KR20130047458A - Composition for preventing, improving, or treating a disease controlled by ppar action - Google Patents

Abstract

PURPOSE: A composition containing Dendrobium moniliforme is provided to prevent, relieve, or treat PPAR activation regulation-related diseases including obesity, metabolic diseases, and cardiovascular diseases. CONSTITUTION: A composition for preventing or treating PPAR activation regulation-related diseases contains Dendrobium moniliforme as an active ingredient. A composition for health functional food for preventing or treating PPAR activation regulation-related diseases contains Dendrobium moniliforme as an active ingredient. Dendrobium moniliforme is used as pulverized Dendrobium moniliforme, a dried material thereof, or a crude extract prepared by using a solvent which is selected from water, C1-C4 alcohol, and a combination thereof. The C1-C4 alcohol is methanol or ethanol. Dendrobium moniliforme is also used as a fraction which is prepared from the crude extract using n-hexane, methylene chloride, or ethyl acetate. [Reference numerals] (AA) Relative value(%); (BB) No treatment group, Troglitazone; (CC) Example <1-1>; (DD) Example <1-2>; (EE) Example <2> n-Hx; (FF) Example <2> MC; (GG) Example <2> EA; (HH) Example <3> fr2; (II) Example <3> fr3; (JJ) Example <3> fr2-2; (KK) Example <3> fr2-5; (LL) Example <3> compound 1; (MM) Example <3> compound 2; (NN) Example <3> compound 3; (OO) Example <3> compound 4

Description

Composition for preventing, improving, or treating a disease controlled by PPAR action}

The present invention relates to a composition for the prevention, amelioration or treatment of PPAR (Peroxisome Proliferator-Activated Receptor) modulators, and more specifically, from a plant herb, an extract of the plant herb, a fraction of the extract, or a plant herb. The present invention relates to a composition for preventing or treating PPAR modulatory diseases comprising the compound as an active ingredient.

Living organisms are deteriorated due to various factors, internal and external, and lose their homeostasis in the cell. As a result, the metabolic efficiency of sugars and fats decreases. In addition, overnutrition due to changes in eating habits increases metabolic dysfunctions such as obesity, hyperlipidemia and diabetes, and cardiovascular diseases such as hypertension and atherosclerosis, and these diseases are complicated by genetic and nutritional factors. I have causes.

Peroxysomes are one of the organelles that cause these metabolic disorders, and have been considered to play a minor role in cellular function for many years. It has been found to play an important role in metabolism. In addition, peroxysomes have been reported to have a wide range of effects on regulation of cell proliferation / differentiation and regulation of inflammatory mediators.

Intensive studies in this area over the last decade have shown that nuclear hormone receptors called peroxisome proliferator-activated receptors (PPARs) are good targets for the pharmacological approach of these diseases. I have given evidence that it will be. PPAR is one of 48 nuclear receptors and regulates the expression of related genes downstream by ligand binding. In PPAR, various fatty acids act as endogenous ligands.

There are three types of PPARs discovered to date: PPARα, PPARβ / δ, and PPARγ. PPARα is mainly found in the blood vessel wall, liver, heart, muscle, kidney, brown adipose tissue, and fibrates such as fenofibrate, bezafibrate, ciprofibrate and gemfibrozil. (Fibrate) is an agonist of PPARα, which is known to prevent or delay the onset of arteriosclerosis in rats and humans, and to have an anti-obesity effect through fatty acid promotion. In addition, PPARα plays an important role in promoting keratinocyte differentiation / proliferation inhibition in the epidermis of the skin, promoting skin barrier formation through lipid metabolism, suppressing inflammation, and repairing wounds. A erythema production inhibitory effect has also been reported (Non-Patent Document 1).

PPARδ, also known as PPARβ, is distributed in many tissues, especially in skin, brain and adipose tissue. PPARδ is involved in cholesterol back transport, myelination, and wound recovery, and acts as an important regulator of fatty acid metabolism and energy homeostasis (Non-Patent Document 2).

PPARγ is most common in adipose tissue and is found in vascular endothelium, macrophages, and pancreatic β-cells. It is less common in tissues where PPARα is found, such as liver, heart, and skeletal muscle. PPARγ is the most widely studied of the three subtypes. PPARγ plays a critical role in regulating the differentiation of fat cells, where it is expressed a lot, and in deciding on systemic lipid homeostasis. Global or partial activating compounds of PPARγ activity may be a target of effective therapeutics against obesity by inhibiting adipocyte differentiation. Moreover, partially activating compounds of PPARγ are effective in treating hyperglycemia as well as treating obesity. Thus, PPARγ total / partially activating compounds are effective in the treatment of obesity and other symptoms commonly occurring in non-insulin dependent diabetes mellitus such as elevated plasma levels of glucose, triglycerides and insulin (Non-Patent Documents 3 and 4). . Among the treatments for diabetes, thiazolidinediones-based drugs are PPARγ agonists, of which troglitazone, which was approved by the US FDA in January 1997, was recovered from the market due to hepatotoxicity, and rosiglitazone approved by the US FDA in 1999. And pioglitazone are currently in use.

In summary, when the PPAR action is activated, obesity, metabolic disease, cardiovascular disease, etc. may be treated, improved, or prevented.

Various studies have been made on PPARs, and patents for the invention of medicinal uses, such as novel agonists, diabetes or obesity, have been filed. As an effective ingredient for diabetic therapeutic agent (Patent Literature 1) using pear scent extract (patent document 1), diabetes prevention and therapeutic agent using Patent Literature leaf extract (patent document 2), and purple sweet potato extract fermentation broth as active ingredients Composition for inhibiting production and accumulation (patent document 3), obesity improving agent composition using wheat bran extract (patent document 4), PPAR delta activity promoting composition of the ginko wormwood extract (patent document 5), PPAR gamma activator of non-wood extract (patent document 6) etc.

Diabetes is one of the leading causes of death in the world, and the number of diabetics is increasing rapidly with the increase in the obese population. It is expected to increase to about 370 million by year. Compared with the severity of diabetes, there are few blood glucose control agents that have excellent efficacy and can be safely used. Biguanide- and glitazone-based drugs that increase insulin sensitivity have side effects such as lactate fructose, indigestion, weight gain, and myocardial infarction, and sulfonylurea-based drugs and meglitinide-based drugs that promote insulin secretion. , Glucagon-like peptide (GLP-1 analog) has side effects such as hypoglycemia, gastrointestinal disorders, headache, abdominal pain, etc., other α-glucosidase inhibitors lower digestive function, amylin analog is hypoglycemia, nausea It shows side effects. In addition to diabetes, obesity, hyperlipidemia, hypertension, etc. are also continuously increasing, and currently used synthetic obesity, hyperlipidemia, hypertension drugs have also been reported various side effects. Therefore, there is a need for a safer and more effective treatment for obesity, hyperlipidemia, hypertension, diabetes and the like.

Seokgok is a perennial herb belonging to the orchid family, whose scientific name is Dendrobium moniliforme , grows about 20 ~ 50 cm and grows in Korea, Japan and China. In oriental medicine, the whole plant except the root is called Seokgok, and when it blooms in summer, it cuts out the outpost and dries it in the sun and uses it as a medicinal herb. The pharmacologically active ingredients contained in the grains are known as alkaloids, dendrobine, nobilonin, dendtoxin, mucin and starch.

As a result of research on Seokgok, application for various medical applications has been made, antimicrobial composition (patent document 7), allergy disease treatment (patent document 8), atopic dermatitis treatment (patent document 9), liver fibrosis inhibitory activity (patent Document 10), VHR inhibitory activity (patent document 11), and the invention regarding inflammation suppression (patent document 12). However, no increase in PPAR activity of the bark or obesity, metabolic disease, or cardiovascular disease is known.

1. Korean Patent Publication 2011-0099369; 2. Korean Patent Publication 2011-0097209; 3. Korean Patent Publication No. 2011-0081760; 4. Korean Patent Publication No. 2011-0077644; 5. Korean Patent Publication No. 2011-0058287; 6. Korean Patent Publication No. 2011-0050394; 7. Korean Patent Publication No. 2011-0096102; 8. Korean Patent Publication No. 2011-0036127; 9. Korean Patent Publication No. 2010-0011767; 10. Korea Patent Registration 0949417; 11. Korean Patent Registration 0508686; 12. Registered Korean patent 0539298.

Kippenberger S, et.al., JID 117 (6): 1430-6, 2001 2. Empress Statue, et al., The Korean Journal of Endocrinology, 19 (3): 250, 2004 Choi et al., Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5, Nature 2010, 466: 451-456 Choi et al., Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation, Nature 2011, 477: 477-481

Accordingly, the present inventors have completed the present invention as a result of researching to find effective herbal and herbal medicine-derived materials that are effective for PPAR action-modulating diseases such as obesity, metabolic diseases, and cardiovascular diseases and without fear of side effects.

Accordingly, an object of the present invention is to provide a pharmaceutical composition and a health food composition comprising a plant herbal medicine, an extract thereof, or an extract fraction thereof, which is effective for PPAR action-modulating diseases.

Another object of the present invention is to provide a pharmaceutical composition and a composition for health food comprising a compound of plant herbal medicine effective for PPAR action-modulating diseases.

In order to achieve the above object,

It provides a pharmaceutical composition for the prevention or treatment of PPAR (Peroxisome Proliferator-Activated Receptor) action-controlled disease comprising a dendrobium moniliforme as an active ingredient.

Another aspect of the present invention provides a health functional food composition for preventing or improving PPAR action-modulating disease comprising a grains as an active ingredient.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating PPAR modulatory disorders, comprising a compound of Formula 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof:

[Formula 1]

R ¹ in Formula 1 is hydrogen or C ₁ -C ₄ alkyl.

[Formula 2]

R ² in Formula 1 is hydrogen or C ₁ -C ₄ alkyl.

Another aspect of the present invention provides a health functional food composition for preventing or treating PPAR function-modulating diseases, including the compound of Formula 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof.

Hereinafter, the present invention will be described in more detail.

The present inventors have studied to find a plant herb that is effective for PPAR action-controlling diseases. As a result, Seokgok extract, a fraction of the extract, and a specific compound obtained from the extract activate PPAR and have an effect on improving weight loss, lowering blood sugar, and improving hyperlipidemia. I found it.

Accordingly, in one aspect, the present invention provides a pharmaceutical composition for preventing or treating PPAR action-modulating diseases, including grains as an active ingredient.

In another aspect, the present invention provides a composition for preventing or ameliorating a PPAR function-controlling disease comprising a grains as an active ingredient.

Health functional foods defined in the present invention is a health function prescribed in the Food and Drug Administration Notice 2008-72 is sufficiently established that the newly defined functional and safety for the human body through the Act on Health Functional Foods amended in 2008 It means that it is a health functional food as listed in the regulations on the recognition of food functional ingredients.

Hereinafter, the pharmaceutical composition according to the present invention and the composition for health functional food are also referred to as "the herbal composition according to the present invention".

The grains contained in the pharmaceutical composition and the health functional food composition may be included in the form of an extract, or may be included as a ground powder of the herbal medicine, or as a dry ground powder of the herbal medicine.

The grains may be grown and used without restriction of purchase, or may be purchased and used commercially, some or all of the above-ground parts of the herb may be used, and preferably all of the above-ground parts may be used.

The extract of the grains may be a crude extract of water, a C ₁ -C ₄ alcohol, and a solvent selected from the group consisting of a combination thereof. The crude extract of the grains may preferably be a C ₁ -C ₄ alcohol extract, more preferably an extract of methanol or ethanol. When extracting with a solvent, the solvent is preferably extracted by adding about 5 to 15 times the amount of the grains, and it is preferable to extract by adding about 10 times the solvent, but is not limited thereto. The extraction may be heat extraction, cold needle extraction, reflux cooling extraction, or ultrasonic extraction. The extraction may be performed at room temperature, but for more efficient extraction, the extraction may be performed under heating conditions, preferably at about 40 to 100 ° C., more preferably at about 80 ° C., but is not limited thereto. It is not. The extraction time is preferably about 2 to 4 hours, more preferably about 3 hours, but is not limited thereto, and may vary depending on conditions such as extraction solvent and extraction temperature. The extraction may be extracted one or more times several times in order to obtain a larger amount of the active ingredient, preferably one to five times, more preferably three times the continuous extraction can be used combined extract.

The herbal composition according to the present invention may include grains as a crude extract, but may also be included as a soluble fraction of the organic solvent obtained by further extracting the crude extract with an organic solvent having a low polarity. Examples of the organic solvent include, but are not limited to, hexane, methylene chloride, ethyl acetate, n-butanol, and the like. Preferably, the crude methanol or ethanol crude extract of sucrose is suspended with distilled water and extracted in the order of n-hexane, methylene chloride, ethyl acetate, n-butanol in order from low polarity of solvent, n-hexane, methylene chloride By obtaining soluble fractions of ethyl acetate, n-butanol, the grains extract can be obtained as a soluble extract of the organic solvent. Of the soluble extracts of the organic solvents, soluble fractions of n-hexane, methylene chloride, and ethyl acetate are preferred because of their high PPAR activation effect.

The extract extracted by the method as described above or a soluble fraction of the extract may be used as it is, but may be used in the form of concentrated X after filtration, may be concentrated and then lyophilized to be used as a lyophilized form. Preferably, the concentrated extract after filtration is lyophilized and used as a lyophilisate.

The present inventors further purified the soluble fraction of the organic solvent having high PPAR activity by column chromatography to isolate specific compounds having high PPAR activity. The column chromatography may be separated and purified by performing column chromatography using a filler selected from the group consisting of silica gel, Sephadex, RP-18, polyamide, Toyopearl, and XAD resin. The column chromatography may be carried out several times by selecting an appropriate filler as necessary.

The inventors have purified the ethyl acetate soluble fraction of the soluble fraction of the organic solvent by column chromatography to obtain from the grains the gintol of formula 1a, tristine of formula 1b, ciprifedine of formula 2a, 3,8- of formula 2b. Dimethoxy-7-hydroxy-1,4-phenanthrendione was isolated and its structure confirmed by ¹ H-NMR and ¹³ C-NMR, confirming that this isolated compound has high PPAR activity.

[Formula 1a]

[Chemical Formula 1b]

(2a)

[Formula 2b]

Accordingly, in another aspect, the present invention provides a pharmaceutical composition for preventing or treating PPAR action-modulating diseases, comprising a compound of Formula 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof:

[Formula 1]

R ¹ in Formula 1 is hydrogen or C ₁ -C ₄ alkyl.

[Formula 2]

R ¹ in Formula 1 is hydrogen or C ₁ -C ₄ alkyl.

In another aspect, the present invention provides a composition for preventing or treating PPAR function-modulating diseases, including a compound of Formula 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof. .

Hereinafter, including the pharmaceutical composition and the health functional food composition according to the present invention also referred to as a compound containing composition according to the present invention.

The compound of Formula 1 is preferably gigantol or tristine, and the compound of Formula 2 is cypripedin, or 3,8-dimethoxy-7-hydroxy-1,4-phenan It is preferred that it is trendydione (3,8-Dimethoxy-7-hydroxy-1,4-phenanthrenedione).

The pharmaceutically acceptable salt may be present as an acid addition salt in which the compound of Formula 1 or 2 together with the free acid forms a salt. The compounds of formula 1 or 2 may form pharmaceutically acceptable acid addition salts according to conventional methods known in the art. The free acid may be an organic acid or an inorganic acid, and the inorganic acid may be hydrochloric acid, bromic acid, sulfuric acid, or phosphoric acid, and the organic acid may be citric acid, acetic acid, lactic acid, tartaric acid, or tartariac acid. ), Maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, methanesulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, galluxuronic acid, embon acid, Glutamic acid or aspartic acid, etc. can be used. In addition, the compound of Formula 1 or 2 according to the present invention may include all salts, hydrates, and solvates that can be prepared by conventional methods, as well as pharmaceutically acceptable salts.

The compound of Formula 1 or 2 may be prepared by synthesis or semisynthesis using conventional knowledge known in the art of organic chemistry, preferably by extraction, concentration, column chromatography from dendrite according to the above method. It may be obtained by purification, or may be extracted by any method in which the compound of Formula 1 or 2 may be obtained in addition to the above method.

The herbal composition and the compound composition according to the present invention can be used to prevent, ameliorate or treat PPAR action-modulating diseases. The "PPAR modulatory disease" refers to any disease in which promoting PPAR activity may be beneficial for the treatment, amelioration or prevention of the disease. The PPAR action-controlling disease may be selected from the group consisting of obesity, metabolic disease, cardiovascular disease, and combinations thereof, but is not limited thereto, and all diseases known to be PPAR action-controlling diseases, and PPAR action-controlling diseases in the future. It includes any disease that will turn out to be.

The metabolic disease may be selected from the group consisting of diabetes, hyperlipidemia, hyperinsulinemia, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X), endothelial dysfunction, and combinations thereof, It is not limited to this. The hypercholesterolemia may be selected from low HDL-cholesterolosis, high LDL-cholesterolosis, hypertriglyceridemia, and combinations thereof.

The cardiovascular disease may be selected from the group consisting of hypertension, precoagulant state, dyslipidemia, atherosclerosis, and combinations thereof, but is not limited thereto.

It is demonstrated in the following examples that the herbal composition and the compound composition according to the present invention have PPAR activity promoting effect. Specifically, the methanol extract of Seokgok according to the present invention, the respective soluble fractions extracted in the order of hexane, methylene chloride, ethyl acetate, and the column fraction separated from the ethyl acetate soluble fraction, the column fraction The effects on the activation of PPARγ involved in fat and sugar metabolism of the compounds of Formulas 1a, 1b, 2a, and 2b obtained from were measured using a luciferase assay system. As a result, the degree of activation of PPARγ was equal or better than when treated with a troglitazone positive control known as a PPARγ agonist, and the higher the throughput, the higher the value (see Table 1 and FIG. 1). Thus, gyolithol extract, soluble fraction of the extract thereof, or gintol, tristine, ciprifedine, and 3,8-dimethoxy-7-hydroxy-1,4-, which are compounds isolated from the fraction, according to the present invention It can be seen that phenanthrendione can function as a PPARγ agonist.

In addition, methanol extract of Seokgok according to the present invention, the respective soluble fractions extracted in the order of hexane, methylene chloride, ethyl acetate, and column fractions separated from the ethyl acetate soluble fraction, obtained from the column fractions The effects on the activation of PPARα for the compounds of Formulas 1a, 1b, 2a and 2b were measured using a luciferase assay system. As a result, the degree of activation of PPARα was equal to or better than that of the Wy-14,643 positive control group, which is a well-known PPARα agonist, and the higher the throughput, the higher the value (Table 2 and FIG. 2). Reference). Thus, Gyotolol, Tristine, Ciprifedine 3,8-dimethoxy-7-hydroxy-1,4-phenanthrendion, which is a grain extract according to the present invention, a soluble fraction thereof, or a compound isolated from the fraction, It can be seen that it can function as a PPARα agonist.

In addition, while feeding the high-fat diet for 8 weeks to C57BL / 6 mice to confirm whether the Seokgok extract according to the present invention has an improved metabolic effect, while the daily oral administration of the Seokgok extract and commercial or developed control drugs to feed the mouse Changes in intake, water intake, and body weight were observed, and changes in fasting blood glucose and cholesterol were measured after administration. As a result, it was confirmed that the Seokgok extract significantly reduced the weight of the high fat diet than the treated group (see Table 3 and FIG. 3). See Table 3 and FIG. 4). In addition, the Seokgok extract was measured after fasting for 18 hours after 8 weeks of administration, fasting glucose was found to be significantly lower than the high-fat diet group (see Table 4 and Figure 5) and confirmed that the level is almost similar to other commercially available drugs Could. In addition, as a result of measuring blood cholesterol, high-fat diet significantly lowered total cholesterol and LDL-cholesterol than the treated group (see Table 5 and FIG. 6). It can be assumed that there is no.

The herbal composition according to the present invention and the compound composition according to the present invention, in addition to the stone extract, its soluble fraction, or the compound of formula 1 or 2, in addition to other active ingredients having a PPAR activity promoting effect, or the obesity, metabolic disease, Or it may further contain one or more other active ingredients effective for cardiovascular diseases.

The pharmaceutical compositions according to the present invention may be formulated in conventional pharmaceutical formulations known in the art. The pharmaceutical formulation may be formulated and administered in any formulation including, but not limited to, oral, injectable, suppository, transdermal, and non-administrative agents, preferably liquids, emulsions, suspensions, Oral formulations, including liquid formulations such as excipients, or syrups and solid formulations such as powders, granules, tablets, capsules, or pills.

When formulating into each of the above-mentioned formulations, a pharmaceutically acceptable excipient or an additive necessary for the preparation of each of the formulations may be added. Typically, when formulated into a solid preparation for oral administration, at least one of a diluent, a lubricant, a binder, a disintegrant, a sweetener, a stabilizer, and an antiseptic can be selected and used as the excipient. Examples of the diluent include lactose, corn starch, soybean oil, microcrystalline cellulose or mannitol as the diluent, magnesium stearate or talc as the lubricant, polyvinylpyrrolidone or hydride as the binder, Roxypropylcellulose is preferred. The disintegrant is preferably carboxymethylcellulose calcium, sodium starch glycolate, polacrilin potassium, or crospovidone. Liquid preparations for oral administration may include various excipients such as wetting agents, sweeteners, fragrances and preservatives in addition to water and liquid paraffin which are simple diluents commonly used in formulation. Examples of the sweetening agent include white sugar, fructose, sorbitol, or aspartame, carboxymethyl cellulose sodium, beta-cyclodextrin, white lead, or xanthan gum as a stabilizer, methyl paraoxybenzoate, propylparabooxybenzoate, desirable. As additives for solid and liquid oral preparations, one or more of flavoring agents, vitamins, and antioxidants may be selected and used. In addition to the above components, natural additives such as natural flavors such as plum flavor, lemon flavor, pineapple flavor and herb flavor, natural fruit juice, natural coloring matters such as chlorophyllin and flavonoid, fructose, honey, sugar alcohol and sugar A sweetening component, or an acid anhydride such as citric acid or sodium citrate may be mixed and used.

Such conventional pharmaceutical formulations may be appropriately prepared by one of ordinary skill in the art according to conventional methods known in the art and described in Remington's Pharmaceutical Science, 15th Edition, 1975, Mack Publishing Company Easton, Pennsylvania 19042 (Chapter 87; Blaug, Seymour ).

As a result of toxicity experiments by orally administering the pharmaceutical composition to rats, 50% lethal dose (LD50) by oral toxicity test was determined to be a safe substance of at least 5 g / kg or more. The pharmaceutical composition is 0.01 to 0.5 as a lyophilized compound or a compound of the herbal extract in a daily daily dose as an active ingredient to prevent or treat PPAR action-control diseases including obesity, metabolic diseases, cardiovascular diseases listed above g / kg, the powder of the herbal medicine itself may be administered by dividing several times arbitrarily so that it may be 0.1-5.0 g / kg. The dosage may be appropriately increased or decreased depending on the route of administration, disease progression, sex, age, weight, or the like, or by clinical judgment of the expert. The pharmaceutical composition according to the present invention may be used alone or in combination with methods using surgery, hormonal therapy, chemotherapy and biological response modulators for the prevention or treatment of PPAR action-modulating diseases.

The composition for health functional food according to the present invention can be formulated into a conventional health functional food formulation known in the art.

 The health functional food may be prepared by conventional formulations such as powders, granules, tablets, pills, capsules, suspensions, emulsions, syrups, Beverages, tea, drinks, alcoholic beverages, and vitamins, such as, for example, beverages, snacks, confectionery, pizza, ramen, other noodles, gums, jellies, ice creams, A pharmaceutically acceptable carrier or additive may be used for the formulation of the health food, and any carrier or additive known to be usable in the art for the preparation of the formulation to be prepared may be used. As the above-mentioned additives, there can be used various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, Carbonating agents, and the like. In addition, it may contain natural fruit juice, fruit juice beverage and flesh for the production of vegetable beverages. These additive components can be used independently or in combination, and the ratio of the additives is not critical but can be 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.

The health functional food composition may be appropriately determined according to the purpose (prevention or improvement) of the herbal ingredients constituting the composition according to the present invention. In general, it may comprise 0.01 to 15% by weight, preferably 0.2 to 10% by weight of the total food weight, when prepared as a beverage in a ratio of 0.1 to 30g, preferably 0.2 to 5g based on 100 mL It may contain.

The beverage may further contain other ingredients in addition to the herbal ingredients, and may further contain various flavors or natural carbohydrates, etc. that are commonly used in beverages. Examples of the natural carbohydrate include conventional sugars such as monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugars such as xylitol, sorbitol, erythritol, Of sugar alcohols may be contained. In addition, as a flavoring agent, a natural flavoring agent (e.g., tau Martin, stevia extract, etc.) and a synthetic flavoring agent (e.g., saccharin, aspartame, etc.) may be contained. The ratio of the natural carbohydrate is preferably about 1 to 20 g, preferably about 5 to 12 g per 100 mL of beverage.

As described above, the composition comprising the stone, the extract of the stone, the soluble fraction of the organic solvent of the extract, the compound of formula 1 or 2 as an active ingredient according to the present invention has the effect of promoting PPAR activity, thus obesity, metabolic It can be usefully used to treat, ameliorate or prevent PPAR action-controlling diseases including diseases, cardiovascular diseases. In addition, the composition has an advantage that it can be used for a long period of time without fear of side effects that may occur in conventional diabetes remedy, hypertension treatment drug, and hypertension treatment drug by using plant herbal medicine which has been used for a long time and safety is established as a raw material.

1 shows PPARγ of Gyotolol, Tristine, Ciprifedine, or 3,8-dimethoxy-7-hydroxy-1,4-phenanthrendione, which is a grain extract, a fraction thereof, and a compound isolated from the fraction. It is a graph showing the result of measuring the degree of activation.
FIG. 2 shows PPARα of Gytolol, Tristine, Ciprifedine, or 3,8-dimethoxy-7-hydroxy-1,4-phenanthrendione, which is a grain extract, a fraction thereof, and a compound isolated from the fraction. It is a graph showing the result of measuring the degree of activation.
Figure 3 is a graph showing the results of measuring the weight change of 8 injections from 0 weeks in the high-fat diet mouse model when administration of the Seokgok extract.
Figure 4 is a graph showing the results of measuring the effect on the weight gain for 8 weeks in the high-fat diet mouse model extract.
Figure 5 is a graph showing the results of measuring the effect of Seokgok extract on fasting blood glucose changes in a high-fat diet mouse model.
Figure 6 is a graph showing the results of measuring the effect of the Seokkok extract on the change of total cholesterol and LDL-cholesterol in high fat diet mouse model.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these embodiments are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

Example 1 Preparation of Stone Grain Extract

Seokgok used in the present invention was purchased and used in Seoul Gyeongdong market herbal medicine.

<1-1> Preparation of Methanol Extract of Seokgok

4 Kg of granite ground parts were soaked in 40 L of 100% methanol and ultrasonically extracted for 3 hours. The extraction was repeated three times. The extract was dried under reduced pressure and concentrated to give 220 g of concentrate.

<1-2> Preparation of Water Extract of Seokgok

4 Kg of granite ground was immersed in 40 L of water and sonicated for 3 hours. The extraction was repeated three times. The extract was dried under reduced pressure and concentrated to give 195 g of concentrate.

<1-3> Preparation of ethanol extract of grains

4 Kg of the tops of the granite trees were soaked in 40 L of 100% ethanol and ultrasonically extracted for 3 hours. The extraction was repeated three times. The extract was dried under reduced pressure and concentrated to give 205 g of concentrate.

Example 2 Preparation of Fractions from Stone Extracts

The extract of Example <1-1> was suspended in distilled water, and n-hexane fractions (n-Hx, 22.3 g), methylene chloride fractions (MC, 27.2 g), and ethyl acetate fractions were sequentially added according to the polarity of solvent therefrom. EA, 9.3 g), n-butanol fraction (n-BuOH, 17.5 g), and water fraction (W, 121.6 g) were obtained. Significant increases in PPAR activity were observed in the organic layers n-hexane, methylene chloride and ethyl acetate.

Example 3 Isolation of Active Compound

To separate the active compound from the organic layer, 22 g of the extract of <1-1> was suspended in 0.5 L of water and re-extracted three times with 0.5 L of ethyl acetate to obtain 10 g of ethyl acetate fraction. This is mixed with n-hexane, ethyl acetate (EA) and methanol (n-Hx: EA = 10: 1->-> n-Hx: EA = 0: 1, EA: MeOH = 10: 1->-> EA : MeOH = 0: 1) was performed by silica gel column chromatography and divided into four small fractions (fr1-fr4). Small fraction 2 (fr2) and small fraction 3 (fr3) showed high PPAR activity, and four compounds 1-4 were isolated by attempting to separate the active ingredient from these small fractions. The subfractions 2 and 3 were combined and subjected to silica gel column chromatography with an n-Hx-EA gradient solvent system (10: 1-> 1: 1) and divided into eight subfractions (fr2-1 -fr2-8). Silica gel column chromatography was performed on the lower fraction 2-2 with n-Hx: EA (200: 1) to obtain compounds of Formula 1a (5 mg) and Formula 1b (3 mg). Silica gel column chromatography was performed on a n-Hx: EA (100: 1) solution to obtain a compound of Chemical Formula 2a (10 mg) and Chemical Formula 2b (5 mg).

The compound was identified by NMR ( ¹ H and 13 C-NMR, Varian 500 MHz spectrometer, Varian USA). The compound of Formula 1a is Gigantol, and the compound of Formula 1b is Tristine, The compound was Cypripedin, and the compound of Formula 2b was identified as 3,8-dimethoxy-1,4-phenanthrendione (3,8-Dimethoxy-1,4-phenanthrenedione).

Compound of Formula 1a (Gigantol)

¹ H NMR (CDCl ₃ , 500 MHz): δ 6.81 (d, 1H, J = 8.0 Hz), 6.62 (d, 1H, J = 8.0 Hz), 6.58 (s, 1H), 6.28 (s, 1H), 6.25 (d, 2H, J = 10.0 Hz), 3.76 (s, 3H, OCH ₃ ), 3.69 (s, 3H, OCH ₃ ), 2.74 (m, 4H); LRMS (ESI): m / z 273 [M ⁻ H] ⁻

Formula 1b Compound (Tristin)

¹ H NMR (CDCl ₃ , 500 MHz): δ 7.94 (d, 1H, J = 9.5 Hz), 6.75 (m, 2H), 6.43 (d, 1H, J = 2.5 Hz), 6.35 (d, 1H, J = 2.0 Hz), 6.26 (d, 1H, J = 1.5 Hz), 3.80 (s, 3H, OCH ₃ ), 2.73 (s, 4H); LRMS (ESI): m / z 259 [M ⁻ H] ⁻

Compound of Formula 2a (Cypripedin)

¹ H NMR (CDCl ₃ , 500 MHz): δ 9.29 (d, 1H, J = 9.5 Hz), 8.39 (d, 1H, J = 8.5 Hz), 8.11 (d, 1H, J = 8.5 Hz), 7.48 ( d, 1H, J = 9.5 Hz), 6.23 (s, 1H), 3.97 (s, 3H, OCH ₃ ), 3.95 (s, 3H, OCH ₃ ); LRMS (ESI): m / z 283 [MH] ^-

Compound of Formula 2b (3,8-Dimethoxy-7-hydroxy-1,4-phenanthrenedione)

¹ H NMR (CDCl ₃ , 500 MHz): δ 9.35 (d, 1H, J = 9.5 Hz), 8.27 (d, 1H, J = 9.0 Hz), 8.21 (d, 1H, J = 8.5 Hz), 7.43 ( d, 1H, J = 10.0 Hz), 6.14 (s, 1H), 3.96 (s, 3H, OCH ₃ ), 3.92 (s, 3H, OCH ₃ ); LRMS (ESI): m / z 283 [MH] ^-

Experimental Example 1 PPARγ Activation Experiment Involved in Fat and Sugar Metabolism

Plasmid has a PPARγ gene after a universal promoter that is expressed even in normal culture conditions, and has a PPPAR (PPARs Response Element) that is activated by binding a ligand-binding PPARγ as a promoter to serve as a reporter. A plasmid (pRL-SV40, Promega, USA) with a firefly luciferase gene and a Renilla luciferase gene bound to a universal promoter to be used as a reference was used (KLIEWER). SA., Proc. Nadl. Acad. Sci. USA, 91: 7355-7359, 1994).

CV-1 cells (CCL-70, ATCC) were placed on a 24-well plate at a concentration of 5 × 10 ⁴ , and then cultured for 24 hours, and then transfected with the three kinds of plasmid genes by transient transfection. . After incubation for 24 hours and washed with 1 x Phosphate Buffered Saline (PBS). The samples of Table 1 were treated by concentration, incubated for 24 hours, washed with 1 x PBS, and then cells were lysed with 1 x Passive Lysis Buffer (PLB), followed by a dual-luciferase receptor assay system kit ( The luciferase activity of samples and references was measured using the dual-Luciferase ^R Reporter Assay System kit (Promega, USA). In this experiment, the control group used troglitazone, which is known as one of the ligands of PPARγ, and the control group was treated as the untreated group. A comparison was shown with the activation degree of the negative control group being 100.

The results are shown in Table 1 and FIG.

Degree of Activation of PPARγ in Seokgok Extract, Fractions thereof, or Compound Isolated from the Fractions sample density Activation degree Untreated group 100 Troglitazone 10 uM 460 Example <1-1> 300 ug / mL 390 100 ug / mL 280 30 ug / mL 190 Example <1-2> 300 ug / mL 380 100 ug / mL 275 30 ug / mL 203 Example <2> n-Hx 100 ug / mL 320 30 ug / mL 250 10 ug / mL 180 Example <2> MC 100 ug / mL 300 30 ug / mL 230 10 ug / mL 162 Example <2> EA 100 ug / mL 250 30 ug / mL 195 10 ug / mL 143 Example <3> fr2 100 ug / mL 395 30 ug / mL 301 10 ug / mL 204 Example <3> fr3 100 ug / mL 373 30 ug / mL 294 10 ug / mL 184 Example <3> fr2-2 30 ug / mL 386 10 ug / mL 297 3 ug / mL 225 Example <3> fr2-5 30 ug / mL 267 10 ug / mL 224 3 ug / mL 183 Example 3 Compound 1 30 uM 390 10 uM 287 3 uM 195 Example 3 Compound 2 30 uM 420 10 uM 326 3 uM 234 Example 3 Compound 3 30 uM 250 10 uM 183 3 uM 132 Example 3 Compound 4 30 uM 260 10 uM 198

As shown in Table 1 and FIG. 1, the Seokgok extract, fractions thereof, or the compounds isolated from the fractions are gintol, tristine, ciprifedine, 3,8-dimethoxy-7-hydroxy-1,4- Phenanthrendione showed higher levels of PPARγ activation when treated with the non-treated controls, and the higher the throughput, the higher the levels. Therefore, Seokgok extract, fractions thereof, or compounds isolated from the fractions of the present invention Since it showed a tendency to activate PPARγ, it can be seen that it is an excellent component that serves to improve fat and sugar metabolism.

Experimental Example 2 PPARα Activation Tests That Promote Fatty Acid Oxidation

Plasmid used PPARα instead of PPARγ and the same one used in Experimental Example 1 above was used.

CV-1 cells were placed on 24-well plates at a concentration of 5 × 10 ⁴ , and then cultured for 24 hours, followed by transient transfection of the three kinds of plasmid genes. After 24 hours of incubation and then washed with 1x Phosphate Buffered Saline (PBS), the samples of Table 2 were treated according to the concentration, and after 24 hours incubation with 1xPBS and washed cells with 1xPLB and then dual-luciferase Receptor Assay System Kit (Dual-Luciferase  Luciferase activity of samples and references was measured using a Reporter Assay System kit (Promega, USA). In this experiment, the positive control group used Wy-14,643 (Sigma, USA), which is known to be the strongest of the PPARα ligands, and the negative control group was the untreated group.

The results are shown in Table 2 and FIG.

Seokgok  Extract, its Fraction , Or above In the fraction  Of isolated compounds PPAR degree of activation for α sample density Activation degree Untreated group 100 Wy14,643 10 uM 690 Example <1-1> 300 ug / mL 700 100 ug / mL 430 30 ug / mL 280 Example <1-2> 300 ug / mL 680 100 ug / mL 420 30 ug / mL 250 Example <2> n-Hx 100 ug / mL 750 30 ug / mL 480 10 ug / mL 301 Example <2> MC 100 ug / mL 542 30 ug / mL 356 10 ug / mL 274 Example <2> EA 100 ug / mL 490 30 ug / mL 299 10 ug / mL 205 Example <3> fr2 100 ug / mL 706 30 ug / mL 502 10 ug / mL 324 Example <3> fr3 100 ug / mL 650 30 ug / mL 492 10 ug / mL 316 Example <3> fr2-2 30 ug / mL 620 10 ug / mL 487 3 ug / mL 283 Example <3> fr2-5 30 ug / mL 330 10 ug / mL 249 3 ug / mL 158 Example 3 Compound 1 30 uM 570 10 uM 380 3 uM 250 Example 3 Compound 2 30 uM 620 10 uM 410 3 uM 270 Example 3 Compound 3 30 uM 370 10 uM 250 3 uM 180 Example 3 Compound 4 30 uM 220 10 uM 150

As shown in Table 2 and FIG. 2, Seokgok extract, fractions thereof, or the compounds isolated from the fractions, gintol, tristine, ciprifedine, 3,8-dimethoxy-7-hydroxy-1,4- Phenanthrendione showed a higher level of activation of PPARα when the materials were treated compared to the untreated control group, and the higher the throughput, the higher the levels.

Experimental Example 3 Metabolic Improvement Efficacy of High-Tag Diet Mouse Extracts

The present inventors performed the following experiment to determine whether the Seokgok extract is effective in improving metabolism in vivo. Seven-week-old C57BL / 6 mice (SPL Co., Ltd.) were used to evaluate the effect of high-fat diet on the metabolic improvement of each grain extract and control group. The control group used Metformin, Pioglitazone and Tesaglitazar, which are currently available or developed drugs for the treatment of diabetes. Mice were acclimated to the laboratory for 1 week and then divided into 7 groups. The group fed the normal diet was the untreated, high-fat diet (AIN-76A, 40% beef tallow). Metformin group for 500 mg / Kg group, high-fat diet and Pioglitazone 30 mg / Kg group for Pioglitazone group, high-fat diet and Tesaglitazar 1 mg / Kg The group given mg / Kg and 200 mg / Kg was set as Example <1-1>. Each drug was suspended orally in 0.8% methylcellulose solution and administered orally every day for 8 weeks. The daily food intake, water intake, and weight change of the animals were observed after administration of the test substance, and blood was collected after 8 weeks of administration, and fasting glucose, total cholesterol, and LDL-cholesterol were measured after meals. The results are shown in Tables 3 to 5 and FIGS. 3 to 6.

Seokgok  Effect of High Fat Diet on Body Weight Change in Mice sample Week 0 (g) Week 8 (g) 8 weeks
Weight gain (g) No treatment 23.1 28.5 5.4 Highland method 23.3 37.9 14.6 Metformin 500 mg / Kg 23.6 29.8 6.2 Pioglitazone 30 mg / Kg 24.6 39.3 14.7 Tesaglitazar 1 mg / Kg 23.3 30.1 6.8 Example <1-1> 100 mg / Kg 22.1 31.3 9.2 200 mg / Kg 22.4 30.0 7.6

As shown in Table 3 and Figures 3 and 4, the Seokgok extract was shown that the high fat diet did not increase the weight than the treatment group, and showed almost the same level of efficacy as the commercial metformin. In addition, when compared with the weight increase rate, it was confirmed that the weight was maintained at a much lower level than the PPAR gamma agonist (agonist) Pioglitazone.

Seokgok Extract  Effect of High Fat Diet on Fasting Glucose Changes in Mice sample density Fasting Blood Sugar (mg / dL) No treatment 99.75 Highland method 180.25 Metformin 500 mg / Kg 106.6 Pioglitazone 30 mg / Kg 129.4 Tesaglitazar 1 mg / Kg 113 Example <1-1> 100 mg / Kg 125.2 200 mg / Kg 116.6

As shown in Table 4 and Figure 5, Seokgok extract was confirmed that the high-fat diet lowering fasting blood sugar than the treatment group has a glycemic control effect, it was confirmed that the effect is almost the same level as other commercial drugs.

Seokgok Extract  Effect of High Fat Diet on Changes of Blood Cholesterol in Mice sample density Total Cholesterol (mg / dL) LDL-cholesterol (mg / dL) No treatment 97.75 15.25 Highland method 160.2 32.6 Metformin 500 mg / Kg 124.8 14.8 Pioglitazone 30 mg / Kg 146.4 31.2 Tesaglitazar 1 mg / Kg 126.8 74.4 Example <1-1> 100 mg / Kg 127.6 21 200 mg / Kg 117.2 21

As shown in Table 5 and Figure 6, the Seokgok extract was found to have a lipid-lowering effect of lowering total cholesterol and LDL-cholesterol than the high fat diet treatment group, which has side effects of increasing cholesterol which is a side effect of other commercial drugs. Could be confirmed.

< Experimental Example  4> Seokgok  Extract, its Fraction  And said In the fraction  Acute Toxicity Test of Oral Administration of Isolated Compounds

The inventors performed the following experiment to determine the acute toxicity of the stone extract, its fractions and the compounds isolated from the fractions. Acute toxicity experiments were performed using 6 week-old SPF rats. Extracts of Seokgok, its fractions and the compounds isolated from the fractions were each suspended in 0.5% methylcellulose solution and administered orally at a dose of 5 g / kg / 15 ml. Hematology and blood biochemical tests were performed by observing the mortality, clinical symptoms, and weight changes of the animals after the administration of the test substance.

As a result, no significant clinical symptoms or dead animals were noted in all animals treated with the test substance, and no toxic changes were observed in body weight changes, blood tests, blood biochemical tests, and autopsy findings.

As a result, the rats showed no toxicity change up to 5 g / kg, and the minimum lethal dose (LD ₅₀ ) for oral administration was found to be a safe substance of 5 g / kg or more.

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

Preparation Example 1 Preparation of Pharmaceutical Formulation

1. Preparation of powder

2 g extract of Example <1-3>

Lactose 1 g

The above components were mixed and packed in airtight bags to prepare powders.

2. Preparation of tablets

100 mg of extract of Example <1-3>

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

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

3. Preparation of Capsule

100 mg of extract of Example <1-3>

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

4. Manufacture of rings

1 g extract of Example <1-3>

Lactose 1.5 g

Glycerin 1 g

0.5 g of xylitol

After mixing the above components, it was prepared to be 4 g per ring according to a conventional method.

5. Manufacture of granules

150 mg of extract of Example <1-3>

Soybean extract 50 mg

200 mg of glucose

600 mg of starch

After mixing the above components, 100 mg of 30% ethanol was added and dried at 60 DEG C to form granules, which were then filled in a capsule.

&Lt; Formulation Example 2 >: Production of health food

Health foods containing the Seokok extract of the present invention were prepared as follows.

1. Preparation of cooking seasoning

20 ~ 95 parts by weight of the extract of Example <1-2> of the present invention to prepare a cooking seasoning for health promotion.

2. Manufacture of tomato ketchup and sauce

0.2 ~ 1.0 parts by weight of the extract of Example <1-2> of the present invention was added to tomato ketchup or sauce to prepare tomato ketchup or sauce for health promotion.

3. Manufacture of flour food

0.5 to 5.0 parts by weight of the extract of Example <1-2> of the present invention was added to the flour, and bread, cake, cookies, crackers and noodles were prepared using the mixture to prepare foods for health promotion.

4. Manufacture of soups and gravies

0.1 ~ 5.0 parts by weight of the extract of Example <1-2> of the present invention was added to soups and gravy to prepare meat products for health promotion, soups and noodles of noodles.

5. Manufacture of ground beef

10 parts by weight of the extract of Example <1-2> of the present invention was added to the ground beef to prepare a ground beef for health promotion.

6. Manufacture of dairy products

5 to 10 parts by weight of the extract of Example <1-2> of the present invention was added to milk, and various dairy products such as butter and ice cream were prepared using the milk.

7. Manufacturing of wires

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. The extract of Example <1-2> of the present invention was concentrated under reduced pressure in a vacuum concentrator, and the dried product obtained by drying with a spray and a hot air dryer was pulverized with a particle size of 60 mesh to obtain a dry powder.

The grains, seeds, and dry powder of the extract of Example <1-2> prepared above were blended in the following proportions.

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

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

The dried powder (3 parts by weight) of the compound isolated from the extract of Example < 1-2 >

(0.5 part by weight),

(0.5 parts by weight)

<Example 3> Preparation of health drink

1. Manufacture of health drink

       1000 mg of extract of Example <1-2>

       Citric acid 1000 mg

       100 g of oligosaccharide

       Plum concentrate 2 g

       Taurine 1 g

       Add 900 ml of purified water

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 ° C for about 1 hour. The resulting solution was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, It is used in the production of the health beverage composition of the invention.

Although the composition ratio is a composition suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and intended use.

2. Manufacture of vegetable juice

5 g of the extract of Example <1-2> of the present invention was added to 1,000 ml of tomato or carrot juice to prepare a vegetable juice for health promotion.

3. Manufacture of fruit juice

1 g of the extract of Example <1-2> of the present invention was added to 1,000 ml of apple or grape juice to prepare a fruit juice for health promotion.

Claims (14)

Pharmaceutical composition for the prevention or treatment of PPAR (Peroxisome Proliferator-Activated Receptor) action-controlling disease comprising a dendrobium moniliforme as an active ingredient. A dietary supplement for the prevention or improvement of PPAR action-controlling diseases comprising dendrobium moniliforme as an active ingredient. The method according to claim 1 or 2, wherein the grains are contained as a crude extract of the crude powder itself, a dry ground powder of the herbal medicine, or water, a C ₁ -C ₄ alcohol, and a solvent selected from the group consisting of a combination thereof. A composition, characterized in that. The composition of claim 3, wherein the C ₁ -C ₄ alcohol is methanol or ethanol. The composition according to claim 1 or 2, wherein the grains are contained as a solvent fraction of n-hexane, methylene chloride, or ethyl acetate of a crude extract of C ₁ -C ₄ alcohol solvent. A pharmaceutical composition for the prophylaxis or treatment of PPAR modulatory disorders comprising a compound of Formula 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[Formula 1]

R ¹ in Formula 1 is hydrogen or C ₁ -C ₄ alkyl.
(2)

R ¹ in Formula 1 is hydrogen or C ₁ -C ₄ alkyl. A health functional food composition for preventing or ameliorating a PPAR function-modulating disease comprising a compound of Formula 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof:
[Formula 1]

R ¹ in Formula 1 is hydrogen or C ₁ -C ₄ alkyl.
(2)

R ² in Formula 1 is hydrogen or C ₁ -C ₄ alkyl. 8. The compound of claim 6 or 7, wherein the compound of formula 1 or 2 is gigantol, tristin, cypripedin, or 3,8-dimethoxy-7-hydroxy- 1,4-phenanthrendione (3,8-Dimethoxy-7-hydroxy-1,4-phenanthrenedione). The composition of claim 6 or 7, wherein the compound of Formula 1 or 2 is extracted from the grains. The method according to any one of claims 1, 2, 6, and 7, wherein the PPAR modulatory disease is selected from the group consisting of obesity, metabolic disease, cardiovascular disease, and combinations thereof. Composition. The group of claim 10, wherein the metabolic disease comprises diabetes, hyperlipidemia, hyperinsulinemia, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic syndrome (Syndrome X), endothelial dysfunction, and combinations thereof. A composition, characterized in that is selected from. The composition of claim 10, wherein the cardiovascular disease is selected from the group consisting of hypertension, precoagulant state, dyslipidemia, atherosclerosis, and combinations thereof. The composition according to claim 1 or 6, which is in the form of a powder, granule, tablet, capsule, suspension, emulsion, syrup, liquid, aerosol, extract, injectable, transdermal or suppository. 8. A composition according to claim 2 or 7, which is in the form of a powder, granule, tablet, capsule, suspension, emulsion, syrup, liquid, aerosol, extract, tea, jelly, or beverage.

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