KR20070100829A - Therapeutic agent - Google Patents

Abstract

A therapeutic agent or preventive agent for a disease requiring an antifoaming action and/or an acyl-CoA-cholesterol acyl transferase inhibitory action on a cell in treatment or prevention, characterized by comprising as an active ingredient, a processed matter derived from Peucedanum japonicum Thunb.

Description

Remedy {THERAPEUTIC AGENT}

The present invention provides a medicament and food useful for the treatment or prevention of diseases, such as atherosclerosis and hyperlipidemia, which require anti-foaming action of cells and / or acyl CoA cholesterol acyltransferase inhibitory action in the treatment or prevention. Or feed.

In recent years, there has been a surge in the so-called lifestyle disorders such as arteriosclerosis, hyperlipidemia, hypertension, and diabetes, accompanied by changes in diet, which include high calorie- and high-cholesterol diets, and an increase in the old age group by prolonging life expectancy. It is becoming a social problem.

Early lesions of atherosclerosis can be seen as spotty or linear fat deposits called fatty streak. This change is mainly due to the integration of foamed macropurge into the vascular endothelium. Foaming of the macropurge occurs when the macropurge absorbs the denatured LDL to produce free cholesterol, is esterified by acyl CoA cholesterol acyltransferase, and this accumulates. These early foamed cell lesions progress to complex lesions, including the foaming of vascular smooth muscle cells. Fatty ancestors soon become fibrous plaques that protrude into the vascular wall, and as the lesions progress further, calcification and adhesion of thrombus narrow the vessel cavity or cause cerebral obstruction, resulting in thrombotic obstruction. Moreover, it is also known that the ground which tends to be crystallized contains many lipid components, such as cholesterol ester. Therefore, inhibition of foaming of macro purge, vascular smooth muscle cells, and the like and inhibition of acyl CoA cholesterol acyltransferase result in stabilization and retraction of atherosclerotic lesions, resulting in acute onset of atherosclerosis or hyperlipidemia. It is expected to lead to reduction of onset and recurrence of vascular syndrome. In addition, by inhibiting the acyl CoA cholesterol-acyltransferase activity, the synthesis of cholesterol esters constituting VLDL occurs in the liver, resulting in a decrease in VLDL synthesis or inhibiting the ester binding of cholesterol in the small intestine and a decrease in cholesterol absorption. In this regard, it can be expected to reduce blood cholesterol and blood triglycerides.

The oily herb is a perennial genus belonging to the genus Peucedanum japonicum of the buttercup and oily herb. It grows on the rocks and grasslands of the coast, and its stem is 30-100cm in height. It is a small white flower from June to September. Smokes a lot. In terms of its physiological activity, it has been considered valuable since ancient times for its effects on colds, fatigue recovery and nourishing tonic. In recent studies, the herb oil has anticancer effects (for example, nonpatent literature 1), disaccharide degrading enzyme inhibitory activity (for example, patent document 1), antioxidant activity (for example, patent document 2, non It is also known that there exists a patent document 2), a cell activating effect (for example, patent document 2), and a melanin production inhibitory effect (for example, patent document 2).

As characteristic chemical constituents contained in the rape sprouts, plural kinds of coumarin derivatives are known, and studies have been conducted on their carcinogenic promoter inhibitory action and the like (for example, Non-Patent Document 3).

Patent Document 1: Japanese Unexamined Patent Publication 2003-26694

Patent Document 2: Japanese Patent Application Laid-Open No. 2004-26697

Non-Patent Document 1: T. Morioka et al. 8, Cancer Letters, 2004, Vol. 205, p133-141

Non-Patent Document 2: M. Hisamoto et al., 2, J. Agric. Food Chem., 2004, Vo1.52, p445-450

Non-Patent Document 3: B.Fan et al. 5, Journal of Japanese Botany, 2000, Vo1.75, No.4, p257-261

Disclosure of the Invention

Problems to be Solved by the Invention

SUMMARY OF THE INVENTION An object of the present invention is to develop a substance having an anti-foaming effect of cells suitable as a food material and a pharmaceutical material that can be safely and simply ingested, and to provide a medicine, food or feed using the composition or substance. .

Means to solve the problem

According to the present invention, a first invention of the present invention comprises a treatment derived from botanical oil herb as an active ingredient, wherein the anti-foaming action and / or acyl CoA cholesterol acyl of a cell is used in the treatment or prevention. The present invention relates to a therapeutic or prophylactic agent for a disease that requires a transferase inhibitory action.

2nd invention of this invention is related with the anti-foaming agent of the cell characterized by containing the processed material derived from rape sprouts as an active ingredient.

The third invention of the present invention relates to an acyl CoA cholesterol acyl transferase inhibitor comprising a treated substance derived from radish sprouts as an active ingredient.

The fourth invention of the present invention relates to a food or feed for anti-foaming and / or acyl CoA cholesterol-acyltransferase inhibition of cells, characterized in that it contains as a active ingredient a treatment derived from radish sprouts. .

5th invention of this invention is 1 type chosen from the group which consists of a 3'- acetoxy-4'- senecioyloxy-3 ', 4'- dihydroserine, its derivative (s), and pharmaceutically acceptable salts thereof. The present invention relates to a therapeutic or preventive agent for a disease which requires an anti-foaming action of a cell and / or an acyl CoA cholesterol-acyltransferase inhibitory action, which comprises the above as an active ingredient.

6th invention of this invention is 1 type chosen from the group which consists of a 3'- acetoxy-4'- ceenioyloxy-3 ', 4'- dihydroserine, its derivative (s), and pharmaceutically acceptable salts thereof. An anti-foaming agent for cells comprising the above as an active ingredient.

7th invention of this invention is 1 type chosen from the group which consists of a 3'- acetoxy-4'- senecioyloxy-3 ', 4'- dihydroserine, its derivative (s), and pharmaceutically acceptable salts thereof. The present invention relates to an acyl CoA cholesterol acyl transferase inhibitor comprising the above as an active ingredient.

8th invention of this invention is 1 type chosen from the group which consists of a 3'- acetoxy-4'- senecioyloxy-3 ', 4'- dihydroserine, its derivative (s), and pharmaceutically acceptable salts thereof. The present invention relates to a food or feed for anti-formulation of cells and / or for acyl CoA cholesterol-acyltransferase inhibition, which contains the above as an active ingredient.

The ninth invention of the present invention is the anti-foaming and / or acyl CoA cholesterol-acyltransferase action of cells in the treatment or prophylaxis, including administering to the subject an effective amount of a treatment derived from botanical oil. It relates to a method of treating or preventing a disease in need.

The tenth invention of the present invention is a treatment derived from seaweed sprouts for the manufacture of a therapeutic agent or a prophylactic agent for a disease that requires anti-foaming action of cells and / or acyl CoA cholesterol acyltransferase inhibitory action in the treatment or prevention. It relates to the use of water.

11th invention of this invention consists of an effective amount of a 3'-acetoxy-4'-senesioyloxy-3 ', 4'- dihydroserine, its derivative (s), and those pharmaceutically acceptable salts to a subject. The present invention relates to a method for the treatment or prevention of a disease requiring an anti-foaming action of a cell and / or an acyl CoA cholesterol-acyltransferase inhibitory action in the treatment or prophylaxis, including administering at least one selected from the group. .

The twelfth invention of the present invention provides a 3'-acetoxy for the manufacture of a therapeutic or preventive agent for a disease that requires anti-formalization of cells and / or acyl CoA cholesterol acyltransferase inhibitory action in the treatment or prophylaxis. And -4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof.

Effects of the Invention

According to the present invention, there is provided a medicament, food or feed for the treatment or prophylaxis of a disease that requires anti-foaming action of cells and / or acyl CoA cholesterol-acyltransferase inhibitory action in the treatment or prophylaxis. The medicine is useful for atherosclerosis, hyperlipidemia, and diseases derived from it. In addition, by ingesting the food as a daily food or drink, it is possible to improve symptoms of diseases that require anti-foaming action of cells and / or acyl CoA cholesterol-acyltransferase inhibitory action for treatment or prevention. Therefore, the food of the present invention is a functional food useful for maintaining homeostasis of a living body by anti-foaming action of cells and / or acyl CoA cholesterol acyl transferase inhibitory action.

To practice the invention  Best form for

Foaming of cells occurs by the accumulation of cholesterol esters in the cells. The anti-foaming action of the cells can be easily measured using an assay system in which the amount of cholesterol ester in the cells as described in Example 1 described later is used as an index. That is, the anti-foaming effect of the cell can be easily measured by culturing the macro purge in the presence of the test substance and acetyl LDL and evaluating the amount of cholesterol ester in the cell. In addition, in the present invention, the cells to be subjected to anti-foaming are not particularly limited, and examples thereof include vascular cells and blood cells such as macro purge and smooth muscle cells.

Acyl CoA cholesterol acyltransferase (also known as acyl CoA: cholesterol O-acyltransferase, hereinafter sometimes abbreviated as ACAT) transfers long-chain fatty acids from acyl CoA to cholesterol to inhibit cholesterol ester synthesis. It is an enzyme that catalyzes. An ACAT inhibitory effect can be measured simply using the assay system as described in Example 2 mentioned later. That is, the ACAT inhibitory effect can be easily measured by mixing the test substance with the enzyme source containing ACAT and evaluating the transfer of the Oleoyl group to cholesterol from the radiolabeled Oleoyl-CoA.

Although it does not specifically limit as the rape sprouts used for this invention, Fruit, a seed, a seedling, a flower, a leaf, a stem, a root, a rhizome, and / or the whole plant as it is can be used.

As a treatment derived from the oil sprouts (hereinafter may be referred to as the treatment of the present invention), which is used as an active ingredient of the present invention, any processing is performed on the raw material plant, and the anti-foaming action of the cells and / or Although it does not specifically limit if it has an ACAT inhibitory effect, For example, extract, a pulverized product, juice, a crushed product, a chemical processed material, and an enzyme processed material are mentioned, Especially preferably, an extract, a pulverized product, and a juice liquid are illustrated. In addition, the treated product of the present invention is particularly preferably an anti-foaming agent for cells, which is 3'-acetoxy-4'-ceenioyloxy-3 ', 4'- which will be described later as an ACAT inhibitor. Treatments high in dihydroserine may be used. In addition, high content here is 3'-acetoxy-4'- in the said processed material rather than the content density | concentration of 3'-acetoxy-4'-senecioyloxy-3 ', 4'- dihydroserine in a raw material plant. It means that the containing concentration of ceneoyloxy-3 ', 4'- dihydroserine is high, It is preferable that it is 1.5 times or more of the density | concentration in oil sprouts, and it is more preferable that it is 2 times or more.

In the present invention, the extract refers to the substance itself that can be obtained through a step of performing an extraction operation on the raw material plant using an extraction solvent. Extraction can be performed as follows by a well-known extraction method. For example, the raw material may be pulverized or chopped, and then batch or continuous may be carried out using a solvent. The extraction solvent for obtaining the extract is not particularly limited, but water, glycerol, glycols (ethylene glycol, propylene glycol, etc.), alcohols (ethanol, methanol, isopropyl alcohol, etc.), ketones (acetone, methyl ethyl ketone Etc.) and a hydrophilic or lipophilic solvent (chloroform, methyl acetate, ethyl acetate, etc.) may be mentioned, and may be used alone or as a mixed solution as desired. Examples of using the mixed solution as the extraction solvent are not particularly limited, but various aqueous solutions can be used, for example, 10 to 95%, preferably 15 to 90%, and more preferably 20 to 85% alcohol. An aqueous solution can be used. Moreover, when using glycerol and glycols (ethylene glycol, propylene glycol, etc.) as a solvent, it is preferable to use it as these aqueous solutions preferably. Although the quantity of an extraction solvent should just be determined suitably, Usually, it is 0.1- of the weight of a raw material plant in the form of the raw material plant at the time of use (for example, a natural plant if a raw plant is a natural plant). 100 times of the extraction solvent may be used. Although extraction temperature may be suitably determined according to the objective, in the case of water extraction, it is usually 4-130 degreeC, More preferably, it is 25-100 degreeC. Moreover, when ethanol is contained in a solvent, the range of 4-60 degreeC is preferable from a viewpoint of safety. The extraction time may also be determined in consideration of the outflow efficiency, but it is usually preferable to set the raw material, the extraction solvent, and the extraction temperature so as to be in the range of several seconds to several days, more preferably 5 minutes to 24 hours. Do. Extraction operation may be performed, for example, stirring or standing still, and may repeat several times as needed. By the above operation, the extract (from which the extract of this invention may be called hereafter) derived from the rape oil sprout used for this invention can be obtained. The extract is subjected to treatment such as filtration, centrifugation, concentration, ultrafiltration, molecular sieve, and the like, if necessary, to form anti-formalizing substances or ACAT inhibitory substances, for example, 3'-acetoxy-4 described later. It is possible to prepare an extract in which '-senesioyloxy-3', 4'-dihydroserine is concentrated. The anti-foaming action and the ACAT inhibitory action of the cells of the extract or the concentrated extract can be measured simply by the methods described in Examples 1 and 2 described later. Moreover, if the oil herb used for this invention is made into the tea leaf state by a well-known method, and the extract using this also has the anti-foaming effect of a cell and / or ACAT inhibitory activity, it can be used as an extract of this invention. Moreover, you may use it, containing 2 or more types of above extracts. Moreover, it can also be used, containing 2 or more types of extracts obtained by the different extraction method from a raw material plant.

In addition, in this invention, the extract obtained by fractionating the extract of this invention by a well-known method, and the fraction obtained by repeating fraction operation multiple times are also included in the extract of this invention. As said fractionation means, extraction, fractional precipitation, column chromatography, thin layer chromatography, etc. are mentioned. Purification of the obtained fraction further proceeds as an index an anti-foaming action or an ACAT inhibitory effect on the cells, and the anti-foaming substance or ACAT inhibitory substance of the cell can be isolated.

Moreover, as a processed material derived from the muddy sprouts used for this invention, what is other than the extract of this invention mentioned above, For example, the grind | pulverized substance derived from the muddy sprouts used for this invention (hereinafter, the grinding | pulverization of this invention) May be referred to as water). As a manufacturing method of the pulverized object of this invention, the method of obtaining the pulverized substance derived from powdery oily sprouts by drying a plant and grind | pulverizing using a grinder, for example is mentioned. In addition, a pulverized product may be obtained by freeze grinding.

Moreover, the juice derived from the oily sprouts used for this invention can also be used as a processed material of this invention. The method of producing the juice is not particularly limited as long as it is a known method of juice of a plant, but can be juiced using a juicer or a juicer such as a screw, gear, or cutter. Further, as a pretreatment, the juice can be obtained by thinly cutting or grinding and squeezing with a juicer or cloth as described above.

The crushed material is obtained by crushing a raw material plant, and in general, the tissue pieces are larger than the pulverized product, and can be produced by, for example, using a crusher. Moreover, although a chemically processed thing is not specifically limited, It means what obtained the raw material plant through acid treatment, alkali treatment, oxidation treatment, reduction treatment, etc. For example, hydrochloric acid, sulfuric acid, nitric acid, citric acid, acetic acid, etc. It can be manufactured by immersing a raw material plant in the aqueous solution containing an inorganic base and organic base, such as an inorganic acid, an organic acid, or sodium hydroxide, potassium hydroxide, and ammonia. The chemical processed material includes everything derived from such chemically treated plants. The enzyme treatment product refers to, for example, an enzyme treatment product such as pectinase, cellulase, xylanase, amylase, mannanase, glucosidase and the like, and an enzyme reaction product (eg, fermentation product) by microorganisms. For example, the enzyme can be produced by reacting the enzyme with a suitable buffer in a suitable plant. Enzyme processed materials include all derived from plants subjected to the above enzyme treatment. Further, the treated oil-derived treatment product of the present invention includes, for example, a juice obtained by cutting a stem of a raw material plant and obtained from the cut surface.

In the present invention, the shape of the treated product of the present invention is not particularly limited as long as it can exert an anti-foaming action and / or ACAT inhibitory effect on cells when used as an active ingredient in each embodiment of the present invention. Any shape of a shape and a liquid phase may be sufficient. Moreover, a processed material can be granulated by a well-known method and can be used as a granular solid. Examples of the granulation method include, but are not particularly limited to, rolling granulation, stirring granulation, fluidized bed granulation, air flow granulation, extrusion granulation, compression molding granulation, disintegration granulation, spray granulation or spray granulation. The powdery treated substance can be dissolved in a liquid, for example, water or alcohol, and brought into a liquid state, and can be used as a treated substance derived from the muddy sprouts of the present invention.

In the present invention, a compound containing a high content of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, which will be preferably used as a treatment product of the present invention, is the compound. From the viewpoint of containing and also serving as edible, for example, ethanol extract, hydrous ethanol extract, hydrothermal extract, glycerol extract or hydrous glycerol extract, glycol extracts such as ethylene glycol, propylene glycol or hydrous glycol extract, pulverized products are preferable. Do.

In addition, the present inventors searched for anti-foaming agents and ACAT inhibitors of cells derived from radish sprouts, and showed 3'-acetoxy-4'-senesioyloxy-3 'shown in the following formula (I). It was found that, 4'-dihydroserine is an anti-foaming agent of cells and an ACAT inhibitor. That is, as an active ingredient of the present invention, 3'-acetoxy-4'-senesioyloxy-3 ', 4'-di, which is a kind of coumarin derived from rape sprouts, in addition to the treatment derived from the above-mentioned rape sprouts Hydroserine, derivatives thereof and / or pharmaceutically acceptable salts thereof may also be used.

Although it does not specifically limit as a manufacturing method of the said 3'- acetoxy-4'- senoxy oil oxy-3 ', 4'- dihydroserine, For example, various chromatography is performed from the ethanol extract of the rape oil sprout. It can also obtain by carrying out, and when synthesize | combining, it can also obtain by combining well-known methods.

As a derivative in this specification, it is hydrolyzed easily in a body, for example, ester, etc., and produces | generates the said 3'- acetoxy-4'- sensioyloxy-3 ', 4'- dihydroserine, The derivative (prodrug) which can exhibit an effect can be prepared. Preparation of such a prodrug may be carried out according to a known method. For example, derivatives produced by metabolism by administering a compound of the present invention to a mammal are also included in the derivative of the present invention. In addition, the derivative may be a salt of 3'-acetoxy-4'-senecioyloxy-3 ', 4'-dihydroserine.

In addition, as the salt of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine or derivatives thereof used in the present invention, a pharmaceutically acceptable salt is preferable. Moreover, the derivative of the said compound which can function as a prodrug may be sufficient as mentioned above. Accordingly, the 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine according to the present invention includes derivatives and salts thereof as long as the desired effect of the present invention can be obtained. will be. In addition, various isomers such as optical isomers of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, ketoenol tautomers, geometric isomers and the like are also isolated. Any one can be used in the present invention as long as it has anti-foaming action or ACAT inhibitory action on the cells.

As a salt used by this invention, an alkali metal salt, an alkaline earth metal salt, the salt of an organic base, etc. are illustrated, for example. In addition, the pharmaceutically acceptable salt used in this invention means the salt of the compound which is substantially nontoxic to an organism, and has the anti-foaming effect of a cell. As the salt, for example, sodium, potassium, calcium, magnesium, ammonium or protonated benzatin (N, N'-di-benzylethylenediamine), choline, ethanolamine, diethanolamine, ethylenediamine, meglamine And salts such as (N-methylglucamine), benetamine (N-benzylphenethylamine), piperazine or tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol). .

Furthermore, in the present invention, the treated product of the present invention, and 3'-acetoxy-4'-senecioyloxy-3 ', 4'-dihydroserine, derivatives thereof and / or pharmaceutically acceptable salts thereof Is an active ingredient of the present invention, and a therapeutic or prophylactic agent of the present invention may be referred to as a therapeutic or prophylactic agent of a disease that requires anti-foaming action and / or ACAT inhibitory effect on cells containing the active ingredient of the present invention. . In addition, in the case of the medicine of the present invention, in addition to the therapeutic agent and the prophylactic agent, an anti-foaming agent and an ACAT inhibitor of a cell to be described later may be included.

The active ingredient of the present invention is derived from a boiled oil herb that has been considered edible from whales, and has high safety even when compared with a synthetic compound having an ACAT inhibitory effect (for example, FR179254 described later), which will be described later. As shown in particular, no toxicity is observed and there is no worry of side effects occurring. Therefore, the treatment or prevention of the disease can be carried out safely and appropriately. Therefore, the therapeutic agent, prophylactic agent, food or feed of the present invention containing the active ingredient is effective for the treatment or prevention of diseases requiring anti-foaming action and ACAT inhibitory action of cells, and can be particularly easily ingested. It is useful as a health food material.

In the present invention, the disease that requires anti-foaming action of cells for treatment or prophylaxis is not particularly limited as long as it is a disease that can provide a therapeutic or prophylactic effect by inhibiting cell foaming. , Arteriosclerosis, diseases caused by this, such as ischemic heart disease, acute myocardial infarction, unstable angina, ischemic sudden death, cerebrovascular disorder, chronic obstructive atherosclerosis, myocardial infarction, angina pectoris, cerebral infarction, subarachnoid hemorrhage, obesity And the like (see, eg, O'Rourkes, J. Biol. Chem., 2002, 277 (45), 42557-42562).

In the present invention, the disease that requires an ACAT inhibitory effect for treatment or prevention is not particularly limited, but in addition to the disease requiring anti-foaming action of cells for the treatment or prevention, hyperlipidemia and high Cholesterolemia, hypertriglyceridemia, multiple risk factor syndrome, or diseases resulting from these causative factors are exemplified (eg, O'Rourkes, J. Biol. Chem., 2002, 277 (45), 42557-42562, Ohishis, Biol. Pharm. Bull., 2003, 26 (8), 1125-1128, and Ohishis, Chem. Pharm. Bull., 2001, 49 (7), 830-839).

As a therapeutic or preventive agent of this invention, what was formulated combining the said active ingredient which concerns on this invention with a well-known pharmaceutical carrier is mentioned. In addition, as the therapeutic or prophylactic agent of the present invention, the active ingredient may be used for the same use as the active ingredient, for example, a component having a therapeutic or prophylactic effect of known hyperlipidemia or atherosclerosis, for example pravastatin, HMG-CoA reductase inhibitors, such as statin compounds such as simvastatin, provastatin, cerivastatin and atollvastatin, antifoaming agents such as fucoidan, ACAT inhibitors such as melinamid, cholesterol ester transfer protein (CETP) Inhibitors, cholesterol absorption inhibitors, squalene synthetase inhibitors, LDL oxidation inhibitors, microsomaltriglyceride transfer protein (MTP) inhibitors, apolipoprotein A1 production promoters, ATP-binding cassette subfamily A1 (ABCA1) inducers, squaleneepoxidase inhibitors , Bile acid-binding resins such as cholestyramine and fibres such as clofibrate It can also be mix | blended with nicotine acid type | system | groups, such as a yit type | system | group, niacin, and neutral fat reducing agents, such as ethyl isosappentate.

Preparation of the therapeutic or prophylactic agent of the present invention is usually carried out by combining the active ingredient with a pharmaceutically acceptable liquid or solid carrier, and if desired, a solvent, a dispersant, an emulsifier, a buffer, a stabilizer, an excipient, a binder. And disintegrants, lubricants, and the like can be added to solid agents such as tablets, granules, powders, powders, capsules, and the like, and usually as pharmaceuticals such as liquids, suspensions, and emulsions. Moreover, it can also be made into the dry goods which can become a liquid state by addition of a suitable carrier before use, or other external preparation.

A medical carrier can be selected according to the dosage form and preparation form of a therapeutic agent or a prophylactic agent. In the case of an oral preparation made of a solid composition, it may be a tablet, a pill, a capsule, a powder, a fine granule, a granule, and the like. For example, starch, lactose, white sugar, mannitol, carboxymethyl cellulose, corn starch, inorganic salt Medical carriers, such as these, are used. Moreover, in preparation of an oral preparation, you may mix | blend a binder, a disintegrating agent, surfactant, a lubricating agent, a fluidity promoter, a mating agent, a coloring agent, a fragrance | flavor, etc. further. For example, when it is a tablet or a pill, you may coat | cover with the film of sugar or gastric or enteric substance, such as sucrose, gelatin, and hydroxypropyl cellulose as needed. In the case of an oral preparation made of a liquid composition, a pharmaceutically acceptable emulsion, solution, suspension, syrup, and the like can be used. For example, purified water, ethanol, or the like is used as a carrier. Moreover, you may add the wetting agent, the adjuvant, such as a suspending agent, a sweetening agent, a flavoring agent, a preservative, etc. further as needed.

On the other hand, when used as a parenteral, distilled water for injection, physiological saline, aqueous solution of glucose, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol using the active ingredient of the present invention as a diluent according to a conventional method. It can be dissolved or suspended in polyethylene glycol or the like and prepared by adding a bactericide, a stabilizer, an isotonicity agent, a non-fatting agent, or the like as necessary. The solid composition may also be prepared and dissolved in sterile water or a sterile solvent for injection before use.

External preparations include solid, semisolid or liquid preparations for transdermal administration or for transmucosal (intraoral, intranasal) administration. Moreover, suppositories etc. are included. For example, liquid preparations such as emulsions such as emulsions and lotions, external tinctures and liquid preparations for transmucosal administration, ointments such as oily ointments and hydrophilic ointments, transdermal administration or transdermal preparations such as films, tapes and papes. It can be used as a patch for mucosal administration.

The therapeutic or prophylactic agent in the above various forms of preparations can be appropriately prepared according to a conventional method using a known pharmaceutical carrier or the like. The content of the active ingredient in such a therapeutic or preventive agent is not particularly limited as long as the content of the active ingredient can be administered in consideration of the dosage form, administration method, and the like, and preferably in the following dosage range. As content of the active ingredient in the medicine of this invention, it is about 1-100 weight% normally.

The therapeutic or prophylactic agent of this invention is administered by the appropriate method of administration according to a preparation form. The method of administration is not particularly limited, and may be administered, for example, by contents, external use or injection. When the therapeutic or prophylactic agent of the present invention is administered by injection, it can be administered, for example, intravenously, intramuscularly, subcutaneously, intradermal, etc., and when administered by external use, for example, external preparations such as suppositories What is necessary is just to administer by the appropriate method of administration.

The dosage of the therapeutic or prophylactic agent of the present invention is not appropriately set and constant depending on the form of the preparation, the method of administration, the purpose of use, and the age, weight and symptoms of the patient to which the therapeutic or prophylactic agent is administered. Generally, depending on the dosage of the active ingredient contained in the formulation, for example, when using the treatment of the present invention as the active ingredient, preferably 0.1 μg to 10 g / kg body weight per adult, more preferably Is 1 µg to 5 g / kg body weight, more preferably 10 µg to 1 g / kg body weight, and 3'-acetoxy-4'-sensiioyloxy-3 ', 4'-dihydroserine, When the derivatives and / or pharmaceutically acceptable salts thereof are used, preferably 0.1 μg to 5 g / kg body weight, more preferably 1 μg to 2 g / kg body weight, more preferably 10 μg to adult per day. 1 g / kg body weight. As a matter of course, since the dosage varies depending on various conditions, an amount smaller than the dosage may be sufficient, or it may be necessary beyond the range. The administration may be performed in a single dose or several times within one day within the desired dosage range. The period of administration is also arbitrary. In addition to the oral administration as it is, the therapeutic or preventive agent of the present invention may be added to any food and consumed daily.

The present invention also provides an anti-foaming agent for cells containing the active ingredient. As said antifoaming agent, the said active ingredient itself may be sufficient, and the composition containing the said active ingredient may be sufficient. The anti-foaming agent may be, for example, another component that can use the active ingredient in the same use as the active ingredient, for example, a component having a therapeutic or prophylactic effect of known arteriosclerosis, for example pravastatin, simvastatin, HMG-CoA reductase inhibitors such as stavatin compounds such as provastatin, cerivastatin and atollvastatin, anti-foaming agents of cells such as fucoidan, ACAT inhibitors such as melinamid, cholesterol ester transfer protein (CETP) Inhibitors, cholesterol absorption inhibitors, squalene synthetase inhibitors, LDL oxidation inhibitors, microsomaltriglyceride transfer protein (MTP) inhibitors, apolipoprotein A1 production promoters, ATP-binding cassette subfamily A1 (ABCA1) inducers, squaleneepoxidase inhibitors , Bile acid-binding resins such as cholestyramine, fibrates such as clofibrate, niacin and the like It can also be mix | blended with neutral fat reducing agents, such as nicotinic acid type | system | group and ethyl isospentate. The anti-foaming agent may be prepared in the form of a reagent which is usually used according to the method for producing the therapeutic or preventive agent. Content of the said active ingredient in the said anti-foaming agent should just be an amount which can express the desired effect of this invention in consideration of the administration method, the purpose of use, etc. of the said anti-foaming agent, and is not specifically limited. . As content of the active ingredient in the anti-foaming agent of this invention, it is about 1-100 weight% normally. Moreover, the usage-amount of the said anti-foaming agent will not be specifically limited if it is an amount from which the expression of the desired effect of this invention can be obtained. In particular, in the case of administration to a living body, it is preferable to use in an amount capable of administering the active ingredient within the dosage range of the therapeutic or prophylactic active ingredient. The administration method is not particularly limited, and may be appropriately set in the same manner as the therapeutic or preventive agent. The anti-foaming agent is useful in the treatment or prophylaxis of diseases in which the anti-foaming action of cells is required for the above-mentioned treatment or prevention, for example, atherosclerosis, and diseases in which this is a causative factor. The anti-foaming agent is also useful for screening drugs for diseases that require anti-foaming action of cells for treatment or prophylaxis. In addition, the anti-foaming agent is also useful for studying the mechanism of atherosclerosis and foaming of various cells and for studying the function of physical changes of the cells. The anti-foaming agent may also be added to foods or beverages.

Moreover, this invention provides the ACAT inhibitor containing the said active ingredient. As said ACAT inhibitor, the said active ingredient itself may be sufficient, and the composition containing the said active ingredient may be sufficient. The ACAT inhibitor is, for example, another component that can use the active ingredient for the same use as the active ingredient, for example, a component having a therapeutic or prophylactic effect of known hyperlipidemia or atherosclerosis, for example pravastatin, simvastatin , HMG-CoA reductase inhibitors such as stavatin compounds such as provastatin, cerivastatin and attolvastatin, antifoaming agents in cells such as fucoidan, ACAT inhibitors such as melinamid, cholesterol ester transfer protein (CETP ) Inhibitors, cholesterol absorption inhibitors, squalene synthetase inhibitors, LDL oxidation inhibitors, microsomaltriglyceridetransfer protein (MTP) inhibitors, apolypoprotein A1 production promoters, ATP-binding cassette subfamily A1 (ABCA1) inducers, squaleneepoxidase Inhibitors, bile acid-binding resins such as cholestyramine, and fibrate such as clofibrate It can also be mix | blended with nicotine acid type | system | groups, such as niacin, and neutral fat reducing agents, such as ethyl isosaptate. The said ACAT inhibitor can also be manufactured in the form of the reagent normally used according to the manufacturing method of the said therapeutic agent or prevention agent. Content of the said active ingredient in the said ACAT inhibitor should just be an amount from which the expression of the desired effect of this invention can be acquired in consideration of the administration method, the purpose of use, etc. of the said ACAT inhibitor, and is not specifically limited. As content of the active ingredient in the ACAT inhibitor of this invention, it is about 1-100 weight% normally. In addition, the amount of the ACAT inhibitor to be used is not particularly limited as long as the expression of the desired effect of the present invention can be obtained. In particular, in the case of administration to a living body, it is preferable to use in an amount capable of administering the active ingredient within the range of the dosage of the active ingredient in the therapeutic or prophylactic agent. It does not specifically limit about the administration method, either, It is good to set suitably similarly to the said therapeutic agent or a preventive agent. The ACAT inhibitor is useful in the treatment or prevention of a disease requiring an ACAT inhibitory effect for the above-mentioned treatment or prevention, for example, atherosclerosis and hyperlipidemia, or a disease caused by these factors. In addition, the ACAT inhibitor is also useful for screening drugs for diseases requiring ACAT inhibitory action in the treatment or prophylaxis. In addition, the ACAT inhibitor is also useful for studying the mechanism of cholesterol ester production and the mechanism related to the progress of the above-described diseases such as hyperlipidemia and arteriosclerosis. Moreover, the said ACAT inhibitor can also be added to a food or a drink.

No toxicity is particularly observed in the active ingredient of the present invention as described later. In addition, there is no worry about the occurrence of side effects. Therefore, it is possible to safely and appropriately express the cell's anti-foaming action and / or ACAT inhibitory action in vivo. Therefore, the medicine, food or feed of the present invention containing the active ingredient is effective for the treatment or prevention of diseases requiring anti-foaming action of cells and / or ACAT inhibitory action for treatment or prevention.

In addition, the present invention provides a food or feed (may be referred to as the food or feed of the present invention in the present specification) for anti-foaming and / or ACAT inhibition of cells containing the active ingredient. The food or feed of the present invention is a disease that requires anti-foaming and / or ACAT-inhibiting action of cells for treatment or prophylaxis, i. Atherosclerosis, ischemic heart disease, acute myocardial infarction, unstable angina, ischemic sudden death, cerebrovascular disorder, chronic obstructive arteriosclerosis, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, improves the symptoms of various risk factor syndrome . That is, the food or beverage of the present invention is very useful as a functional food (specific health foods, etc.) attached to the object of preventing, ameliorating or treating the above-mentioned diseases, and is worried about people who are worried about blood cholesterol levels and triglycerides. It is a very useful food or drink for people who are concerned about body fat.

In the food or feed of the present invention, the active ingredient of the present invention and other substances having an improvement, treatment or prophylaxis of hyperlipidemia or atherosclerosis, for example, components having a treatment or prophylactic effect of known hyperlipidemia or atherosclerosis. For example, HMG-CoA reductase inhibitors such as statin compounds such as pravastatin, simvastatin, provastatin, cerivastatin, and attolvastatin, antifoaming agents of cells such as fucoidan, and ACAT inhibitors such as melinamid , Cholesterol ester transport protein (CETP) inhibitors, cholesterol absorption inhibitors, squalene synthase inhibitors, LDL oxidation inhibitors, microsomaltriglyceridetransfer protein (MTP) inhibitors, apolipoprotein A1 production promoters, ATP-binding cassette subfamily A1 (ABCA1 ) Bile acid binding resins such as inducers, squalene epoxidase inhibitors, cholestyramine, By blending as ropi fibrate such as a fibrate, niacin, such as niacin-based, Ikoma four pent acid triglyceride lowering agent, such as ethyl, it may be prepared for a more effective high food or feed. Moreover, it can also mix | blend with a well-known health food raw material, for example, fresh vinegar, its processed material, a peptide, glucomannan, chitosan, a plant sterol ester, EPA, DHA, etc.

In addition, in the food or feedstuff of this invention, "containing" means containing, addition, and / or dilution. Here, the "containment" means the aspect which the active ingredient used for this invention is contained in a foodstuff or feed, and the "addition" means the aspect which adds the active ingredient used for this invention to the raw material of a foodstuff or feedstuff, " Dilution "means the aspect which adds the raw material of a foodstuff or feed to the active ingredient used for this invention.

It is not specifically limited to the manufacturing method of the food or feed of this invention. For example, the formulation, cooking, processing, etc. may be a general food or feed, and can be prepared according to their production methods, and the present food or feed may have a cell having anti-foaming action and / or ACAT inhibitory action. What is necessary is just to contain the said active ingredient which concerns on this invention.

Although it does not specifically limit as a foodstuff of this invention, For example, the grain processed product (wheat flour processed product, starch processed product, premix processed product, noodles, noodles, macaroni, bread, bean jam) which the said active ingredient which concerns on this invention is contained is contained, for example. Buckwheat, buckwheat, bran, rice noodles, vermicelli, rice cakes, etc.), oils and fats (plastic oil, tempura, salad oil, mayonnaise, dressing, etc.), soybean products (tofu, miso, natto, etc.), meat products (ham , Bacon, Press Ham, Sausage, etc., Seafood (Frozen Sumi, Kamaboko, Chikuwa, Hanpen, Satsuma-age, Tsumire, Suji, Fish Ham, Sausage, Kazuobushi, Fish Processing, Canned Fish, Tsukudani Etc.), dairy products (raw milk, cream, yogurt, butter, cheese, condensed milk, powdered milk, ice cream, etc.), vegetable and fruit processed products (pastes, jams, pickles, fruit drinks, vegetable drinks, mixed drinks, etc.), confectionery (chocolate) , Vis Kets, sweets, cakes, rice cakes, rice cakes, etc., alcoholic beverages (Japanese sake, Chinese sake, wine, whiskey, shochu, vodka, brandy, gin, rum, beer, soft alcoholic beverages, fruit wine, liqueurs, etc.), Favorite drinks (green tea, black tea, oolong tea, coffee, soft drinks, lactic acid drinks, etc.), seasonings (soy sauce, sauce, vinegar, mirin, etc.), canned food, canned food, retort food (gyumeshi, stone rice, red bean rice, curry, other Various cooked foods), semi-dried or concentrated foods (lever pastes, other spreads, buckwheat and udon soups, concentrated soups), dried foods (immediate noodles, instant curry, instant coffee, powdered juices, powdered soups, instant foods) Miso soup, cooked food, cooked drink, cooked soup, etc.), frozen food (hot pot, steamed egg, unagi kabayaki, hamburger steak, shumai, dumplings, various sticks, fruit cocktail, etc.), solid food, Liquid food (such as soup), Such sinryo acids there may be mentioned agricultural and forestry processed products, livestock processed products, processed marine products and the like. In addition, in this specification, a food also includes a drink.

The food of the present invention is particularly effective as long as the active ingredient is contained alone, in a plurality, and / or diluted, and the content thereof corresponds to a necessary amount for expressing the anti-foaming action and / or the ACAT inhibitory action of the cells. There is no limitation in shape, and also the orally ingestible shape, such as powder form, a tablet form, granule form, a capsule form, is also included. Moreover, the foodstuff of this invention also includes what processed the oily sprouts raw product as it is, or it mixed suitably with an appropriate emulsifier, an excipient, etc. These foods can be eaten as a drink as it is or in admixture with water.

Moreover, about the foodstuff of this invention, it mixes with the juice of the active ingredient of this invention and the plant (vegetables, fruits, etc.) other than the plant used for this invention, or it extracts simultaneously with the plant used for this invention, and makes it a healthy drink. It may be. For example, the juice of various plants used in the present invention may be diluted with water or fresh herbs, parsley, celery, licorice, carrots, greens, turnips, bok choy, tomatoes, tangerines, lemons, grapefruit, kiwi, spinach, radish Mixed with juices such as radishes, cabbages, cabbage, salad vegetables, lettuce, leek, okra, bell pepper, cucumbers, kidney beans, green beans, peas, corn, garlic, rucola, loquat, summer tangerines, tangerines, milk, soy milk, etc. It can be made into a health drink which has anti-foaming effect of a cell, and / or ACAT inhibitory effect.

Content of the said active ingredient in the foodstuff of this invention is not specifically limited, Although it can select suitably from a viewpoint of the sensory function and active expression, For example, when making the processed material of this invention an active ingredient, Preferably it is among foodstuffs. 0.1 weight% or more, More preferably, it is 0.5 to 95 weight%, More preferably, it is 1 to 90 weight%. In the case of using 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, its derivatives and / or pharmaceutically acceptable salts thereof as the active ingredient, Is 0.00001% by weight or more, more preferably 0.0001 to 10% by weight, still more preferably 0.0006 to 6% by weight.

In the case of using the processed product of the present invention, for example, as an active ingredient, the food of the present invention preferably contains 0.1 µg to 10 g / kg body weight, more preferably 1 µg per adult, per day. It is -5 g / kg body weight, More preferably, it is 10 micrograms-2 g / kg body weight, As an active ingredient, it is 3'-acetoxy-4'- senecioyloxy-3 ', 4'- dihydroserine, its derivative (s), and And / or when using those pharmaceutically acceptable salts, preferably 0.1 μg to 5 g / kg body weight, more preferably 1 μg to 2 g / kg body weight, more preferably 10 μg to 1 g / kg per adult Eat it to gain weight.

The present invention also provides a biological feed having an anti-foaming action and / or an ACAT inhibitory effect on cells, which contain, that is, contain, add, and / or dilute the active ingredient. In one aspect, there is also provided a method of breeding a living organism, characterized in that the active ingredient is administered to the living organism. In another aspect of the present invention, there is provided a biological breeding agent, which contains the active ingredient.

In this specification, although it is not limited to a living thing, aquaculture animals, pets, etc. are mentioned, for example. Examples of aquaculture animals include livestock such as horses, cattle, pigs, sheep, goats, camels, and llamas, experimental animals such as mice, rats, malmots, rabbits, poultry, fish, crustaceans, and shellfish such as chickens, ducks, turkeys, and ostrichs. do. Examples of pet animals include dogs and cats. Examples of the feed include feed for maintenance and / or improvement of condition. Examples of the biological breeding solvent include immersion solvents, feed additives, and beverage additives.

According to these inventions, the above-mentioned therapeutic or preventive agent of the present invention is based on the anti-foaming action and / or ACAT inhibitory action of the cells of the active ingredient used in the present invention in the organisms as exemplified above. The expression of the same effect as that by can be expected. That is, the feed of the present invention is a disease that requires anti-foaming and / or ACAT inhibitory action of cells for treatment or prevention in the organism, such as atherosclerosis or hyperlipidemia, a disease caused by these factors. Can have a therapeutic or prophylactic effect.

The active ingredient used in the present invention is usually used, for example, when using the processed material of the present invention as the active ingredient, the active ingredient contained therein is preferably 0.1 µg to 10 g / kg body weight per day, more than Preferably it is 1 microgram-5 g / kg body weight, More preferably, it is 10 microgram-2 g / kg body weight, and it is 3'-acetoxy-4'- cesinoyloxy-3 ', 4'- dihydro as an active ingredient. When using serine, its derivatives and / or pharmaceutically acceptable salts thereof, preferably 0.1 μg to 5 g / kg body weight, more preferably 1 μg to 2 g / kg body weight, more preferably per day of the subject organism 10 μg to 1 g / kg body weight. The administration may be performed by, for example, adding and mixing the active ingredient in a raw material of an artificial compound feed provided to the target organism or by mixing with a powder raw material of an artificial compound feed, and then additionally mixing and mixing with other raw materials. Can be. Moreover, content in the feed of the said active ingredient is not specifically limited, What is necessary is just to set suitably according to the objective, For example, when using the processed material of this invention as an active ingredient, Preferably it is 0.1 weight% in a feed. As mentioned above, More preferably, it is 0.5 to 95 weight%, More preferably, it is 1 to 90 weight%. In addition, in the case of using 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, its derivatives and / or pharmaceutically acceptable salts thereof as the active ingredient, Preferably it is 0.00001 weight% or more, More preferably, it is 0.0001-10 weight%, More preferably, it is 0.0006-6 weight%. What is necessary is just to content content of the active ingredient of this invention in a biological breeding solvent.

It does not specifically limit to the manufacturing method of the feed of this invention, Moreover, what is necessary is just to mix | blend with a general feed, The said active ingredient which concerns on this invention which has the anti-foaming effect of a cell and / or ACAT inhibitory effect in the manufactured feed is You may contain it. Biobreeding can also be prepared in the same way.

In the present invention, for example, the present invention includes a feed having an antifoaming effect of cells or / or an antifoaming effect of a cell containing a feed comprising the active ingredient used in the present invention having an ACAT inhibitory effect. Maintaining good condition of livestock, laboratory animals, poultry, pets and the like by immersing the target organism in a liquid containing the active ingredient (for example, the immersion agent dissolved in water) used in the invention. May be improved or improved. Moreover, these aspects are one aspect of the breeding method of the organism in this invention.

The present invention also provides a method for treating or preventing a disease requiring anti-foaming action of a cell and / or ACAT inhibitory action in the treatment or prophylaxis, including administering to the subject the active ingredient.

In the present specification, the subject is preferably a human who requires anti-foaming action and / or ACAT inhibitory action on the cells, but may be aquaculture animals, pets, and the like as described above.

In addition, in this specification, an effective amount means that when the said active ingredient is administered to the said subject, compared with the subject which did not administer the active ingredient, it exhibits the anti-foaming effect of a cell and / or ACAT inhibitory effect. The amount of that ingredient. The specific effective amount is not appropriately set and constant depending on the dosage form, the method of administration, the purpose of use, and the age, weight, symptoms, etc. of the subject, but is preferably the same as the above medicine, for example, as the active ingredient In the case of using the treated product, the active ingredient contained therein is preferably 0.1 μg to 10 g / kg body weight, more preferably 1 μg to 5 g / kg body weight, more preferably per human (eg adult) per day. Is 10 µg to 2 g / kg body weight, and 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and / or pharmaceutically acceptable salts thereof as active ingredients When used, the human body (eg adult) is preferably 0.1 μg to 5 g / kg body weight, more preferably 1 μg to 2 g / kg body weight, more preferably 10 μg to 1 g / kg body weight per day. Administered.

In the method for the treatment or prophylaxis of a disease requiring anti-foaming action of cells and / or ACAT inhibitory action in the treatment or prevention of the present invention, an effective amount of the active ingredient may be administered to the subject as it is, and You may administer as said medicine, food, or feed. Moreover, there is no limitation also in the administration method, For example, it is good to administer by oral administration, injection, etc. similarly to the said medicine.

According to the treatment method or the prevention method of the present invention, it is possible to treat or prevent the disease, which is the object of the medicine, food or feed of the present invention, for example, arteriosclerosis, hyperlipidemia, The effects of treatment or prevention can be exerted.

Toxicity is not observed in the above-mentioned active ingredient used in the present invention even if the effective amount of administration in its action expression is administered to a living body. For example, in the case of oral administration, even if the ethanol extract of the oil extract, 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine at 1 g / kg body weight, No death is observed. In the oral administration to the rats, no death was observed even if the 1 g / kg body weight was administered orally once.

Example

Hereinafter, although an Example is given and this invention is demonstrated further more concretely, this invention is not limited to these description at all. In addition, all% in an Example means the volume% unless there is particular description.

Preparation Example 1 Preparation of ethanol spilled fractions of boiled oil herb stems and 70% ethanol extracted fractions of boiled oil herb stems

40 g of ethanol or 70% ethanol was added to 2 g of the freeze-dried product of the stem part of the oil sprouts, followed by extraction at room temperature for 30 minutes, and centrifuged to separate the extract and the residue. Subsequently, the extraction operation with 30 ml of the same solvent was repeated twice with respect to the residue. The obtained extract was collected and concentrated in a rotary evaporator. Finally, the ethanol extract fraction was dissolved in 1 ml of dimethyl sulfoxide and the 70% ethanol extract fraction was dissolved in 2 ml of dimethyl sulfoxide. Got it.

Preparation Example 2 Preparation of Sprout Root Ethanol Extract Fraction

40 g of ethanol was added to 2 g of the lyophilized product of the root of the oil sprouts, followed by extraction at room temperature for 30 minutes, and centrifuged to separate the extract and the residue. Subsequently, the extraction operation with 30 ml of the same solvent was repeated twice with respect to the residue. The obtained extract was collected and concentrated in a rotary evaporator. Finally, it dissolved in 1 ml of dimethyl sulfoxide, and extracted the fraction of ethanol root of ethanol.

Preparation Example 3 Preparation of Sprout Oil Leaf Ethanol Extract Fraction

40 g of ethanol was added to 2 g of the freeze-dried product of the oil leaf leaf portion, which was extracted at room temperature for 30 minutes, and centrifuged to separate the extract and the residue. Subsequently, the extraction operation with 30 ml of the same solvent was repeated twice with respect to the residue. The obtained extract was collected and concentrated in a rotary evaporator. Finally, it melt | dissolved in 1 ml of dimethyl sulfoxide, and obtained the fraction of ethanol extract of the rape leaf.

Preparation Example 4 Fraction by Reversed-Phase Column of Ethanol Extract Fractions

(1) 200 g of ethanol was added to 10 g of the freeze-dried product of the oil leaf leaf portion, which was pulverized, and extracted at room temperature for 30 minutes, and the mixture was separated into an extract and a residue by suction filtration. Subsequently, the extraction operation with 150 ml of the same solvent was repeated twice with respect to the residue. The obtained extract was collected and concentrated in a rotary evaporator. Finally, it melt | dissolved in 5 ml of dimethyl sulfoxide, and the ethanol extract of radish sprouts was obtained.

(2) Methanol sprout leaf ethanol extract obtained in Preparation Example 4- (1) was fractionated by reverse phase chromatography. Cosmosil 75 C18-OPN (manufactured by Nakaray Tesque Co., Ltd .: 50 ml) equilibrated in 20% ethanol was used. After adding the oil herb leaf ethanol extract to resin, it eluted in order of 200 ml of 20% ethanol, 600 ml of 40% ethanol, and 400 ml of 60% ethanol.

(3) The 20% ethanol eluate obtained in Preparation Example 4- (2), 400 ml of the first half of the 40% ethanol eluate and 200 ml of the second half of the 40% ethanol eluate and 60% ethanol eluate were combined, respectively, in a rotary evaporator. Concentrated. Each was finally dissolved in 5 ml of dimethyl sulfoxide to obtain fractions of ethanol extract ethanol extract -Fr.1, -Fr.2 and -Fr.3.

Preparation Example 5 Fraction by Reversed-Phase Column of Oil Sprout Leaf Ethanol Extract Fraction -Fr.2

(1) 0.9 ml of the fractions of ethanol extract of the rape oil leaf obtained in the preparation example 4- (3) -Fr.2 were fractionated by reverse phase chromatography. The column used TSK gel ODS-80Ts (21.5 mm x 30 cm: manufactured by Tosoh Corporation). The solvent was distilled water: acetonitrile = 30: 70, the elution rate was 5 ml / min, detection was performed at 215 nm. The eluate was fractionated in the index of ultraviolet absorption of the eluate.

(2) Each fraction containing the peaks of 23.7 minutes, 35.1 minutes, and 41.8 minutes of holding time obtained in Preparation Example 5- (1) was concentrated in a rotary evaporator. Finally, each was dissolved in 0.9 ml of dimethyl sulfoxide to obtain ethanol extract fractions -Fr.2-1, -2, and -3.

(3) Mass spectrometry (MS) of the oil bran leaf ethanol effluent fraction -Fr.2-2 obtained in Preparation Example 5- (2) was measured by a mass spectrometer (API300: manufactured by Applied BioSystems / MDS Sciex). , signal of m / z 387 ([M + H] ⁺ ) was detected. Subsequently, various NMR spectra were measured using a nuclear magnetic resonance (NMR) spectrum apparatus (AVANCE600 type: manufactured by Burka Biospin Co., Ltd.). As a result of the measurement of MS spectrum and various NMR spectra, the fraction of ethanol extract of lupe herb leaf -Fr.2-2 is 3'-Acetoxy-4'-senecioyloxy-3 ', 4'-dihydroseselin represented by Formula (I). Confirmed.

Example 1 Measurement of Antifoaming in Macropurge

Macropurge inserts denatured LDL (acetyl LDL (Ac-LDL), etc.) into cells and synthesizes cholesterol esters and foams them. The anti-foaming activity of macropurge by each test sample was measured.

(1) Foaming of Macro Purge

Containing 10% fetal bovine serum (Canblex Corporation), Dulbecco's Improved Eagle Medium (Sigma, D5796), suspended RAW264.7 cells (ATCC TIB 71) to 4 × 10 ⁵ cells / ml, 24 holes 1 ml each was added to the wells of a micro titer plate and incubated overnight at 37 ° C in the presence of 5% carbon dioxide gas. Next, it exchanged with the UltraCHO medium (B2724 by Kanblex Co., Ltd.), and added 2 microliters of the dimethyl sulfoxide solutions of each test sample prepared by the preparation example mentioned above to each concentration so that it may become the concentration shown in following Table 1, respectively. . In addition, what refine | purified refined oil leaf ethanol extract fraction -Fr.2-2 was used for the 3'- acetoxy-4'- senecioyloxy-3 ', 4'- dihydroserine of Table 1. In addition, Ac-LDL (Bio Technology Co., Ltd., BT-906) having a final concentration of 20 µg / ml was added to each well, and cultured for 24 hours. In addition, the division which did not add Ac-LDL and the division which adds dimethyl sulfoxide were set as a control.

(2) Measurement of the amount of cholesterol ester biosynthesis

As an indicator of the foaming of the macro purge, the amount of total cholesterol and the amount of free cholesterol in the cells were measured, and the amount of cholesterol ester was calculated.

After the end of the culture, the medium was removed, the cells were washed with 0.3% (w / v) BSA (Sigma, A-8022) containing phosphate buffer solution, and further washed with phosphate buffer solution. 0.5 mL of hexane: isopropanol = 3: 2 solvent was added to the cells, and the supernatant was collected after leaving it at room temperature for 30 minutes. This operation was repeated again, and the 1 ml supernatant was concentrated to dryness. After the precipitate was dissolved in 30 µl of isopropanol, the total amount of cholesterol contained in 10 µl of the solution was measured using a cholesterol E-test (439-17501, manufactured by Wako Pure Chemical Industries, Ltd.), and the amount of free cholesterol was measured using a free cholesterol E-test ( It was measured using Wako Pure Chemical Industries Ltd., 435-35801). In addition, all the measurements were performed in 2 sets. The amount of cholesterol ester biosynthesis was obtained by subtracting the amount of free cholesterol from the total amount of cholesterol. In addition, anti-foaming activity was computed by the following formula | equation.

Anti-foaming activity (%) = 100-((Amount of cholesterol ester biosynthesis when test sample was added)-(Amount of cholesterol ester biosynthesis in category without adding Ac-LDL)) ÷ ((Dimethyl sulfoxide Biosynthesis Amount of Cholesterol Ester)-(Cholesterol Ester Biosynthesis Amount without Ac-LDL)) × 100

The results are shown in Table 1. That is, Table 1 shows the inhibitory activity against cholesterol esters accumulated in the macro purge at the respective concentrations of each test sample, and significant anti-foaming activity was observed in each sample described in the table.

Test sample final concentration (%) Anti-foaming activity (%) Oil Sprout Stalk 70% Ethanol Extract Fraction 0.2 78 0.1 33 Oil Sprout Stem Ethanol Extract Fraction 0.05 86 0.025 70 Sprout Oil Root Ethanol Extract Fraction 0.0125 27 Oil herb leaf ethanol extract fraction 0.025 97 0.0125 52 Ethanol Extract of Ethanol Extract Fraction-Fr.2 0.1 88 0.05 34 Ethanol Extract of Ethanol Extract Fraction-Fr.2-2 0.2 72 0.1 34 Sprout Oil Leaf Ethanol Extract Fraction-Fr.2-3 0.2 35 Test Sample Final Concentration (μM) Antifoaming Activity (%) 3'-acetoxy-4'-senecioyloxy-3 ', 4'- 40 98 dihydroserine 20 19

Example 2

(1) Preparation of Rat Microsomes

Four Sprague-Dawley rats were bred for one week, then slaughtered, and the liver was immediately extracted, washed with cold brine, and then sucrose buffer (0.3 M sucrose, 50 mM Tris-HCl, 1 mM EDTA, 50 mM NaC1, pH7.4). Immersion was carried out (25 ml / l). The obtained soy sauce was homogenized and centrifuged at 10,000 x g for 30 minutes to remove the precipitate twice. The obtained supernatant was centrifuged at 105,000 xg for 70 minutes, the precipitate was collect | recovered, and suspended in the suitable quantity 100mM phosphate buffer (pH7.4). It was suspended again in phosphate buffer so that the protein concentration might be 10 mg / ml, and EDTA was added so that the final concentration might be 1 mM, and it was cryopreserved at -80 degreeC until use.

(2) Measurement of ACAT inhibitory activity by each sample

Enzyme activity of ACAT was measured by some improvements, according to Lee's method (Planta Med., 2004, 70, 678-679).

Aqueous solution containing 1.5 µl of rat liver microsomes prepared in Example 2- (1) in 1.5 ml Eppen tube (0.05 M potassium phosphate, 1 mM dithiositol, 9 mg / ml fatty acid free bovine serum albumin, 200 µg / 1 µl of dimethyl sulfoxide solution of each test sample was added to 92 µl of cholesterol, pH7.4) to maintain the final concentration shown in Table 2, and the mixture was kept at 37 ° C for 30 minutes. In addition, what refine | purified refined oil leaf extract fraction -Fr.2-2 was used for the 3'- acetoxy-4'- cesinoyloxy-3 ', 4'- dihydroserine of Table 2. As a control section, a section in which only a dimethyl sulfoxide solution was added without addition of a compound, and a section in which a compound FR179254 (final concentration 10 µM, manufactured by Merck, 344235), in which ACAT inhibitory activity was known, were added as a positive control. Thereafter, 0.05mCi / ㎖ of Oleoyl Coenzyme A, [Oleoyl-9 , 10- 3 H] - ( morabek greater Biochemicals, LTD. Preparation, MT1649) 2㎕ and 0.2㎎ / ㎖ of Oleoyl Coenzyme A (ICN Co., 591 5 µl of the mixed solution was added to each tube, and the mixture was kept at 37 ° C for 5 minutes. Thereafter, the reaction was stopped by adding 0.5 ml of a solution of isopropanol: heptane = 4: 1 to each tube. 0.2 ml of 0.1M potassium phosphate solution (pH7.4) and 0.3 ml of heptane were added to each tube, followed by stirring for 15 seconds, followed by centrifugation for 15 seconds. Radiation activity was measured by liquid scintillation counter LS6500 (manufactured by Beckman) using Life Sciences Inc., 6013329) as a scintillation cocktail. In addition, each reaction was performed in 2 sets. The ACAT inhibitory activity (%) of each test sample was computed by making into 100% the inhibition rate when adding 10 micrometers FR179254 of a positive control by the following formula | equation.

Inhibitory activity (%) = (([radiation activity of control fraction (cpm)]-[radiation activity of control sample addition fraction (cpm)]) / ([radiation activity of control fraction (cpm)]-[10 μM FR179254 addition Division of Radiation Activity (cpm)]) × 100

The results are shown in Table 2. That is, Table 2 shows the inhibitory activity against ACAT at each species concentration of each test sample, and remarkable ACAT inhibitory activity was recognized in each test sample described in the table.

Subject sample concentration (%) ACAT inhibitory activity (%) Oil Sprout Root Ethanol Extract Fraction 0.1 105 0.05 71 0.025 48 Oil herb leaf ethanol extract fraction 0.1 61 0.05 66 0.025 48 Subject sample concentration (μM) ACAT inhibitory activity (%) 3'-acetoxy-4'-senecioyloxy-3 ', 4'- 100 87 dihydroserine 50 65 25 40

According to the present invention, the treatment derived from the oily sprouts, 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and / or pharmaceutically acceptable salts thereof Provided is a medicament, food or feed for the treatment or prophylaxis of diseases requiring anti-foaming and / or ACAT inhibitory action of cells for the treatment or prophylaxis. The medicament is useful as a therapeutic or preventive agent for atherosclerosis, hyperlipidemia and diseases caused by them. Moreover, by ingesting the food as a daily food, the symptoms can be improved or prevented. Therefore, the food containing the active ingredient of this invention is a functional food useful for the maintenance of homeostasis of a living body by anti-foaming action of the cell and / or ACAT inhibitory action.

Claims (16)

A therapeutic or prophylactic agent for diseases requiring anti-foaming and / or acyl CoA cholesterol-acyltransferase-inhibiting action of cells in the treatment or prophylaxis, which comprises a treatment derived from mung bean sprouts as an active ingredient. . The method of claim 1, 1, wherein the treated substance derived from seaweed oil is selected from the group consisting of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof. A therapeutic or preventive agent that is a treatment containing more than one species. An anti-foaming agent for cells, comprising a treatment derived from boiled oil herb as an active ingredient. The method of claim 3, wherein 1, wherein the treated substance derived from seaweed oil is selected from the group consisting of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof. An anti-foaming agent for cells, which is a treatment containing more than one species. An acyl CoA cholesterol acyl transferase inhibitor characterized by containing the processed material derived from a rape sprout as an active ingredient. The method of claim 5, 1 kind selected from the group consisting of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof An acyl CoA cholesterol acyl transferase inhibitor which is a process containing the above. A food or feed for anti-foaming and / or acyl CoA cholesterol-acyltransferase inhibition of cells, characterized by containing a treated substance derived from radish sprouts as an active ingredient. The method of claim 7, wherein 1 kind selected from the group consisting of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof Food or feed which are processed products containing the above. Containing at least one selected from the group consisting of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof as an active ingredient A therapeutic or prophylactic agent for a disease, characterized in that the antifoaming action of a cell and / or an acyl CoA cholesterolacyltransferase inhibitory action is required in the treatment or prophylaxis. Containing at least one selected from the group consisting of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof as an active ingredient An anti-foaming agent for cells. Containing at least one selected from the group consisting of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof as an active ingredient An acyl CoA cholesterol acyl transferase inhibitor. Containing at least one selected from the group consisting of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof as an active ingredient Food or feed for anti-foaming and / or acyl CoA cholesterol acyltransferase inhibition of the cell. A method of treating a disease requiring anti-foaming and / or acyl CoA cholesterol-acyltransferase inhibitory activity of cells in the treatment or prophylaxis, including administering to the subject an effective amount of a treatment derived from oily sprouts. Or preventive measures. Use of a treatment derived from radish sprouts for the manufacture of a therapeutic or prophylactic agent for a disease in need of anti-foaming and / or acyl CoA cholesterolacyltransferase inhibitory action of cells in the treatment or prophylaxis. At least one member selected from the group consisting of an effective amount of 3'-acetoxy-4'-senesioyloxy-3 ', 4'-dihydroserine, derivatives thereof, and pharmaceutically acceptable salts thereof. A method of treating or preventing a disease that requires anti-foaming and / or acyl CoA cholesterolacyltransferase inhibitory action of cells in the treatment or prophylaxis, including administration. 3'-acetoxy-4'-sencioyloxy- for the preparation of a therapeutic or prophylactic agent for diseases requiring anti-foaming and / or acyl CoA cholesterol acyltransferase inhibitory activity of cells in the treatment or prophylaxis. At least one use selected from the group consisting of 3 ', 4'-dihydroserine, derivatives thereof and pharmaceutically acceptable salts thereof.