolar organic solvent fraction thereof, a linarool compound of Formula 1 or a pharmaceutically acceptable salt thereof.
&Lt; Formula 1 >

The composition of claim 1, wherein the coriander seed extract is extracted from coriander seed using water, an organic solvent or a mixed solvent thereof. The organic solvent of claim 2, wherein the organic solvent is methanol, ethanol, isopropanol, butanol, ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N, N-dimethylformamide (DMF), di Methyl sulfoxide (DMSO), 1,3-butylene glycol, propylene glycol and a mixed solvent thereof. The composition of claim 1, wherein the nonpolar organic solvent fraction is fractionated from coriander seed extract with a nonpolar organic solvent selected from the group consisting of hexane, ether, dichloromethane, chloroform, ethyl acetate and mixed solvents thereof. Coriander seed having acyl coay: cholesterol acyltransferase (ACAT) inhibitory activity, comprising extracting coriander seed with water, an organic solvent or a mixed solvent thereof by cold extraction, heating extraction, ultrasonic extraction or reflux extraction. Preparation of Seed Extract. The organic solvent of claim 5, wherein the organic solvent is methanol, ethanol, isopropanol, butanol, ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N, N-dimethylformamide (DMF), di Methyl sulfoxide (DMSO), 1,3-butylene glycol, propylene glycol and a mixed solvent thereof is selected from the group consisting of. The method of claim 5, further comprising fractionating the extract using a nonpolar organic solvent or a mixed solvent thereof. 8. The method of claim 7, wherein the nonpolar organic solvent is selected from the group consisting of hexane, ether, dichloromethane, chloroform and ethyl acetate. 1) extracting coriander seed with water, an organic solvent or a mixed solvent thereof to obtain coriander seed extract;
2) fractionating the coriander seed extract obtained in step 1) with a nonpolar organic solvent to obtain a nonpolar organic solvent fraction; And
3) separating the linarol compound from coriander seed, comprising: purifying the nonpolar organic solvent fraction obtained in step 2) by chromatography to separate the linarol compound. The method of claim 9, wherein the organic solvent in step 1) is methanol, ethanol, isopropanol, butanol, ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N, N-dimethylformamide ( DMF), dimethylsulfoxide (DMSO), 1,3-butylene glycol, propylene glycol and mixed solvents thereof. 10. The method according to claim 9, wherein the coriander seed extract is dried in step 1) with a 2-5 times volume of water, an organic solvent or a mixed solvent of dried coriander seeds at 15 to 30 ° C. for 3 to 10 days by cold extraction, heat extraction, Which is obtained by ultrasonic extraction or reflux cooling extraction. 10. The process of claim 9, wherein in step 2) the nonpolar organic solvent is selected from the group consisting of hexane, ether, dichloromethane, chloroform and ethyl acetate. 10. The method of claim 9, wherein the nonpolar organic solvent fraction in step 3) is silica gel column chromatography using a concentration gradient solvent system of n-hexane: ethyl acetate, normal phase column chromatography using n-hexane: ethyl acetate as elution solvent, and Acetonitrile: A method which is sequentially purified by high performance liquid chromatography using water as an eluting solvent. Prevention or treatment of acyl coei: cholesterol acyltransferase (ACAT) -mediated disease comprising the composition of any one of claims 1 to 4 as an active ingredient and comprising a pharmaceutically acceptable carrier, excipient or diluent. Pharmaceutical composition for. The method of claim 14, wherein the acyl coay: cholesterol acyltransferase (ACAT) -mediated disease is hypercholesterolemia, hyperlipidemia, arteriosclerosis, atherosclerosis, coronary atherosclerosis, aortic aneurysm, Alzheimer's disease, obesity, atherosclerosis, vascular disease A pharmaceutical composition selected from the group consisting of restenosis and occlusion. An acyl coay: cholesterol acyltransferase (ACAT) -health functional food comprising the composition of any one of claims 1-4. The method of claim 16, wherein the acyl coay: cholesterol acyltransferase (ACAT) -mediated disease is hypercholesterolemia, hyperlipidemia, atherosclerosis, atherosclerosis, coronary atherosclerosis, aortic aneurysm, Alzheimer's disease, obesity, atherosclerosis, vascular disease Health functional food is selected from the group consisting of restenosis and occlusion.

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